Disposable reactor for mixing two liquids

Abstract

A jet impingement reactor is disclosed having a housing made of a polymeric material with at least two housing pieces secured together. The housing encloses a substantially spherical reaction chamber (2) having at least two fluid inlets (3, 4) provided by a nozzle (5) and a fluid outlet (6). Also provided are a method of making the reactor based on injection molding, and the use of the reactor for the sterile production of sterile liquid pharmaceutical compositions, particularly compositions containing nanoparticles such as lipid nanoparticles.

Description

[Background technology]

[0001] Jet impingement reactors are fluid reactors for mixing fluids or for generating particulate fluids through collision. These reactors can be used, for example, to produce nanoparticle fluids incorporating poorly water-soluble active ingredients. Their function is based on the use of two fluid streams (at least one of which typically contains the active ingredient) injected into the reactor cavity and colliding in a turbulent mixing zone, thereby generating nanoparticles. One of the main principles used in conjunction with jet impingement reactors is solvent / non-solvent precipitation, in which a first fluid containing the active ingredient dissolved in a suitable solvent is contacted with a non-solvent or anti-solvent under defined conditions to precipitate nanoparticles containing the active ingredient. When one of the solvents contains lipids, lipid nanoparticles can be produced using a jet impingement reactor, which can then be loaded with a biologically active compound, for example, by pH shift.

[0002] A jet impingement reactor includes a reaction chamber with two fluid inlets with associated nozzles that allow two fluids to be injected into the reaction chamber, typically at pressures greater than ambient pressure. The two fluid streams are injected through the first and second fluid inlets so that they meet within the reaction chamber, forming a collision or mixing zone. An outlet is also provided for the resulting nanoparticle suspension.

[0003] An example of a jet impingement reactor is the microjet reactor disclosed in EP 1165224. Such a microjet reactor has at least two nozzles or pinholes arranged opposite each other, each with an associated pump and supply line for directing liquids toward a common impingement point within a reaction chamber enclosed by a reactor housing having a metal body. The reaction chamber has two orifices that intersect with each other and form a small cavity where the two fluids impinge, possibly without contacting the walls of this cavity. One of the orifices accommodates two fluid inlets, while the second orifice accommodates an additional opening within the reactor housing that can introduce a gas, evaporating liquid, cooling liquid, or cooling gas to maintain or cool the gas atmosphere within the reaction chamber. The other end of the second orifice is provided with an additional opening for removing the product and excess gas from the reactor. This reactor also requires an external source of gas or cooling liquid as a third fluid, making it more complex and less straightforward to produce particles under sterile conditions. The reactor or reactor housing is also made of metal and therefore requires specific processes for its manufacture, assembly, and cleaning between uses.

[0004] WO 2018 / 234217 discloses another jet impingement reactor having a housing enclosing a reaction chamber and collinearly oriented first and second fluid nozzles. The second nozzle is positioned directly opposite the first fluid nozzle in terms of the nozzle's jet direction. The nozzles reach the reaction chamber and form a disk-shaped impingement zone with each other. This reactor type has at least one rinse fluid inlet located on the side of the first fluid nozzle and at least one product outlet located on the side of the second fluid nozzle, making it suitable for continuous preparation of fine particle fluids. Furthermore, the rinse fluid conducting structure is designed as a parallel channel on the side of the first fluid nozzle, which generates a rinse fluid flow directed toward the jet direction of the first fluid nozzle and directs the rinse fluid toward the impingement disk, causing a slight deformation of the impingement disk. This transports particles present in the nanoparticle fluid formed on the impingement disk away from the impingement zone. When carried out in a reactor as disclosed in WO 2018 / 234217, the manufacturing process relies on the presence of rinse fluid conducting structures and rinse fluids, and adds complexity, cost, and time to the manufacturing of the reactor itself and cleaning between uses, particularly for the sterile manufacturing of nanoparticles, making rapid and small batch manufacturing more difficult.

[0005] The quality and reproducibility of the resulting nanoparticle fluid depend, among other things, on the precision of the production method protocol and the reactor. The method protocol may define different parameters, such as the volumetric flow rates of the fluid streams injected through the nozzle, the ratio of these flow rates, the concentration of dissolved components in the streams, or the temperature settings. These parameters may also be influenced by the reactor itself. The nozzle size, for example, affects the flow rate of the streams, since its diameter only allows a certain amount of fluid to pass through the nozzle, depending on the respective pressure of the streams. The proper adaptation of the parameters for the production of nanoparticles and the selection of an appropriate reactor are always challenges in product and process development or upscaling processes.

[0006] It is also known that particle size distribution and reproducibility of results depend on the precise setting of the reactor, especially the nozzle, and precise control of the fluid flow. To achieve further improvements in terms of product particle size, particle size distribution or other quality parameters, improved jet impingement reactors are needed that allow better control of process parameters.

[0007] Thus, there is a need for a jet impingement reactor that can be used to produce nanoparticles with desirable particle size distributions and morphologies, reducing the risk of undesired side reactions, as well as allowing for efficient and rapid small batch production, particularly in ready-to-use forms, or sterilizable disposable hardware, which may reduce the need for sterilization or complex cleaning protocols between batches and allow for increased production efficiency. Another object is to provide a jet impingement reactor that can be easily manufactured in a cost-effective and reproducible manner. A further object is to overcome one or more drawbacks of jet impingement reactors and related methods proposed in the prior art. These needs and objects are addressed by the invention disclosed herein. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] European Patent No. 1165224 [Patent Document 2] International Publication No. 2018 / 234217 Summary of the Invention

[0009] In a first aspect, the present disclosure relates to a jet impingement reactor (1) comprising a reaction chamber (2), the chamber having a substantially spherical shape interrupted by: (a) a first fluid inlet (3) and a second fluid inlet (4), the first fluid inlet (3) and the second fluid inlet (4) being arranged facing each other at opposite positions on a first central axis (x) of the reaction chamber (2), each of the first fluid inlet (3) and the second fluid inlet (4) being provided by a nozzle (5); and (b) a fluid outlet (6) arranged at a position located on a second central axis (y) of the 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), the first fluid conduit (7) and the second fluid conduit (8) being configured to direct a first fluid to the first fluid inlet (3) and a second fluid to the second fluid inlet (4), and the third fluid conduit (9) being configured to direct a third fluid downstream from the fluid outlet (6), the third fluid being formed by mixing or reacting the first and second fluids in the reaction chamber (2). The reactor (1) comprises at least two pieces fixed to each other, a first piece (121, 171, 181) of which is made of a polymer material and comprises at least a portion of the first fluid conduit (7) or the second fluid conduit (8) and at least a hemispherical portion of the reaction chamber (2), and a second piece (132, 172, 182) of the two pieces is at least partially insertable into the first piece (121, 171, 181), said second piece comprising a fluid outlet (6).

[0010] Further aspects relate to a method for manufacturing the reactor (1) or first piece (121, 171, 181), said method comprising the step of injection molding the first piece (121, 171, 181). Further aspects presented in the present disclosure relate to the use of such a reactor in the sterile production of sterile liquid pharmaceutical compositions, and to an apparatus for the sterile production of sterile liquid pharmaceutical compositions, the apparatus comprising a reactor. [Brief explanation of the drawings]

[0011] [Figure 1] A cross-sectional view of one embodiment of the first piece (121) of the jet impingement reactor is shown. [Figure 2] FIG. 2 shows a cross-sectional view of one embodiment of a second piece (132) of a jet impingement reactor designed to match the first piece (121) shown in FIG. 1 and be insertable into the first void (21) of the first piece (121). [Figure 3] FIG. 2 shows a cross-sectional view of one embodiment of a connecting piece (33) designed to be used with the first piece (121) shown in FIG. [Figure 4] 1 shows a cross-sectional view of one embodiment of a jet impingement reactor (1) comprising a first piece (121) as shown in FIG. 12 together with a second piece (132) as shown in FIG. 2 and two connecting pieces (33) as shown in FIG. 3. [Figure 5] FIG. 1 is a cross-sectional view of a particular embodiment of a substantially spherical reaction chamber (2) formed by a first piece (121) and an at least partially inserted second piece (132), with only portions of the first piece (121) and second piece (132) shown. [Figure 6] A cross-sectional view of one embodiment of the first piece (171) of the jet impingement reactor is shown. [Figure 7] FIG. 7 shows a cross-sectional view of one embodiment of a jet impingement reactor (1) comprising a first piece (171) as shown in FIG. 6 together with a second piece (172) and two connecting pieces (73). [Figure 8] FIG. 1 shows a cross-sectional view of another embodiment of a jet impingement reactor (1), not drawn to scale, comprising a first piece (181) fixed together with a second piece (182) and two connecting pieces (83). [Figure 9] 1 shows an enlarged cross-sectional view of a particular embodiment of a substantially spherical reaction chamber (2) formed by a first piece (181) and a partially or fully inserted second piece (182), with only portions of the first piece (181) and second piece (182) shown. [Figure 10] A cross-sectional perspective view of a first piece (181) (A) is shown along with a cross-sectional perspective view of the first piece (181) secured to a second piece (182) (B). [Figure 11] 1 shows a graphical depiction of particle size (mean diameter (nm), graph A) and polydispersity index (PDI, graph B) characterized for PLGA nanoparticles obtained using polymer jet impingement reactors according to the present invention (A, B, and C) and obtained using a comparative stainless steel reactor (M), as described in Example 1. [Figure 12] FIG. 1 shows a graphical depiction of particle size (mean diameter (nm), graph A) and polydispersity index (PDI, graph B) characterized for liposomal nanoparticles obtained as described in Example 2 using polymer reactors according to the present invention (A, B, and C) and obtained using a comparative stainless steel reactor (M). [Figure 13] FIG. 1 shows a cross-sectional view of an example of an alternative jet impingement reactor (1) with a housing (10) made from a polymer material, the housing consisting of two pieces (11, 12) fixed together. [Figure 14] FIG. 14 shows a perspective view of the second housing piece (12) of the housing (10) of the jet impingement reactor (1) as shown in FIG. [Figure 15] FIG. 14 shows a perspective view of the first housing piece (11) of the housing (10) of the jet impingement reactor (1) as shown in FIG. [Figure 16] 1 shows a cross-sectional view of another alternative jet impingement reactor (1) with a housing (40), which consists of two pieces (41, 42) fixed together. [Figure 17] 17 shows a perspective cross-sectional view of the first housing piece (41) of the housing (40) shown in FIG. 16. FIG. [Figure 18] 17 shows a cross-sectional view of the first housing piece (42) of the housing (40) as shown in FIG. 16. [Figure 19] 17 shows a perspective view of the second housing piece (42) of the housing (40) as shown in FIG. 16. FIG. [Figure 20] 1 shows a cross-sectional view of yet another example of an alternative jet impingement reactor (1) with a housing (80), the housing consisting of two pieces (81, 82) that are fastened together. [Figure 21] 21 shows a perspective cross-sectional view of the first housing piece (81) of the housing (80) as shown in FIG. 20. FIG. [Figure 22] 21 shows a cross-sectional view of the second housing piece (82) of the housing (80) as shown in FIG. 20. [Figure 23] 21 shows a perspective view of the second housing piece (82) of the housing (80) as shown in FIG. 20. DETAILED DESCRIPTION OF THE INVENTION

[0012] According to a first aspect of the present invention, there is provided a jet impingement reactor comprising a reaction chamber having a substantially spherical shape, the spherical shape being interrupted by (a) first and second fluid inlets and (b) a fluid outlet. The first and second fluid inlets are disposed at opposing positions on a first central axis of the reaction chamber so as to face each other, and each of the first and second fluid inlets is provided by a nozzle. The fluid outlet is disposed at a position on a second central axis of the reaction chamber (6) perpendicular to the first central axis. The reactor further comprises first, second, and third fluid conduits, the first and second fluid conduits configured to direct a first fluid to the first fluid inlet and a second fluid to the second fluid inlet, and the third fluid conduit configured to direct a third fluid downstream from the fluid outlet, the third fluid being formed by mixing or reaction of the first and second fluids within the reaction chamber. Further, the reactor comprises at least two pieces secured together: a first piece made from a polymeric material and comprising at least a portion of the first or second fluid conduit and at least a hemispherical portion of the reaction chamber; and a second piece at least partially insertable into the first piece, the second piece comprising the fluid outlet. Optionally, the second piece is also made from a polymeric material.

[0013] This reactor, assembled from at least two pieces secured together, is particularly useful as a disposable reactor for sterilely producing small batches of liquid compositions from at least two liquid substrates. The inventors have discovered that preparing a reactor from two pieces as described herein allows for the use of highly efficient manufacturing processes, such as injection molding for at least the first piece of the reactor, and also for the second piece if it is also made from a polymeric material. Alternative methods for producing reactors with substantially spherical reaction chambers require specialized tooling and are less efficient. Furthermore, the reactor design disclosed herein, assembled from at least two potentially moldable pieces, allows for nozzles to be equipped on the reactor with particularly high precision regarding the nozzle's position and orientation, as well as the dimensions of the first and second fluid inlets potentially provided by the nozzle. Another advantage is versatility. That is, for example, reactors with a variety of different fluid inlet sizes can be manufactured using the exact same molding tool for the first piece, and then first and second fluid inlets with desired dimensions can be added using (for example) laser drilling. Furthermore, adapting the outlet shape does not require modification of the first piece. It has also been found that the reactor corresponds to a static mixing device that is easily installed in a device adapted to mix two fluid streams, where the fluid streams are driven by external gas pressure, as disclosed, for example, in WO 2023 / 079039.

[0014] Some of these advantages are particularly pronounced in embodiments in which the first and second fluid conduits are designed to be relatively short, as described in more detail below, and each nozzle location is fully accessible to high-precision tools and processes during manufacturing. For example, if the nozzle orifices are introduced by precision mechanical drilling or laser drilling, the drilling tool can be located in close proximity to the nozzle location, thereby minimizing tolerances.

[0015] In a more general sense, the reactor according to the present disclosure also addresses the problem of providing a suitable device for enabling cost-effective, sterile or aseptic production of small batches of liquid products, such as liquid pharmaceutical compositions for injection obtained by mixing two or more liquid substrates, in that the reactor is substantially polymeric and can be designed as a disposable processing device that simultaneously meets all precision requirements. Compared to metal reactors, as a disposable, cost-effective device for manufacturing and production, and as a modular system, the reactor according to the present disclosure can be advantageously used as a flexible tool for process development. For example, different nozzle orifice sizes and various different compositions of the fluid substrate can be easily tested.

[0016] The important features of the reactor will now be described in more detail.

[0017] As mentioned above, the reactor is a jet impingement reactor. In the context of the present invention, a jet impingement reactor is a static mixing device having a reaction chamber with at least two fluid inlets, typically provided by nozzles, that allow two fluids, in particular two liquids, to be injected into the reaction chamber at a pressure higher than ambient pressure. Through the inlets, the fluid streams are injected so that they collide (i.e., collide with each other) in the reaction chamber, which can result in rapid, intensive, and turbulent mixing. According to a general preferred embodiment, the fluids are liquids. According to a further general preferred embodiment, the two fluids or liquids mixed in the reactor are different from each other, and a third fluid or liquid is obtained as a result of the mixing.

[0018] The first piece occupies a major portion of the reactor housing, in that it contains at least a substantial portion of the reaction chamber and the first and second inlets, and is made of a polymeric material. As used herein, being made of a polymeric material does not exclude the presence of a certain amount of non-polymeric material. In other words, the phrase "made of a polymeric material" should be understood to mean being predominantly or primarily made of a polymer. For example, the first piece may include a specific structure, such as an identification tag, that is not itself polymeric. Furthermore, the primary material from which the first piece is constructed may correspond to a (e.g., thermoplastic) polymeric material, further comprising one or more additives, such as glass fiber, ceramic filler, plasticizer, antioxidant, colorant, antimicrobial agent, antistatic agent, UV stabilizer, flame retardant, etc. In some preferred embodiments, at least the first and second pieces of the reactor disclosed herein are based on or substantially made of a polymeric material, optionally including one or more additives. In some embodiments, the reactor consists essentially of the first and second pieces described herein, and both the first and second pieces are made of a polymeric material.

[0019] As used herein, a reaction chamber is a chamber within a reactor that provides a space where two fluids come into contact with each other so that they can mix or react. Typically, a reaction chamber requires a shape and internal dimensions that distinguish it from a simple T- or Y-piece, for example, consisting essentially of two (or three) tubes joined together with lumens that form a T- or Y-shaped flow path. For example, a reaction chamber preferably includes at least one diameter that is larger than the diameter of its fluid inlet.

[0020] According to this aspect of the invention, the overall shape of the reaction chamber is spherical, with the spherical shape being interrupted by the fluid inlet and fluid outlet. As will be appreciated by those skilled in the art, the overall shape of a chamber within a device may not necessarily be perfectly spherical. For example, small deviations within manufacturing tolerances or minor features that enhance manufacturability may still fall within the scope of the expression "spherical." Accordingly, the overall shape of the reaction chamber may also be described as spheroidal. A spheroidal overall shape means that at least a major portion of the reaction chamber defined by the interior surfaces of the chamber walls at least resembles a sphere. For example, a spheroid may be shaped such that a portion of its cross section is, strictly speaking, elliptical rather than circular as in a perfect sphere. In one embodiment, all portions or portions of the interior surfaces of the reaction chamber or chamber walls, except for portions defining the inlet or outlet, or small planar wall sections as described below, are substantially spheroidal or spherical.

[0021] In this context, a fluid inlet refers to an opening, orifice, or interruption in the reaction chamber wall that allows fluid to enter the chamber. The first and second fluid inlets are each provided by a nozzle. For example, if the nozzle is a simple, flat-mouth nozzle containing a narrow hole or lumen with an upstream end and a downstream end, the downstream end of the hole or lumen forms the fluid inlet. In more general terms, a "nozzle" refers to a device or device component that is adapted to control the direction, velocity, and / or other characteristics of fluid flow and includes 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 otherwise. Preferably, the downstream end of the nozzle providing the first and second fluid inlets is substantially flush with the reaction chamber wall.

[0022] Optionally, the reactor may have one or more additional fluid inlets. For example, third and fourth fluid inlets may be positioned to provide additional fluid impingement points or to form a common fluid impingement point with the first and second fluid inlets. However, in one currently preferred embodiment, the first and second fluid inlets are the only fluid inlets for the reactor.

[0023] As described above, the first and second fluid inlets are positioned at opposite positions on the first central axis of the reaction chamber so as to face each other. Preferably, the nozzles providing the first and second fluid inlets are oriented so as to face each other at an angle of about 180°. This orientation allows the injection of two fluid streams into the reaction chamber so that the two fluid streams collide head-on or collide with each other at an angle of about 180°, depending on the pressure and / or velocity of the fluid streams.

[0024] A fluid outlet is to be understood as an opening in the reaction chamber wall adapted to allow a fluid to exit the chamber. As mentioned above, the fluid outlet is located on a second central axis of the reaction chamber that is perpendicular to the first central axis on which the fluid inlet is located. For example, the first central axis may have a substantially horizontal orientation when the reactor is operated, and the second central axis may have a substantially vertical orientation. Furthermore, the orientation of the reactor during operation may be such that the fluid outlet is located at a position above the reaction chamber so that the direction of fluid flow within the reaction chamber is at least partially against gravity.

[0025] As previously described, the first and second fluid conduits are configured to direct a first fluid to the first fluid inlet and a second fluid to the second fluid inlet. In other words, the first and second fluid vapors are supplied to the reaction chamber via these fluid conduits. In this regard, the fluid conduits are three-dimensional structures including internal fluid pathways that provide fluid connections between the upstream and downstream ends of the respective fluid conduits. The third fluid conduit is adapted to direct a third fluid resulting from the mixing or reaction of the first and second fluids downstream from the reaction chamber. For the avoidance of doubt, the downstream direction may be either an upward or anti-gravity direction of flow, depending on the orientation of the reactor.

[0026] According to one important feature of the reactor disclosed herein, the reactor consists of at least two pieces secured together. In this regard, the securing between the pieces can be separable or peelable (i.e., without damage) or permanent. The first piece comprises at least a portion of the first or second fluid conduit and at least a hemispherical portion of the reaction chamber. The second piece comprises at least a fluid outlet, and in some embodiments, a portion of the reaction chamber. In some embodiments, the first piece further comprises or is adapted to receive two nozzles providing first and second fluid inlets, as described in more detail below.

[0027] The second piece may be secured to the first piece by simply forcing it partially or completely into the first gap, for example if the first gap is slightly tapered. This may not require additional fastening means. The polymeric material from which at least the first piece and optionally the second piece are made typically has some elasticity so that contact between the two pieces is maintained.

[0028] In other embodiments, the first and second pieces may be held together by fastening means such as screws, or they may be glued or fused together. Alternatively, or additionally, they may be held together by a snap-fit ​​or press-fit mechanism provided on either the first piece or the second piece, or more preferably on both the first and second pieces. For example, a suitable snap-fit ​​or press-fit mechanism may include a rim and a corresponding groove, such as a rim provided on the contact surface of the first piece and a corresponding groove provided on the contact surface of the second piece to receive the rim, or vice versa. Optionally, at least one of the materials used to provide such rim or groove should have some degree of flexibility or elasticity. In some preferred embodiments, the first and second pieces are press-fit, and preferably no additional fastening means are present.

[0029] In some embodiments, the first piece may include one or more insertion guides to facilitate insertion of the second piece in a predetermined orientation relative to the first piece. Conversely, a second piece shaped and adapted for insertion into the first piece may include complementary insertion guides or features to ensure proper insertion and mating orientation relative to the first piece. For example, in one embodiment, the contact surface of the second piece is provided with one or more protruding features that are complementary to one or more complementary-shaped grooves or recesses located on the first piece.

[0030] Additional features may optionally be used to ensure that the first and second pieces are not only securely fastened to one another, but also that the contact between the pieces is sufficiently tight to prevent even leakage of fluid from the reactor. For example, a gasket may be provided between the first and second pieces to seal the contact between the two pieces. In other embodiments, no gasket is present between the first and second pieces.

[0031] In some embodiments, one of the two pieces is overmolded onto the other piece, which may be considered similar to welding, since heat is used to partially soften or melt material at a desired contact surface of at least one of the two pieces and fuse that surface with the corresponding contact surface of the other of the two pieces. Overmolding may be a useful technique if at least one of the two housing pieces is made of a polymeric material that can be formed by melt injection or injection molding. In some embodiments, more than one means or method for permanently or non-permanently securing the two housing pieces together may be used.

[0032] In some embodiments, the reactor or reactor housing consists essentially of a first and a second piece. In other words, the reactor body consists of only the two parts described herein. As one skilled in the art will appreciate, this does not preclude the presence of additional structural or functional components that may be associated with the housing. Non-limiting examples of such additional components include fastening means such as screws, bolts, luer fittings, or nuts; identification means such as RFID chips or QR codes; sensors such as temperature probes; gaskets; etc.

[0033] As described above, the first piece of the reactor comprises at least a portion of the first or second fluid conduit and at least a hemispherical portion of the substantially spherical reaction chamber. A hemispherical portion, in this context, is a portion of the reaction chamber that comprises or surrounds a portion of the chamber having the shape of a hemisphere. In some preferred embodiments, the first piece comprises a portion larger than a hemisphere, such as at least about 55% or at least about 60% of the reaction chamber's internal volume calculated based on an approximate sphere that would result from the reaction chamber wall if uninterrupted by fluid inlets and outlets, and optionally other slight deviations from the spherical shape of the reaction chamber wall. In another preferred embodiment, the first piece of the reactor comprises about 50% of the reaction chamber's internal volume calculated based on an approximate sphere that would result from the reaction chamber wall if uninterrupted by fluid inlets, outlets, or non-spherical wall protrusions or recesses.

[0034] The second piece, which includes the fluid outlet, is designed to be at least partially insertable into the first piece. In a related embodiment, the first piece is molded to include a cavity (hereinafter referred to as the first cavity) for receiving the second piece by insertion, i.e., at least partial insertion, and the second piece is molded and adapted to be insertable, i.e., at least partially insertable into the first cavity.

[0035] The first gap can be shaped to facilitate insertion. For example, its surface can have a cylindrical, columnar, or tapered shape. In this context, a columnar shape should be understood as a cylindrical overall shape, but with one or more slight deviations from the shape of a perfect cylinder. A tapered columnar shape, in this context, should be tapered so that its upstream end, i.e., its upstream end located in the reaction chamber, is narrower than its downstream end. The second piece, or at least its insertable portion, can advantageously have a shape that substantially matches the shape of the first gap.

[0036] In some preferred embodiments, the second piece comprises an upstream end, which also comprises a fluid outlet for the reaction chamber and a portion of the reaction chamber, a downstream end, and a third fluid conduit, which fluidly connects the upstream end and the downstream end. In this particular context, the portion of the reaction chamber should be understood as the second piece also providing a portion of the reaction chamber wall. Such wall typically surrounds the fluid outlet and, when inserted into the first void, is flush with a complementary portion of the reaction chamber wall provided by the first piece. In terms of dimensions, the portion of the reaction chamber wall provided by the second piece may occupy, for example, 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 piece is 5 to 50% of the surface of the reaction chamber wall. In yet another embodiment, the second piece of the reactor comprises up to 50% of the interior volume of the reaction chamber, as calculated based on an approximate sphere that would result from the reaction chamber wall if it were not interrupted by a non-spherical wall element, such as a fluid outlet or a recess or protrusion. Furthermore, the portion of the reaction chamber wall provided by the second piece may be shaped as a spherical zone. In this context, the spherical region is the surface of the spherical portion excluding the base.

[0037] In a further preferred embodiment, the second piece is fully insertable into the first void, and in a related embodiment, the downstream end of the second piece is flush with the surface of the first piece that surrounds the first void.

[0038] In some embodiments, the downstream end of the second piece may be adapted for or comprise a connector for securing a tube or pipe, such as a luer fitting or a barbed connector, or a barbed fitting.

[0039] As mentioned above, at least a first piece of the reactor is made from a polymeric material. In some preferred embodiments, the first piece is made at least primarily from a thermoplastic polymeric material, preferably comprising polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU), or polyetherimide (PEI). In some embodiments, both the first and second pieces are made at least primarily from such a thermoplastic polymeric material.

[0040] In this context, being made primarily of thermoplastic polymer material does not exclude the presence of small amounts of one or more non-thermoplastic or non-polymeric materials. In other words, the thermoplastic polymer material is the major component of each piece, even if it is not the only component. In this context, predominantly means that the thermoplastic polymer material represents the largest proportion of the composition by weight and / or defines the physical properties of the composition. For example, the material composition from which each piece is made includes a sufficient amount of 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.

[0041] In some preferred embodiments, the first piece, or both the first and second pieces, are made at least primarily of PEEK. For example, unfilled grades of PEEK consisting essentially of polymer may be used. Alternatively, PEEK grades containing one or more fillers, such as glass fiber or carbon fiber, may be used.

[0042] Examples of further 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 and second pieces of the housing disclosed herein are based on or made substantially of a thermoplastic polymer material, optionally including one or more additives.

[0043] In some embodiments, the first and second fluid conduits each have a central longitudinal axis that coincides with the first central axis (x) of the reaction chamber. Additionally, the third fluid conduit can have a central longitudinal axis that coincides with the second central axis (y) of the reaction chamber. In this context, the central longitudinal axis of a fluid conduit should be understood as the central longitudinal axis of the lumen of the conduit. In practice, these embodiments provide for a direction of fluid flow within each conduit that is the same as the direction of fluid flow into and out of the reaction chamber, i.e., there is no change in the direction of flow within the conduit or between the reaction chamber and each conduit.

[0044] According to some further embodiments, the first and / or second fluid conduits have a lumen with an upstream portion and a downstream portion, the upstream portion being cylindrical or columnar and having a diameter substantially larger than that of the downstream portion. In this context, substantially larger means at least about 20% larger, and optionally at least about 50% larger, based on the diameter of the downstream portion. The diameter of the fluid conduits in this context should be understood as the internal diameter, i.e., the diameter of the cross section of the lumen of the respective portion or segment of the fluid conduit.

[0045] In some further embodiments, the downstream portions of the first and second fluid conduits each have a downstream end that forms or coincides with the first and second fluid inlets, respectively. In other words, these two fluid inlets of the reaction chamber are provided by the downstream ends of the downstream portions or segments of the fluid conduits. Thus, the downstream portions, or at least their downstream ends, can also be understood to be part of a nozzle structure that provides the fluid inlets, as described above. A nozzle can also be understood to be provided by the downstream portions of the fluid conduits.

[0046] In some embodiments, the downstream portions or segments of the first and second fluid conduits are tapered toward or away from their downstream ends. In some other preferred embodiments, the downstream portions are substantially cylindrical. In this context, substantially cylindrical should be understood to cover cylindrical shapes with slight deviations from a perfect cylinder, typically resulting from laser or micro-drilling processes. For example, laser drilling may result in a substantially cylindrical downstream conduit portion in which the diameter at one end may differ slightly from the diameter at the other end, but typically by no more than about 2-5% (the percentage being based on the smaller diameter).

[0047] As previously mentioned, an advantage of the present invention is the improved accessibility of the reactor housing locations of the first and second fluid conduits and fluid inlets of the reaction chamber, making processes such as laser or micro-drilling more feasible. The inventors have also found that a substantially cylindrical downstream section does not appear to significantly affect the flow of the first and second fluids in terms of flow resistance, compared to a tapered section. This is particularly true when the narrow cylindrical downstream section is relatively short, e.g., less than about 1 mm, or about 0.5 mm or less, e.g., about 0.2 mm to about 0.5 mm, e.g., about 0.3 mm. In some embodiments, the lumen diameters of the cylindrical downstream sections or segments of the first and second fluid conduits are independently substantially the same as the diameter of the fluid inlets that coincide with their downstream ends.

[0048] In some further embodiments, the lumens of the first and second fluid conduits further comprise an intermediate section between the upstream and downstream sections, the intermediate section tapering toward the downstream section, and if the downstream section is also tapered, the intermediate and downstream sections may optionally have different taper angles.

[0049] These embodiments are particularly useful when the nozzles providing the first and second fluid inlets are part of the first piece. As mentioned above, the first and second fluid inlets are each provided by a nozzle. In principle, various different options exist regarding the nature of these nozzles. In some preferred embodiments, the nozzles—at least one of them—are integral with the first piece of the reactor in which they are housed. In this context, monolithically coherent means that the nozzle is an integral part of the piece and is made of the same material. For example, if the nozzles are designed as flat orifice nozzles, they can be directly introduced into the respective housing pieces by precision drilling or laser drilling. In other embodiments, the nozzles may be introduced by wire overmolding.

[0050] In some other embodiments, the nozzle providing the first or second fluid inlet is an insert housed within the first piece of the reactor. Note that the insert is not integral with the housing piece, regardless of its material. Optionally, the nozzle provided as an insert is made from the same material as the first piece into which it is inserted. Alternatively, the nozzle may be made from a different material than the first piece.

[0051] For example, when provided as an insert, the nozzle may be molded to comprise or consist of a cylindrical pipe. Such a nozzle therefore represents a plain orifice nozzle. In this embodiment, it is further preferred that both nozzles are plain orifice nozzles. As used herein, a plain orifice nozzle is a nozzle characterized by a simple orifice having the shape of an essentially simple (i.e., substantially cylindrical) through-hole, which may also be referred to as a pinhole given its small dimensions. Alternatively, the nozzle may be provided as a shaped orifice nozzle, so long as the selected shape results in the generation of a fluid stream capable of head-on collision with a second fluid stream in the reaction chamber at the respective operating pressure.

[0052] When insertable plain orifice nozzles are used, they may be provided as a piece made of a particularly hard material, such as sapphire, ruby, diamond, ceramic, glass ceramic, glass (such as borosilicate glass), or metal such as steel, e.g., stainless steel. In the case of steel, a steel quality with high hardness and low wear properties is preferably used, such as high-speed steel (HSS), which is an alloy steel containing carbide-forming elements such as tungsten, molybdenum, chromium, vanadium, and cobalt, with the total amount of alloying elements typically ranging from about 10 to 25% by weight. Alternatively, tungsten steel, also known as a hard alloy, in which tungsten and cobalt are the primary alloying elements, may be used. The nozzle may be prefabricated and inserted into the first piece of the reactor, and secured thereto, for example, by crimping or gluing.

[0053] Thus, in some embodiments, the downstream portions of the lumens of the first and / or second fluid conduits are also cylindrical or substantially cylindrical, and such downstream portions may coincide with the lumen of the cylindrical nozzle insert.

[0054] As mentioned above, in some preferred embodiments, the downstream portion of the lumen of the first and / or second fluid conduit, regardless of its shape, i.e., cylindrical or tapered, has a downstream end that coincides with the respective fluid inlet. Furthermore, said downstream end may advantageously be flush with the wall of the reaction chamber. The downstream portion of the lumen, or at least its downstream end, may be understood as part of or feature of the respective nozzle.

[0055] In some embodiments, the lumen of the first and / or second fluid conduit, and more preferably the lumen of each of the first and second fluid conduits, is substantially cylindrical, columnar, or slightly tapered, with the taper angle being constant throughout the lumen length. In this case, the lumen can have a diameter at its downstream end that is substantially larger than the diameter of the first or second fluid inlet. As previously mentioned, the fluid inlet is provided by a nozzle. This contrasts with simple T-piece or Y-piece mixers, which essentially consist of two (or three) tubes joined together with lumens forming a T- or Y-shaped flow path, where the lumen diameter of each tube is uniformly the same up to the junction that forms the fluid mixing zone. The function of the nozzle is, among other things, to control the direction and increase the velocity of the fluid flow as it passes through the nozzle and enters the reaction chamber. To enhance the nozzle effect and reduce the influence of the fluid conduit geometry, it is further preferred that the lumen diameter at the upstream end of the first and second fluid conduits is at least twice the diameter of the larger of the first and second fluid inlets. In related embodiments, the lumen of the first and / or second fluid conduit has a diameter at its upstream end that is at least 5 times, or optionally at least 10 times, the diameter of the first or second fluid inlet, respectively. In some embodiments, the lumen of each of the first and / or second fluid conduits is cylindrical or columnar and has a downstream portion that includes a downstream end that coincides with the fluid inlet, and the lumen diameter of each downstream portion of the first and / or second fluid conduit is independently substantially the same as the diameter of the fluid inlet (also referred to herein as the orifice diameter).

[0056] The first and / or second fluid conduits can further comprise a connector disposed at their upstream end. In this context, a connector is understood as a geometric feature that can facilitate connection with a corresponding geometric feature on, for example, a tubing end piece. Examples of potentially useful connectors include male or female Luer tapers, also known as Luer tips, Swagelok® tube fittings or connectors, barb plug-in type connectors, or couplers such as quick couplers. Similarly, the third fluid conduit can feature a connector disposed at its downstream end. The types of connectors that feature the first, second, and third fluid conduits can be selected independently and, in some embodiments, are the same type, while in other embodiments they may be different from each other.

[0057] In some further embodiments, the fluid inlet provided by the first and / or second nozzle has a diameter in the range of about 20 μm to about 600 μm. The fluid inlet diameter provided by a nozzle may also be referred to as the orifice diameter of that nozzle. In some embodiments, both the first and second nozzles have an orifice diameter in the range of 20 μm to 500 μm, or about 50 μm to 600 μm, or about 50 μm to 500 μm. In other embodiments, both the first and second nozzles have an orifice diameter in the range of about 50 μm to 450 μm, or about 100 μm to 450 μm. In particularly preferred embodiments, the maximum orifice diameter of one or both of the nozzles is equal to or less than 500 μm. In other reactor configurations, at least one of the orifice diameters 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, even smaller diameters, for example, less than 20 μm, may be contemplated.

[0058] In some embodiments, the fluid inlet diameter, i.e., the orifice diameter, of the first and second nozzles are the same, such as about 400 μm, about 300 μm, about 200 μm, or about 100 μm, etc. While such configurations appear to work well for some jet impingement processes, they do not work reliably for all jet impingement processes.

[0059] In many processes based on jet impingement technology, the best results are achieved with a reactor according to the present invention that has two nozzles with different orifice diameters, i.e., the nozzles provide first and second fluid inlets 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 can be advantageous in various ways. For example, it can be used to control the introduction of solvents that are necessary for processing purposes but undesirable in the final product. An asymmetric nozzle configuration can also be used to generate two liquid streams with different flow rates but similar kinetic energy that are injected through the nozzles into the reaction chamber where they collide.

[0060] 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 further embodiments, the ratio of the first orifice diameter to the second orifice diameter is in the range of about 1.2 to about 5, or about 1.2 to 2. Also preferred are embodiments in which the diameter of the first fluid inlet (i.e., the first orifice) is in the range of about 200 μm to about 500 μm, or in the range of about 200 to 400 μm, and the diameter of the second fluid inlet (i.e., the second orifice) is in the range of about 50 μm to about 200 μm.

[0061] For example, the following nozzle pairs can be used, where the first value represents the approximate diameter of the first orifice and the second value represents the approximate diameter of the second orifice: 100 μm and 50 μm; 200 μm and 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 μm and 200 μm; 400 μm and 100 μm; 400 μm and 50 μm; 500 μm and 400 μm; 500 μm and 300 μm; 500 μm and 200 μm; 500 μm and 100 μm; 500 μm and 50 μm; 600 μm and 500 μm; 600 μm and 400 μm; 500 μm and 300 μm; 500 μm and 200 μm; 500 μm and 100 μm; 500 μm and 50 μm. Again, these pairs are non-limiting examples and other orifice diameter combinations may be useful depending on the particular product or process.

[0062] The reaction chamber provided by the jet impingement reactor according to the present disclosure, and in some embodiments, resulting from the combination and fastening of the first and second housing pieces, is generally small. In some embodiments, reactors are provided having a reaction chamber diameter of no more than 100 times the diameter of the nozzle orifice (i.e., inlet opening), or, if nozzles of different sizes are used, a reactor having a chamber diameter of no more than about 100 times the diameter of the orifice diameter of the larger nozzle. For example, if the larger fluid inlet has a diameter of 100 μm, according to this particular embodiment, the reaction chamber diameter is preferably no more than about 10 mm. In one embodiment, where the nozzle or larger inlet opening has a diameter of 200 to 300 μm, the diameter of the reaction chamber along the first central axis is preferably in the range of 2 to 5 mm.

[0063] In a related embodiment, the ratio of the diameter of the reaction chamber along the first central axis to the first fluid inlet diameter is in the range of 6 to 60. For example, if the diameter of the first fluid inlet is about 200 μm, then according to this particular embodiment, the diameter of the reaction chamber along the first central axis is in the range of about 1.2 mm to about 12 mm. However, reactors with larger nozzles may require other dimensional considerations.

[0064] According to a further related embodiment, the ratio of the diameter of the reaction chamber along the first central axis to the diameter of the fluid outlet is in the range of about 1.2 to about 3. For example, according to this particular embodiment, a reaction chamber having a diameter of about 3 mm has a fluid outlet diameter of about 1 mm to about 2.5 mm. In one preferred embodiment, the fluid outlet diameter is about 1 to 2 mm.

[0065] When selecting the inlet diameter, the fluid outlet diameter must also be considered. For example, a small nozzle orifice or fluid inlet diameter, such as less than 100 μm, should be combined with a small fluid outlet diameter, such as less than 1 mm, to ensure a pressure in the reaction chamber high enough to support turbulent flow and rapid mixing of the two fluids during reactor operation. For example, when using two nozzles with 50 μm orifices, a fluid outlet diameter of 0.5 mm can be used. Based on the above disclosure and guidance, it will be apparent to those skilled in the art that further variations in dimensional factors may also be useful to accommodate specific product or process requirements.

[0066] As previously mentioned, a key feature of the reactor is the substantially spherical or spheroidal 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 fluid outlets. In other words, the necessary inlets and outlets are the only exceptions or interruptions to the otherwise perfectly spherical inner surface of the reaction chamber wall.

[0067] 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 planar wall sections, each having an area smaller than the area of ​​the fluid outlet. Such small planar wall sections may be minor artifacts and further small deviations from the overall spherical shape of the reaction chamber. For example, the planar wall sections may be provided as protrusions on the first piece section, and the second piece section may have recesses to receive these protrusions. In some further embodiments, the spherical shape of the reaction chamber is as shown in any of the embodiments shown in Figures 7, 8, 9, or 10.

[0068] As understood herein, the term "flat wall" refers to a wall whose shape deviates from that of a perfectly spherical cap and may have a generally flat or at least partially planar shape. In some embodiments, the flat wall is provided as a protrusion on the first piece that is generally planar at its distal end and features two right-angled corners. Non-limiting examples of small flat walls are shown in Figures 5, 9, and 10.

[0069] In alternative embodiments, one or more planar walls may be provided as protrusions on the second piece, and the first piece may have one or more recesses to receive them. In preferred embodiments, the planar walls are integral with the first piece and made from the same material.

[0070] In one particular embodiment, the spherical shape of the reaction chamber is interrupted by first and second fluid inlets, a fluid outlet, and two or at least two planar walls, each of which independently has an area smaller than the area of ​​the fluid outlet. As previously mentioned, such planar walls are small and represent only a small deviation from the overall spherical shape of the reaction chamber.

[0071] In some preferred embodiments, the first piece presents a generally hemispherical wall portion having two planar walls disposed as protrusions from its orthodromic or great circle. The dimensions of the planar walls may be independently selected, in other words, the respective dimensions of the at least two planar walls may be different. Alternatively, the dimensions of the at least two planar walls may be essentially the same.

[0072] When the first piece comprises two small planar walls, these are preferably positioned at diametrically opposed positions relative to the spherical shape of the reaction chamber. In some embodiments, the first and second planar walls are positioned at opposing positions along the first central axis (x) of the reaction chamber.

[0073] The second piece of the reactor, including the fluid outlet and a portion of the reaction chamber, is complementary to the first piece, such that the two pieces can be secured together to form the substantially spherical reaction chamber of the jet impingement reactor. In some embodiments, the second piece includes at least two recesses complementary to the first piece, i.e., first and second recesses located in the first piece and shaped or adapted to receive two flat protrusions included in the first piece, allowing the two pieces to be secured together to form the reaction chamber of the jet impingement reactor. In some alternative embodiments, the recesses and small flat wall protrusion features for the first and second pieces can be interchanged.

[0074] To supply the first and second fluids to the first and second fluid conduits, respectively, the first piece of reactor can be equipped with connectors, such as barbs or luer fittings, that allow external supply tubes or pipes to be connected to the first piece of reactor to establish fluid connections with the fluid conduits. In some preferred embodiments, these connections are achieved by connecting a partially insertable piece to the first piece of reactor.

[0075] In some related embodiments, the first piece includes a second cavity and a third cavity, each of which is shaped to receive a connecting piece for conducting a first or second fluid from an upstream fluid source to the first or second fluid conduit, respectively. Such a connecting piece can have an upstream end, a downstream end, and a fluid conduit extending from the upstream end to the downstream end, with at least the downstream end being insertable into the second or third cavity such that the fluid conduit of the connector is in fluid communication with the lumen of the first or second fluid conduit of the reactor. The upstream end of the connecting piece can have a connector for securing a tube or pipe, such as a Luer fitting or a barbed connector, or a barbed fitting.

[0076] In some embodiments, the connecting piece features an external circular groove at or near its downstream end for retaining an O-ring seal to seal the connecting piece to the first piece of housing. In some related embodiments, the connecting piece can include more than one, e.g., two or a plurality of such external grooves, located at or near its downstream end for retaining an O-ring seal to seal the connecting piece to the first housing piece. Optionally, additionally, or alternatively, it may be envisioned to use other means, e.g., external means, adapted to retain, e.g., releasably seal, the connecting piece to the first piece of reactor.

[0077] In some embodiments, the connecting piece is also made of a polymeric material, such as any one of the polymeric materials or combination of materials described herein with reference to the first and / or second pieces of the jet impingement reactor. In some embodiments, the connecting piece is made of the same polymeric material as the first and / or second pieces.

[0078] A connecting piece, whose lumen can form part of a flow path for a first or second fluid from a fluid source disposed further upstream in the first or second fluid conduit of the reactor, can have an upstream portion or segment and a downstream portion or segment, which portions differ in terms of their diameter. For example, the lumen diameter of the upstream portion can be larger than the lumen diameter of the downstream portion. In other embodiments, the upstream and downstream portions have different diameters and the same. In some embodiments, the lumen of the connecting piece can be essentially cylindrical. In other embodiments, the lumen diameter of the upstream portion can be smaller than the lumen diameter of the downstream portion. In related embodiments, the difference in lumen diameter between the upstream and downstream segments can be gradual, i.e., the lumen is tapered cylindrical. In one embodiment, the lumen can be shaped as a tapered cylinder, with the lumen diameter being smaller at the upstream portion of the connecting piece but gradually expanding to the lumen diameter at the downstream end of the connecting piece. A small taper angle is preferred. For example, the difference in diameter between the upstream and downstream ends of the lumen of the connecting piece is 0.5% or less, 1% or less, or 5% or less. In other related embodiments, the difference in lumen diameter between the upstream and downstream portions may be stepped or segmented.

[0079] In some embodiments, the lumen of the connecting piece may have the same diameter as the lumen diameter of the upstream portion of the first and / or second fluid conduit of the reactor. In other embodiments, the lumen diameter of the downstream portion or segment of the connecting piece that forms part of the flow path of the first and second fluids to the first and second fluid conduit of the reactor is essentially 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 piece, or the lumen diameter of the downstream portion or segment of the connecting piece, is different, e.g., may be larger or smaller than the lumen diameter of the first or second fluid conduit of the reactor.

[0080] The reactor may be designed to be substantially symmetrical with respect to the fluid features upstream of the nozzles providing the first and second fluid inlets, for example, the shapes and dimensions of the first and second fluid conduits may be essentially the same, the shape and dimensions of the second cavity may match the shape and dimensions of the third cavity, and the connecting pieces insertable into each cavity may also be the same or similar in design.

[0081] Alternatively, the inner diameter of the fluid conduit of the connecting piece for insertion into the second gap and for supplying the (first) fluid to the reactor may be larger than the diameter of the connecting piece designed for insertion into the third gap. To prevent assembly errors in this case, the outer shapes or dimensions of the downstream ends of the connecting pieces may also differ from each other so that the connecting pieces can be (partially) inserted into the correct gaps.

[0082] In a further aspect, the present invention provides (a) a reactor housing having the features of the first piece described above, (b) a connecting piece as described above, and (c) a piece having the features of the second piece of the reactor described above.

[0083] In a still further aspect, the present invention provides a first piece of the reactor described above, optionally including any feature or combination of features disclosed as being optional or part of a preferred embodiment in the context of the detailed disclosure of the reactor.

[0084] In a further aspect, the present invention provides a method for making a reactor as described hereinabove. The method includes the step of injection molding a first piece. As previously mentioned, the first piece typically provides a major portion of the reactor housing. Optionally, the method may include the following steps: (a) injection molding the first piece; (b) injection molding the second piece; and (c) securing the first and second pieces to one another. In some embodiments, the securing step (c) includes or consists of partially or entirely inserting the second piece into a first cavity of the first piece.

[0085] Alternatively, the method may include the following steps: (a) injection molding a first piece; (b) overmolding a second piece onto the first piece, or vice versa: (a) injection molding a second piece; (b) overmolding the first piece onto the second piece. In some embodiments, the molding step (a) also includes forming first and second fluid inlets in the first piece.

[0086] In certain embodiments, the method can include inserting a pre-fabricated nozzle into the first piece, which may occur before or after the first and second pieces are secured together, or before the overmolding step, if any, occurs.

[0087] Alternatively, according to some other preferred embodiments, the first and / or second fluid inlets are generated by a mechanical micro-drilling or laser drilling step in the first piece. This step may be performed before or after step (c), i.e., before or after fastening the first and second pieces together. According to some further preferred embodiments, the first and second fluid inlets have different diameters and are generated by laser drilling, with the larger of the two inlets being prepared first, followed by the smaller inlet being prepared by laser drilling, with the laser beam generating the smaller inlet being directed through the larger inlet already present. In this way, precise alignment of the fluid inlets on the first central axis (x) of the reaction chamber can be achieved.

[0088] Optionally, the smaller inlet may be drilled completely through the larger inlet. In some alternative preferred embodiments, a very small hole may first be drilled through the larger inlet to mark the location of the smaller inlet, followed by subsequent drilling from the opposite side (i.e., not through the larger inlet) to create the smaller inlet with the desired diameter. This procedure may also be used to create two inlets with the same diameter.

[0089] Such methods of preparing jet impingement reactors including housings made from polymeric materials can provide a more efficient manufacturing process; for example, in some embodiments, it may be contemplated that the same mold or molding tool may be used to make the pieces, yet different reactors may be made by adapting only the drilling step to adjust the first and / or second fluid inlet diameters. It is also contemplated that in some embodiments, the reactor pieces, and optionally the connecting pieces, may be prepared solely by injection molding, without mechanical drilling, laser drilling, or machining to create the first and / or second fluid inlets.

[0090] In a related aspect, the present disclosure also provides a method of making a connecting piece as described hereinabove, wherein the connecting piece can be secured to a jet impingement reactor and used to deliver first and second fluids from an upstream fluid source to first and second fluid conduits of the jet impingement reactor. The method includes injection molding the connecting piece. In some embodiments, the lumen of the connecting piece may be provided by mechanical drilling or machining of the connecting piece.

[0091] A further aspect of the present invention relates to the use of the reactor. In some particularly preferred embodiments, the reactor is used for the sterile production of sterile liquid pharmaceutical compositions. The sterile liquid pharmaceutical compositions may generally contain nanoparticles, such as lipid nanoparticles, as in the case of nucleic acid-based therapeutic or prophylactic agents. In some embodiments, the sterile liquid pharmaceutical compositions may contain liposomes, which are nanoparticles typically in the form of spheroidal vesicles, composed of phospholipids, and containing at least one lipid bilayer.

[0092] More specifically, such use may include: (i) fluidly connecting a first fluid conduit to an upstream source of a first fluid via a first connecting piece; (ii) fluidly connecting a second fluid conduit to an upstream source of a second fluid, different from the first fluid, via a second connecting piece; and (iii) flowing the first fluid from the first fluid source into the reactor at a first flow rate and simultaneously flowing a second fluid from the second fluid source into the reactor at a second flow rate, thereby causing the first and second fluids to mix within the reaction chamber to form a third fluid that exits the reaction chamber through a fluid outlet. The third fluid, representing a mixture or reaction product of the first and second fluids, then exits the reactor through a fluid outlet provided by the second piece and the third fluid conduit. As will be understood by those skilled in the art, such use may also be expressed as a process or method, i.e., a process or method comprising steps (i) to (iii) above. Furthermore, those skilled in the art will understand that the order of steps (i) and (ii) is not important, but that step (iii) is performed after steps (i) and (ii). In some processes, the first and second flow rates may be similar or essentially the same, depending on the type of material being prepared using the reactor. In many other processes, typically including the production of lipid nanoparticles used in nucleic acid-based therapeutic or prophylactic drugs, different volumes of first and second fluids must be mixed, which requires different first and second flow rates. For example, a larger volume of the first fluid, representing an aqueous liquid optionally containing an active ingredient such as a nucleic acid construct, may need to be mixed with a smaller volume of the second fluid, representing an organic solution of lipids capable of forming lipid nanoparticles. Thus, in some preferred embodiments, the first flow rate is greater than the second flow rate, and preferably, in such processes, the first fluid inlet also has a larger diameter than the second fluid inlet.

[0093] In a still further aspect, the present invention provides an apparatus for the sterile production of a sterile liquid pharmaceutical composition, the apparatus comprising a jet impingement reactor as disclosed herein.

[0094] The following numbered paragraphs list embodiments included in this disclosure.

[0095] 1. A jet impingement reactor (1) comprising a reaction chamber (2), said chamber having a substantially spherical shape, the spherical shape comprising: (a) a first fluid inlet (3) and a second fluid inlet (4), the first fluid inlet (3) and the second fluid inlet (4) being arranged to face each other at opposite positions on a first central axis (x) of the reaction chamber (2), and each of the first fluid inlet (3) and the second fluid inlet (4) being provided by a nozzle (5); (b) a fluid outlet (6) disposed at a position located on a second central axis (y) of the chamber (2), the second central axis (y) being perpendicular to the first central axis (x); is interrupted by The reactor (1) further comprises a first fluid conduit (7), a second fluid conduit (8), and a third fluid conduit (9), the first fluid conduit (7) and the second fluid conduit (8) being configured to direct a first fluid to the first fluid inlet (3) and a second fluid to the second fluid inlet (4), and the third fluid conduit (9) being configured to direct a third fluid downstream from the fluid outlet (6), the third fluid being formed by mixing or reacting the first and second fluids in the reaction chamber (2); The reactor (1) comprises at least two pieces fixed to each other, a first piece (121, 171, 181) of which is made of a polymer material and comprises at least a portion of the first fluid conduit (7) or the second fluid conduit (8) and at least a hemispherical portion of the reaction chamber (2), and a second piece (132, 172, 182) of the two pieces is at least partially insertable into the first piece (121, 171, 181) and comprises a fluid outlet (6); Jet impingement reactor (1).

[0096] 2. The reactor (1) of item 1, wherein the first piece (121, 171, 181) is molded to have a first cavity (21) for receiving the second piece (132, 172, 182) by insertion, and the second piece (132, 172, 182) is molded and adapted to be insertable into the first cavity (21).

[0097] 3. The reactor (1) of item 1 or 2, wherein the first gap (21) is cylindrical, columnar, or tapered.

[0098] 4. The second piece (132, 172, 182) is an upstream end (24) comprising a fluid outlet (6) and a portion (16) of the reaction chamber (2); - downstream end (25); a third fluid conduit (9) fluidly connecting the upstream end (24) and the downstream end (25); The reactor (1) according to any one of items 1 to 3,

[0099] 5. The reactor (1) of any of items 1 to 4, wherein the second piece (132, 172, 182) is fully insertable into the first gap (21).

[0100] 6. The reactor (1) of any of items 1 to 5, wherein the first piece (121, 171, 181) is made at least primarily of a thermoplastic polymer material, and the thermoplastic polymer material preferably comprises polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU), or polyetherimide (PEI).

[0101] 7. The reactor (1) of any of items 1 to 6, wherein the first fluid conduit (7) and the second fluid conduit (8) each have a longitudinal central axis that coincides with the first central axis (x) of the reaction chamber (2), and the third fluid conduit (9) has a longitudinal central axis that coincides with the second central axis (y) of the reaction chamber (2).

[0102] 8. The reactor (1) of any of paragraphs 1 to 7, wherein the first fluid conduit (7) and / or the second fluid conduit (8) has a lumen (28) with an upstream portion (29a) and a downstream portion (29c), and the upstream portion (29a) is cylindrical or columnar and has a diameter substantially larger than the downstream portion (29c).

[0103] 9. The reactor (1) of item 8, wherein the downstream portions (29c) of the first fluid conduit (7) and the second fluid conduit (8) have downstream ends that form or coincide with the first fluid inlet (3) and the second fluid inlet (4), respectively.

[0104] 10. The reactor (1) of item 9, wherein the downstream portions (29c) are tapered toward their downstream ends.

[0105] 11. The reactor (1) of any one of paragraphs 1 to 8, wherein the downstream section (29c) is substantially cylindrical.

[0106] 12. The reactor (1) of any of items 1 to 11, wherein the lumen (28) of each of the first fluid conduit (7) and the second fluid conduit (8) further includes an intermediate section (29b) between the upstream section (29a) and the downstream section (29c), and the intermediate section (29b) tapers toward the downstream section (29c).

[0107] 13. The reactor (1) of item 12, wherein the tapered middle section (29b) and the tapered downstream section (29c) have different taper angles.

[0108] 14. The reactor (1) of any of items 1 to 13, wherein the nozzle (5) is provided by the downstream section (29c).

[0109] 15. The reactor (1) of any one of paragraphs 8 to 14, wherein the nozzle (5) providing the first fluid inlet (3) or the second fluid inlet (4) is integral with the first piece (121, 171, 181) of the reactor (1).

[0110] 16. The reactor (1) of any one of paragraphs 8 to 14, wherein the nozzle (5) providing the first fluid inlet (3) or the second fluid inlet (4) is an insert.

[0111] 17. The reactor (1) of item 16, wherein the insert is made of metal.

[0112] 18. The reactor (1) of any of paragraphs 1 to 17, wherein the first fluid inlet (3) and the second fluid inlet (4) have a diameter in the range of about 50 μm to about 600 μm.

[0113] 19. The reactor (1) of any of paragraphs 1 to 18, wherein the diameter of the first fluid inlet (3) is different from the diameter of the second fluid inlet (4).

[0114] 20. The reactor (1) of item 18 or 19, wherein the diameter of the first fluid inlet (3) is within the range of about 200 μm to about 500 μm, and the diameter of the second fluid inlet (4) is within the range of about 50 μm to about 200 μm.

[0115] 21. The reactor (1) of any of paragraphs 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) and the fluid outlet (6).

[0116] 22. The reactor (1) of any one of paragraphs 1 to 20, wherein the spherical shape of the reaction chamber (2) is interrupted only by the first and second fluid inlets (3) and (4), the fluid outlet (6), and a planar wall (31) having an area smaller than the area of ​​the fluid outlet (6).

[0117] 23. The reactor (1) of item 22, wherein the flat wall portion (31, 319) is provided by the first piece (121) as a protrusion of the first piece (121), and the second piece (132, 172, 182) has a recess (32) for receiving the protrusion.

[0118] 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 and second fluid inlets (3) and (4), the fluid outlet (6), and at least two planar walls (31, 319), each independently having an area smaller than the area of ​​the fluid outlet (6), and the first and second planar walls are arranged at opposite positions on the first central axis (x) of the reaction chamber (2).

[0119] 25. The reactor (1) of item 24, wherein at least two planar wall portions (31, 319) are provided by a first piece (121, 171, 181) as protrusions of the first piece (121), and the second piece (132, 172, 182) has first and second recesses (32, 329) adapted to receive the protrusions.

[0120] 26. The reactor (1) of any of paragraphs 1 to 25, wherein the first piece (121, 171, 181) comprises a second cavity (8) and a third cavity (9), and each of the second cavity (8) and the third cavity (9) is shaped to receive a connecting piece (33, 73, 83) for conducting a first fluid or a second fluid, respectively, from an upstream fluid source to the first fluid conduit (7) or the second fluid conduit (8).

[0121] 27. The reactor (1) of item 26, wherein the connecting piece (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), and at least the downstream end (35, 75, 85) is insertable into the second gap (22) or the third gap (23) so that the fluid conduit (36, 76, 86) of the connecting piece (33, 73, 83) is in fluid communication with the lumen of the first fluid conduit (7) or the second fluid conduit (8) of the reactor (1).

[0122] 28. The reactor (1) of item 27, wherein the upstream end (34, 74, 84) of the connecting piece (33, 74, 83) has a connector (37, 77, 87) for fastening a tube or pipe, such as a luer fitting or a barbed connector or fitting.

[0123] 29. The reactor (1) of any one of paragraphs 26 to 28, wherein the connecting piece (33, 73, 83) is characterized by an outer circular groove (38, 78, 88) at or near its downstream end (35, 75, 85) for holding an O-ring seal (39, 79) for sealing the connecting piece (33, 73, 83) to the first piece (121, 171, 181) of the reactor (1).

[0124] 30. A first piece (121, 171, 181) of a reactor (1) as defined in any one of paragraphs 1 to 29.

[0125] 31. A method for manufacturing a first piece (121, 171, 181) of the reactor (1) of any one of items 1 to 29 or the reactor (1) of item 30, comprising the step of injection molding the first piece (121, 171, 181).

[0126] 32. The method of paragraph 31, wherein the step of injection molding the first piece (121, 171, 181) includes forming a first fluid inlet (3) and a second fluid inlet (4).

[0127] 33. The method of paragraph 31, wherein the first fluid inlet (3) and the second fluid inlet (4) are formed by a step of micro-drilling or laser drilling.

[0128] 34. Use of a reactor (1) according to any one of paragraphs 1 to 29 for the sterile production of a sterile liquid pharmaceutical composition.

[0129] 35. (i) fluidly connecting a first fluid conduit (7) to an upstream source of a first fluid via a first connecting piece (33, 73, 83); (ii) fluidly connecting the second fluid conduit (8) via a second connecting piece (33, 73, 83) to an upstream source of a second fluid different from the first fluid; (iii) flowing a first fluid from a first fluid source into the reactor (1) at a first flow rate and simultaneously flowing a second fluid from a second fluid source into the reactor (1) at a second flow rate, thereby causing the first and second fluids to mix in the reaction chamber (2) to form a third fluid that exits the reaction chamber (2) through the fluid outlet (6); Item 35. The use according to item 34, comprising

[0130] 36. Use according to paragraph 35, wherein the first flow rate is greater than the second flow rate and the first fluid inlet (3) has a larger diameter than the second fluid inlet (4).

[0131] 37. The use according to paragraphs 34 to 36, wherein the liquid pharmaceutical composition comprises lipid nanoparticles.

[0132] Alternative jet impingement reactors provided by alternative piece fastenings or configurations are also described in this disclosure in Figures 13-23. The following numbered paragraph list also relates to alternative jet impingement reactor embodiments.

[0133] 1. A jet impingement reactor (1) comprising a housing (2) made of a polymeric material, the housing enclosing a reaction chamber (2), the chamber having a substantially spherical shape, the spherical shape being: (a) at least a first fluid inlet (3) and a second fluid inlet (4), the first fluid inlet (3) and the second fluid inlet (4) being arranged facing each other at opposite positions on a first central axis (x) of the reaction chamber (2), and each of the first fluid inlet (3) and the second fluid inlet (4) being provided by a nozzle (5); and (b) a fluid outlet (6) disposed at a position located on a second central axis (y) of the chamber (x), the second central axis (y) being perpendicular to the first central axis (x); interrupted only by The reactor (1) further comprises a first fluid conduit (7), a second fluid conduit (8), and a third fluid conduit (9), the first fluid conduit (7) and the second fluid conduit (8) being configured to direct a first fluid to the first fluid inlet (3) and a second fluid to the second fluid inlet (4), and the third fluid conduit (9) being configured to direct a third fluid in a downstream direction from the fluid outlet (6), the third fluid being formed by mixing or reaction of the first and second fluids in the reaction chamber (2); The housing of the jet impingement reactor (1) comprises at least two pieces fixed to each other, a first piece (11, 41, 81) of which comprises at least a main portion of the first fluid conduit (7) or the second fluid conduit (8), and a second piece (12, 42, 82) of which comprises at least one of the nozzles (5).

[0134] 2. The reactor of item 1, wherein the first piece comprises at least a major portion of each of the first, second, and third fluid conduits.

[0135] 3. The reactor of paragraph 1 or 2, wherein the first piece is molded to provide a void for receiving the second piece by insertion.

[0136] 4. The reactor of any of paragraphs 1 to 3, wherein the second piece is shaped and adapted to be insertable into the first piece.

[0137] 5. The reactor of item 3 or 4, wherein the molding of the first piece includes an insertion guide (51, 91) for receiving the second piece in a specific orientation, and / or the molding of the second piece includes an insertion guide (52, 92) for inserting the second piece into the gap of the first piece in a specific orientation relative to the first piece.

[0138] 6. The reactor of any of paragraphs 1 to 5, wherein the second piece comprises at least a major portion of the reaction chamber.

[0139] 7. The reactor of any of paragraphs 1 to 6, wherein the second piece comprises a fluid outlet.

[0140] 8. The reactor of any of paragraphs 1 to 7, wherein the second piece comprises both the first and second fluid inlets.

[0141] 9. The reactor of any of paragraphs 1 to 3, wherein the second piece comprises the entire reaction chamber.

[0142] 10. The reactor of any of paragraphs 1 to 9, wherein the second piece comprises a minor portion of at least one of the first, second, and third conduits.

[0143] 11. The reactor of any of paragraphs 1 to 10, wherein the housing consists essentially of first and second pieces.

[0144] 12. The reactor of any of paragraphs 1 to 11, wherein the first piece and the second piece are secured to one another by one or more fastening means, and optionally, the first piece and the second piece are held together by fastening means in the form of screws.

[0145] 13. The reactor of any of paragraphs 1 to 12, wherein the first piece is overmolded onto the second piece or the second piece is overmolded onto the first piece.

[0146] 14. The reactor of any of paragraphs 1 to 13, wherein the first piece and / or the second piece are made at least primarily from a thermoplastic polymer material.

[0147] 15. The reactor of item 14, wherein the thermoplastic polymer material includes polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyether ether ketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU), or polyetherimide (PEI).

[0148] 16. The reactor of any of paragraphs 1 to 15, wherein the first piece and / or the second piece include one or more snap-fit ​​or press-fit features (98, 108) for holding the first piece and the second piece together.

[0149] 17. The reactor of any of paragraphs 1 to 16, further comprising a gasket between the first piece and the second piece.

[0150] 18. The reactor of any of paragraphs 1 to 17, wherein the first and second fluid conduits each have a longitudinal central axis that coincides with the first central axis (x) of the reaction chamber.

[0151] 19. The reactor of any of paragraphs 1 to 18, wherein the third fluid conduit has a longitudinal central axis that coincides with the second central axis (y) of the reaction chamber.

[0152] 20. The reactor of any of paragraphs 1 to 19, wherein the first and / or second fluid conduits have lumens (13, 14) extending from the upstream end to the downstream end of the conduits, and the lumens are cylindrical or tapered toward the downstream end.

[0153] 21. The reactor of paragraph 20, wherein the lumen of the first and / or second fluid conduit has a diameter at its downstream end that is at least 10 times the diameter of the first or second fluid inlet, respectively.

[0154] 22. The reactor of paragraph 20 or 21, wherein the lumen of the first and / or second fluid conduit has a tapered upstream segment and a tapered downstream segment, the taper angle of the downstream segment exceeding the taper angle of the upstream segment.

[0155] 23. The reactor of any of paragraphs 1 to 22, wherein the first and / or second fluid conduits have an upstream end with a connector (27, 37, 57, 97).

[0156] 24. The reactor of any of paragraphs 1 to 23, wherein the third fluid conduit comprises a lumen (15) having an upstream end and a downstream end, the upstream end coinciding with the fluid outlet (6) of the reaction chamber.

[0157] 25. The reactor of any of paragraphs 1 to 24, wherein the nozzle (5) providing the first or second fluid inlet is integral with the first or second piece of the housing.

[0158] 26. The reactor of any of paragraphs 1 to 25, wherein the nozzle providing the first or second fluid inlet is an insert housed within the first or second piece of the housing.

[0159] 27. The reactor of paragraph 26, wherein the nozzle is made of a different material than the piece inserted therein.

[0160] 28. The reactor of any of paragraphs 1 to 27, wherein the nozzle providing the first or second fluid inlet is shaped as a tube of cylindrical pipe.

[0161] 29. The reactor of any of paragraphs 1 to 28, wherein the first and second fluid inlets have diameters ranging from about 50 μm to about 600 μm.

[0162] 30. The reactor of any of paragraphs 1 to 29, wherein the diameter of the first fluid inlet is different from the diameter of the second fluid inlet.

[0163] 31. The reactor of any of paragraphs 1 to 30, wherein the ratio of the diameter of the reaction chamber (2) along the first central axis (x) to the first fluid inlet diameter is in the range of 6 to 60.

[0164] 32. The reactor of any of paragraphs 1 to 31, 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) is within the range of about 1.2 to 3.

[0165] 33. A method for manufacturing the reactor of paragraphs 1 to 32, comprising injection molding the first piece and / or the second piece of the housing.

[0166] 34. The method of paragraph 33, wherein the first and / or second fluid inlets are created by mechanical or laser drilling of the first and / or second pieces of the housing.

[0167] 35. Use of a reactor according to paragraphs 1 to 32 for the sterile production of a sterile liquid pharmaceutical composition.

[0168] 36. Use according to paragraph 35, wherein the liquid pharmaceutical composition comprises lipid nanoparticles.

[0169] 37. An apparatus for the sterile production of a sterile liquid pharmaceutical composition, comprising a reactor according to paragraphs 1 to 32.

[0170] Detailed Description of the Drawings FIG. 1 shows a cross-sectional view of one embodiment of a first piece (121) of a jet impingement reactor (not drawn to scale) comprising at least a portion of a first fluid conduit (7) and a second fluid conduit (8), or each of these. It further comprises or contains a portion of a substantially spherical reaction chamber (2). The portion provided by the first piece (121) comprises two or more hemispherical segments or portions of the reaction chamber (2). Also shown are a first fluid inlet (3) and a second fluid inlet (4), which are positioned facing each other at opposite positions on a first central axis of the reaction chamber (2), allowing the first and second fluid jets to enter the reaction chamber (2) in a forward or mutually impinging manner. Each of the first and second fluid inlets (3) and (4) is provided by a nozzle (5). The first piece (121) is cylindrical, slightly tapered, and further includes a first cavity (21) shaped to receive the second reactor piece by insertion. The first and second fluid conduits (7, 8) each have a lumen with an upstream portion (29a), a downstream portion (29c), and an intermediate portion (29b) therebetween that tapers toward the downstream portion (29c). The downstream portion (29c) also tapers toward the respective fluid inlets (3, 4), with a taper angle different from that of the intermediate portion (29b). The downstream end of the downstream portion (29c) coincides with the respective fluid inlets (3, 4). The upstream portion (29a) of each fluid conduit (7, 8) has a cylindrical shape. The first piece (121) further comprises a second cavity (22) and a third cavity (23), each of which is shaped to receive a connecting piece for conducting a first fluid or a second fluid from an upstream fluid source to the first fluid conduit (7) or the second fluid conduit (8), respectively.

[0171] Figure 2 shows a cross-sectional view of one embodiment of a second piece (132) of a jet impingement reactor (not drawn to scale) designed to match the first piece (121) shown in Figure 1 and be insertable into the first gap (21) of the first piece (121). The second piece (132) comprises an upstream end (24) and a downstream end (25). The lumen therebetween corresponds to a third fluid conduit (9) that fluidly connects the upstream end (24) and the downstream end (25). The upstream end (24) is designed to provide a portion of the reaction chamber wall (16) in its inserted state and includes a fluid outlet (6).

[0172] Figure 3 shows a cross-sectional view, not drawn to scale, of one embodiment of a connecting piece (33) designed to fit the first piece (121) shown in Figure 1 and direct a first or second fluid from an upstream fluid source to the first or second fluid conduit (7) or (8) of the first piece (121). The connecting piece (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). The connecting piece is shaped so that at least the downstream end (35) is insertable into the second or third cavity (22) or (23) of the first piece (121). Additionally, the connecting piece (33) features an outer circular groove (38) at its downstream end (35) for retaining an O-ring seal (39) to seal the connecting piece (33) to the first piece (121) shown in Figure 1. Another outer circular groove holding another O-ring seal is located at the downstream end 35 and further upstream from the first circular groove 38. The upstream end 34 of the connecting piece 33 has a barbed connector 37 or fitting for securing a tube or pipe.

[0173] Figure 4 shows a cross-sectional view of one embodiment of a jet impingement reactor (1) comprising the first piece (121) shown in Figure 1 along with the second piece (132) of Figure 2 and two connecting pieces (33) as shown in Figure 3. The second piece (132) is fully inserted into the first cavity (21). The downstream end (35) of the connecting piece (33) is inserted into the second cavity (22) and the third cavity (23) located in the first piece (121) of the reactor (1). Here, the upstream end (24) of the second piece (132) forms part of the wall of the reaction chamber (2) and the fluid outlet (6). For a description of other illustrated features, please refer to Figures 1, 2, and 3.

[0174] 5 is a cross-sectional view of a particular embodiment of a substantially spherical reaction chamber (2) formed by a first piece (121) and a partially or fully inserted second piece (132), with only portions of the first piece (121) and second piece (132) shown. A small planar wall section (31) of the reaction chamber wall is provided by the first piece (121). The second piece (132) has a recess (32) that receives a protrusion that forms the planar wall section (31).

[0175] 6 shows a cross-sectional view of another embodiment of a first piece (171) of a jet impingement reactor (not drawn to scale) comprising a first fluid conduit (7) and a second fluid conduit (8), or at least a portion of each of these. Furthermore, the first piece comprises or contains a portion of a generally spherical reaction chamber (2), the portion representing a generally hemispherical segment or approximately 50% of the reaction chamber (2). Also shown are a first fluid inlet (3) and a second fluid inlet (4), which are positioned facing each other at opposite positions on a first central axis of the reaction chamber (2), allowing the first and second fluid jets to enter the reaction chamber (2) in a forward or mutually impinging manner. Each of the first and second fluid inlets (3) and (4) is provided by a nozzle (5). The first piece (171) is cylindrical and slightly tapered, and further includes a first cavity (21) shaped to receive the second reactor piece by insertion. The first fluid conduit (7) and the second fluid conduit (8) each have a lumen with an upstream portion (29a), a downstream portion (29c), and an intermediate portion (29b) therebetween. The intermediate portion (29b) of the lumen tapers toward the downstream portion (29c). In this illustrated embodiment, the downstream portions (29c) of the lumens of the first fluid conduit (7) and the second fluid conduit (8) are cylindrical or columnar, and the lumen diameter is substantially smaller than the lumen diameter of the upstream portion (29b), e.g., less than half the diameter of the upstream portion (29b) of the lumen. The downstream end of the downstream portion (29c) coincides with the respective fluid inlet (3, 4), i.e., the downstream portion (29c) has a lumen diameter substantially the same as the orifice diameter of the respective fluid inlet (3, 4). The upstream portion (29a) of each fluid conduit (7, 8) has a cylindrical shape. The first piece (171) further comprises a second cavity (22) and a third cavity (23), each of which is shaped to receive a connecting piece for conducting a first fluid or a second fluid from an upstream fluid source to the first fluid conduit (7) or the second fluid conduit (8), respectively.

[0176] Figure 7 shows a cross-sectional view, not drawn to scale, of one embodiment of a jet impingement reactor (1) comprising a first piece (171) as shown in Figure 6, together with a second piece (172) and two connecting pieces (73). The second piece (172) is fully inserted into the first cavity (21) of the first piece (171). The second piece (172) comprises an upstream end (24) and a downstream end (25). The lumen therebetween represents a third fluid conduit (9) that fluidly connects the upstream end (24) and the downstream end (25) of the second piece (172). 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 substantially spherical portion of the reaction chamber (2) provided by the second piece (172) can provide up to 50% of the internal volume of the reaction chamber (2), calculated based on the approximate sphere that would result from the reaction chamber wall if not interrupted by the fluid inlets (3, 4) and fluid outlet (6), and optionally, the sphere can be interrupted, any other features not shown.

[0177] The downstream ends (75) of the two connecting pieces (73) are inserted into the second gap (22) and the third gap (23) disposed in the first piece (171) of the reactor (1). The two connecting pieces (73) are for conducting a first fluid or a second fluid from an upstream fluid source to the first fluid conduit (7) or the second fluid conduit (8) of the first piece (171), as shown in FIG. 6. The connecting pieces (73) have an upstream end (74), a downstream end (75), and a fluid conduit (76) extending from the upstream end (74) to the downstream end (75). They are shaped so that at least the downstream end (75) can be inserted into the second gap (22) or the third gap (23) of the first piece (171).

[0178] As shown in this figure, the fluid conduit (76) of the connecting piece (73) has different lumen diameters in its upstream portion or segment (744) and its downstream portion or segment (755). As shown, the lumen diameter of the upstream portion (744) is larger than the diameter of the downstream portion (755). The length of the downstream portion (755) of the connecting piece (73), which is coaxial with the first central axis (x), corresponds approximately to the portion of the connecting piece that is insertable or insertable into the second (22) or third cavity (23) of the first piece (171) of the reactor.

[0179] Additionally, the connecting piece (73) features at least one outer circular groove (78) at its downstream end (75) for holding an O-ring seal (79) for sealing the connecting piece (73) to the first piece (171). Another outer circular groove for holding another O-ring seal is located upstream of the first circular groove (78). The upstream end (74) of the connecting piece (73) has a barbed connector (77) or fitting for securing a tube or pipe.

[0180] 8 shows a cross-sectional view, not drawn to scale, of another embodiment of a jet impingement reactor (1), comprising a first piece (181) secured together with a second piece (182) and two connecting pieces (83). The second piece (182) is fully inserted into the first cavity (21) of the first piece (181). The second piece (182) comprises an upstream end (24) and a downstream end (25). The lumen between these ends corresponds to a third fluid conduit (9) that fluidly connects the upstream end (24) and the downstream end (25) of the second piece (182). 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 piece (182) may be up to 50% of the internal volume of the reaction chamber (2), calculated based on an approximate sphere that would result from the reaction chamber wall if it were not interrupted by the fluid inlet, fluid outlet (6), and possibly any small non-spherical elements (not shown) that may protrude or recess from the reaction chamber wall.

[0181] The downstream ends (85) of the two connecting pieces (83) are inserted into the second cavity (22) and the third cavity (23) disposed in the first piece (181) of the reactor (1). The two connecting pieces (83) are for conducting a first fluid or a second fluid from an upstream fluid source to the first fluid conduit (7) or the second fluid conduit (8) of the first piece (181). For reference to similar first fluid conduit (7) and second fluid conduit (8), see FIG. 6. The connecting pieces (83) have an upstream end (84), a downstream end (85), and a fluid conduit (86) extending from the upstream end (84) to the downstream end (85). The connecting pieces are 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 piece (181).

[0182] The fluid conduit 86 of the connecting piece 83 has different lumen diameters at its upstream portion or segment 844 and its downstream portion or segment 855. As shown, the lumen diameter at the upstream portion 844 is smaller than the diameter at the downstream portion 855. The lumen is tapered, i.e., it gradually expands from a smaller lumen diameter at the upstream end 84 to a larger lumen diameter at the downstream end 85. The connecting piece 83 also features at least one exterior circular groove 88 at its downstream end 75 for retaining an O-ring seal (not shown) to seal the connecting piece 83 to the first piece 181. Another exterior circular groove for retaining another O-ring seal is located further upstream from the downstream end 85 and the first circular groove 88. The upstream end 84 of the connecting piece 83 has a barbed connector 87 or fitting for securing a tube or pipe.

[0183] FIG. 9 shows a cross-sectional perspective close-up view (not drawn to scale) of a particular embodiment of a substantially spherical reaction chamber (2) formed by a first piece (181) and a partially or fully inserted second piece (182). Only a portion of the first piece (181) and the second piece (182) is shown. A small planar wall section (319) of the reaction chamber wall is provided by the first piece (181). As shown, the fluid inlet (3) is contained in the first piece (181) and is positioned on a first central axis (x, not shown, see FIG. 8). In this embodiment, the first piece (181) and the second piece (182) join at the orthodromic intersection of the substantially spherical reaction chamber (2), i.e., at the circular intersection of the reaction chamber (2) with a plane passing through the center point of the sphere at the first central axis (x). A small planar wall portion (319) is characterized as a protrusion arising from the first piece (181) and arising from and extending beyond the orthodromes. The second piece (182) provides a portion of the generally spherical reaction chamber wall, a fluid outlet (6), and a recess (329) that receives the protrusion of the first piece (181) that forms the planar wall portion (319).

[0184] FIG. 10 shows a cross-sectional perspective view (A) of a first piece (181) along with a cross-sectional perspective view (B) of the same first piece (181) secured to a second piece (182). The first piece (181) includes a fluid inlet (3) located at the base of a planar wall (319) and a first gap (21) for inserting the second piece (182). As shown in (A), the planar wall (319) is a small protrusion arising from the hemispherical chamber portion provided by the first piece (181). An insertion guide (109a) is also shown, which in this embodiment is depicted as a recess located at the downstream end of the first gap (21). Other features of the first piece (181) are referenced in FIG. 8 or FIG. 9, and similar features are referenced in FIG. 6.

[0185] Figure (B) shows the inserted second piece (182) with an insertion guide mechanism (109b), such as a protrusion or barb, complementary to the insertion guide (109a) of the first piece (181) to ensure accurate insertion and fixation of the second piece (182) into the first piece (181), i.e., so that the second piece (182) has the correct orientation relative to the first piece (181). The first and second pieces (181) and (182) fixed together form a substantially spherical reaction chamber (2), with the planar wall (319) received in a complementary recess (329, not shown) located in the portion of the reaction chamber wall (16) provided by the second piece (182). The second piece also provides a fluid outlet (6). For other features, see Figures 8, 9, and 6.

[0186] 11 shows a graphical depiction of particle size (mean diameter (nm); graph A) and polydispersity index (PDI; graph B) characterized for PLGA nanoparticles obtained using polymer jet impingement reactors (A, B, and C) according to the present invention and obtained using the stainless steel reactor (M) described in Example 1. The mean particle size of the obtained PLGA nanoparticles is less than about 200 nm. The mean PDI measured for the PLGA nanoparticles is less than 0.2.

[0187] FIG. 12 shows a graphical depiction of particle size (mean diameter (nm); graph A) and polydispersity index (PDI; graph B) characterized for liposomal nanoparticles obtained using polymer reactors according to the present invention (A, B, and C) or a stainless steel reactor (M) as described in Example 2. The mean particle size of the obtained liposomal nanoparticles is less than about 40 nm. The mean PDI measured for the liposomal nanoparticles is less than 0.1.

[0188] 13 shows a cross-sectional view, not to scale, of an alternative example of a jet impingement reactor (1) comprising a housing (10) made of a polymeric material, the housing consisting of two pieces (11, 12) fixed together, the first piece of the housing (11) comprising at least a major portion of the second fluid conduit (14) and at least a major portion of the third fluid conduit (9), as well as a portion of the wall of the reaction chamber (2). The second housing piece (12) comprises the remaining portion of the wall forming the reaction chamber (2) and the first fluid conduit (7). The reaction chamber wall is divided so that approximately half of it, including half of the fluid inlet (4) and fluid outlet (6), is formed by the first housing piece, while the other half of the reaction chamber wall, the other fluid inlet (3) and the other half of the fluid outlet (6) are housed within the second housing piece (12). The contact area between the first and second pieces includes a portion extending through the center of the reaction chamber along a second central axis (y), which may be perpendicular to the reactor operation direction when the reactor is operated. The housing (10) surrounds 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 a fluid outlet (6). The first fluid inlet (3) and the second fluid inlet (4) are positioned at opposite positions on the first central axis (x) of the reaction chamber so as to face each other, and each of the first and second fluid inlets is provided by a nozzle (5). The fluid outlet (6) is positioned at a position located on a second central axis (y) of the reaction chamber 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 a lumen, the lumens of the first fluid conduit (13) and the second fluid conduit (14) each having a longitudinal axis that coincides with the first central axis (x) of the reaction chamber and extends from an upstream end that is fluidly connected to the nozzle (5) to a downstream end, and the lumen (15) of the third fluid conduit has an upstream end and a downstream end, the upstream end of which coincides with the fluid outlet (6) of the reaction chamber.Thus, first and second fluid conduits are disposed within the reactor to direct a first fluid to the first fluid inlet and a second fluid to the second fluid inlet, and a third fluid conduit is disposed to direct a third fluid downstream from the fluid outlet, the third fluid being formed by mixing or reaction of the first and second fluids within the reaction chamber.

[0189] Figure 14 shows a perspective view, not drawn to scale, of a second housing piece (10) corresponding to the housing (12) of the alternative jet impingement reactor (1) described in Figure 13. The second housing piece (12) comprises the first fluid conduit (7) and approximately half of the wall forming the reaction chamber (2), and is hemispherical in shape, interrupted only by approximately half of the fluid inlet (3) and fluid outlet (6). The housing (12) further comprises the first fluid conduit (7) having a connector (27) at its upstream end, and a plurality of fastening means (26), such as in the form of cavities adapted or shaped to receive complementary or corresponding fastening means, such as screws or push-in or snap-fit ​​pegs (not shown), for securing the housing piece to the first housing piece (11, not shown).

[0190] When presented in plural as shown in this and subsequent figures to secure two housing pieces together, the fastening means should not be understood as limited to or necessarily representing the same or a single type of fastening means. Instead, as contemplated herein, the fastening means or configuration at each of the shown locations may be independently selected or configured, and in some embodiments, different means at each of the locations may be used. Similarly, the connectors shown in this and any of the subsequent figures should be understood as exemplary and not limited to the shapes and configurations shown. Instead, it will be understood that the selection of connectors and each location may be independently adapted according to requirements or preferences for connecting fluid conduits and fluid outlets to other components, means, or devices that may be associated with the use and operation of the impinging jet reactor.

[0191] Figure 15 shows a perspective view, not drawn to scale, of the first housing piece (10) of the housing (11) of the alternative jet impingement reactor (1) described in Figure 13. As shown, the first housing piece (11) provides approximately half of the walls of the reaction chamber (2) and is hemispherical in shape, interrupted only by approximately half of the fluid inlet (4) and fluid outlet (6). The housing (11) further comprises a third fluid conduit (9) having a molded 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 comprises a molded connector (37) disposed at its upstream end. Also shown are fastening means (36), such as a complementary fastening means (not shown), such as a screw, or in the form of a cavity shaped or adapted to receive a press-fit or snap-fit ​​mechanism, such as a peg, for securing the housing to the second housing piece (12, not shown).

[0192] FIG. 16 shows a cross-sectional view, not drawn to scale, of another example of an alternative jet impingement reactor (1) comprising a housing (40) made of a polymeric material, the housing consisting of two pieces (41, 42) secured together. The first piece of the housing (41) comprises a major portion of each of the first and second fluid conduits (7) and (8), excluding the downstream ends of the conduits. It also comprises the entire third fluid conduit (9) and a minor portion of the wall of the reaction chamber (2), including the fluid outlet (6). The first piece of the housing (41) is molded to include a cavity adapted to receive the second piece by insertion. As shown, the second housing piece (42) is molded to fit into the first housing piece (41) and is inserted. The second housing piece (42) comprises the downstream ends of the first and second fluid conduits (7) and (8), their respective fluid inlets (3, 4), a nozzle (5), and a major portion of the wall of the reaction chamber (2). The first and second fluid inlets (3, 4) are positioned at opposite positions on a first central axis (x) of the reaction chamber (2) formed by inserting and securing the second housing piece (42) into the first housing piece (41). The fluid outlet (6) is positioned at a position on a second central axis (y) of the reaction chamber that 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 a lumen, the lumens of the first fluid conduit (13) and the second fluid conduit (14) each having a longitudinal axis that coincides with the first central axis (x) of the reaction chamber and extending from an upstream end fluidly connected to the nozzle (5) to a downstream end, and the lumen of the third fluid conduit (15) has an upstream end and a downstream end, the upstream end coinciding with the fluid outlet (6) of the reaction chamber. Thus, the first and second fluid conduits are disposed within the reactor to direct a first fluid to the first fluid inlet and a second fluid to the second fluid inlet, and the third fluid conduit is disposed to direct a third fluid downstream from the fluid outlet, the third fluid being formed by mixing or reaction of the first and second fluids within the reaction chamber.

[0193] Figure 17 shows a perspective cross-sectional view, not drawn to scale, of the first housing piece (41) as depicted in Figure 16. The housing piece (41) comprises a major portion of each of the first and second fluid conduits (7) and (8), excluding the downstream ends of the conduits. It also comprises the entire third fluid conduit (9) and a minor portion of the wall of the reaction chamber (2), including the fluid outlet (6). As shown, the housing (41) comprises a cavity shaped and adapted to receive the second housing piece (42, not shown), and the molding also provides an insertion guide (51) for inserting the second housing piece in a specific intended orientation relative to the first housing piece (41) to form the housing (40). The lumens (13, 14, 15) of the first, second, and third fluid conduits (7, 8, and 9) are each cylindrical. The first and second conduits (7, 8) also include connectors (57) that facilitate further connection to correspondingly shaped features such as the end of a tube or another connector. The housing piece (41) also includes fastening means (56) in the form of cavities adapted or shaped to receive complementary fastening means (not shown), such as screws or press-fit or snap-fit ​​pegs, that can be used to secure the first housing piece (41) to the second housing piece (42, not shown).

[0194] Figure 18 shows a cross-sectional view of the second housing piece (42) of the housing (40) as shown in Figure 16. The housing piece (42) comprises the downstream ends of the first and second fluid conduits (7) and (8), their respective fluid inlets (3, 4), a nozzle (5), and a major portion of the wall of the reaction chamber (2). As used herein, a major portion of the reaction chamber wall means more than 50% of the surface area of ​​the reaction chamber wall. The nozzle (5) is integral with the housing piece, and the diameters of the fluid inlets (3) and (4) are different, although in other embodiments, the diameters of the fluid inlets (3) and (4) may be the same.

[0195] Figure 19 shows a perspective view of the second housing piece (42) of the housing (40) as shown in Figure 16. The housing piece (42) is shaped so that it can be inserted into the first housing piece (41, not shown), and the molding also provides insertion guides (52) that allow insertion of this piece only in a specific orientation relative to said first housing piece (41) to form the housing (40). The housing (42) also includes fastening means (76) in the form of cavities adapted or shaped to receive complementary fastening means such as screws, or press-fit or snap-fit ​​pegs to secure the two housing pieces together to form the housing (40) of the jet impingement reactor (1).

[0196] Figure 20 shows a cross-sectional view, not drawn to scale, of yet another example of an alternative jet impingement reactor (1), comprising a housing (80) made up of two pieces (81, 82) secured together. The first piece of the housing (81) comprises a major portion of each of the first and second fluid conduits (7, 8), excluding the downstream ends of the conduits, and the first piece also comprises a major portion of the third fluid conduit (9), excluding the upstream end of the conduit that coincides with the fluid outlet (6) of the reaction chamber (2). The first piece of the housing (81) is further shaped to comprise a cavity adapted to receive the second housing piece (82) by insertion. The second housing piece (82) is shaped to fit within the first housing piece (81) and is inserted into the first housing piece (81). The second piece of housing (82) includes the entire reaction chamber (2), a minor portion of the upstream end of fluid outlet (6) and third fluid outlet (9), and the downstream ends of first fluid conduit (7) and second fluid conduit (8), each with its own nozzle (5) having a respective fluid inlet opening (see FIG. 10). The nozzles providing the fluid inlets are positioned at opposite positions on a first central axis (x) of reaction chamber (2) formed by inserting and securing second housing piece (82) into first housing piece (81). Fluid outlet (6) is positioned at a position located on a second central axis (y) of the reaction chamber 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 a lumen, and the lumens of the first fluid conduit (13) and the second fluid conduit (14) each have a longitudinal axis that coincides with the first central axis (x) of the reaction chamber and extend from an upstream end in fluid connection with the nozzle (5) to a downstream end, and the lumen (15) of the third fluid conduit has an upstream end and a downstream end, the upstream end coinciding with the fluid outlet (6) of the reaction chamber (2).Thus, a first fluid conduit (7) and a second fluid conduit (8) are arranged within the reactor (1) to direct a first fluid to the first fluid inlet and a second fluid to the second fluid inlet provided by the nozzle (5), and a third fluid conduit (9) is arranged to direct a third fluid downstream from the fluid outlet, the third fluid being formed by mixing or reaction of the first and second fluids within the reaction chamber (2).

[0197] Figure 21 shows a perspective cross-sectional view, not drawn to scale, of the first housing piece (81) of the housing (80) as shown in Figure 20. The first piece of the housing (81) comprises a major portion of each of the first and second fluid conduits (7) and (8), excluding the downstream ends of the conduits, and the first piece also comprises a major portion of the third fluid conduit (9), excluding the upstream end of the conduit that coincides with the fluid outlet (6) of the reaction chamber (2). As shown, the housing (81) comprises a cavity shaped and adapted to receive the second housing piece (82, not shown), and the molding also provides an insertion guide (91) for inserting the second housing piece (82) in a specific orientation relative to the first housing piece (81) to form the housing (80), as well as a rim / groove molding that corresponds to a snap-fit ​​or press-fit feature (98) that allows for securing to the second housing piece (82). The lumens (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 conduits (7, 8) also include connectors (97) that facilitate further connection to correspondingly shaped features, such as the end of a tube or another connector. The housing piece (81) also includes fastening means (96) in the form of a cavity shaped and adapted to receive complementary fastening means, such as a screw or a press-fit or snap-fit ​​peg (not shown), that can be used to secure the first housing piece (41) to the second housing piece (82, not shown).

[0198] Figure 22 shows a cross-sectional view, not drawn to scale, of the second housing piece (82) of the reactor housing (80) as shown in Figure 20. The housing piece (82) generally comprises the reaction chamber (2), the downstream ends of the first and second fluid conduits (7) and (8), the nozzle (5), and the respective fluid inlets (3, 4), the reaction chamber (2) being substantially spherical in shape and interrupted only by the first and second fluid inlets (3) and (4) and the fluid outlet (6), with only a minor portion of the upstream end of the fluid conduit (9) (i.e., less than 50% of the fluid path length) coinciding with the fluid outlet (6). The nozzle (5) is integral with the housing piece, and the diameters of the fluid inlets (3) and (4) are different, although in other embodiments, the diameters of the fluid inlets (3) and (4) may be the same. Also shown are snap or press fit features in the form of rim and groove mouldings adapted to mate with corresponding features on first housing piece (81) for securing (82) to housing piece (81).

[0199] Figure 23 shows a perspective view (not drawn to scale) of the second housing piece (82) of the housing (80) as shown in Figure 20. The housing piece (82) is shaped to be insertable into the first housing piece (81, not shown), and the molding also provides insertion guides (92) that allow the piece to be inserted in a specific intended orientation relative to said first housing piece (81) to form the housing (80). The housing piece (82) also includes snap-fit ​​or press-fit features (108) in the form of a rim and groove molding adapted to mate with corresponding features on the first housing piece (81) to secure the piece to the first housing piece (81). The housing (82) also includes fastening means (116), for example in the form of cavities adapted to receive screws, to secure the two housing pieces together to form the housing (80) of the jet impingement reactor (1).

[0200] The following examples serve to illustrate the present invention but should not be understood as limiting the scope of the invention. [Example]

[0201] Example 1 An impingement jet reactor according to the present invention was assembled from first and second pieces, as defined in the claims, both made from polymeric materials and fitted with connecting pieces as disclosed herein, and used to prepare model PLGA (lactic-co-glycolic acid, also known as polylactide-co-glycolide) nanoparticles. To assess reproducibility, three reactors (A, B, and C) with identical specifications were assembled and tested. As a further control and comparison, a jet impingement reactor fabricated from stainless steel and with the same specifications, as described in WO 2023 / 025736, was tested. Each reactor was connected to equipment providing the vessels, tubing, pumps, valves, pressure gauges, flow meters, and temperature gauges necessary to operate the reactor and produce nanoparticles. PLGA nanoparticles were prepared using essentially the same reactor geometry and process parameters, as shown in the table below. The dimensions provided are manufacturing specifications, not measurements. [Table 1]

[0202] The resulting nanoparticle samples were collected and immediately diluted with 0.1% polysorbate 20 (Tween® 20) in deionized water to a 10% solvent concentration. Dynamic light scattering (DLS) measurements were then performed to measure the particle size and polydispersity index (PDI) of the nanoparticle size distribution. DLS measurements were performed at a scattering angle of 90° using a Zetasizer Nano ZS90 (Malvern Panalytical). Each polymer reactor (A, B, C) and comparative stainless steel reactor (M) were run in triplicate.

[0203] Results: As shown in the graph featured in Figure 11, the polymer impinging jet reactor of the present invention was found to result in PLGA nanoparticles having particle sizes similar to those produced using stainless steel reactor M under the same specifications and conditions. The particles produced were also found to have a low PDI (polydispersity index), i.e., below the threshold of 0.2, indicating the production of high-quality nanoparticles with a narrow size distribution. Furthermore, the PLGA nanoparticles obtained from the three polymer reactors A, B, and C were found to have similar nanoparticle sizes and PDIs, indicating good reproducibility and robustness in the methods of manufacturing, adapting, and assembling these reactors.

[0204] Example 2 An impinging jet reactor according to the invention, assembled from first and second pieces as defined in the claims, made from a polymeric material and fitted with a connecting piece as defined in accordance with the invention, was used for the preparation of model liposomal nanoparticles. Compared to the model PLGA particles prepared in Example 1, liposomes are more complex in that they represent spheroidal vesicles composed of amphiphilic lipids, usually comprising at least one lipid bilayer surrounding an aqueous core.

[0205] To assess reproducibility, three reactors (A, B, and C—not the same test pieces as used in Example 1) with the same specifications were assembled and tested for liposome production. As an additional control and comparison, a jet impingement reactor described in WO 2023 / 025736 made from stainless steel with the same specifications was also tested in parallel. Each reactor was connected to equipment providing the vessels, tubing, pumps, valves, pressure gauges, flow meters, and temperature gauges necessary to operate the reactor and produce nanoparticles. Liposomes were prepared using essentially the same reactor geometry and process parameters, as shown in the table below. Again, the dimensions provided are manufacturing specifications, not measurements. [Table 2]

[0206] Each polymer reactor A, B, C and comparative stainless steel reactor M were run in triplicate at chamber temperature.

[0207] Liposome samples were collected and diluted immediately after production with PBS buffer (same as Fluid 2) to a concentration of 16.5% ethanol in the sample, followed by dynamic light scattering (DLS) measurements to measure particle size and particle size polydispersity index (PDI). DLS measurements were performed within 10 minutes after sample collection and dilution, with a scattering angle of 173° on a Zetasizer Ultra (Malvern Panalytical).

[0208] Results: As shown in the graph featured in Figure 12, the polymer impinging jet reactor of the present invention was found to result in liposome nanoparticles having similar small particle sizes to those produced using stainless steel reactor M under the same specifications and conditions. The particles produced were also found to have a low PDI (polydispersity index) of less than 0.1, indicating the production of high-quality nanoparticles with a very narrow size range distribution. Furthermore, the liposome nanoparticles produced by each of the three individual polymer reactors A, B, and C were found to have similar nanoparticle size and PDI, indicating good reproducibility and robustness with respect to the manufacture, fitting, and assembly of the reactor pieces. [Explanation of symbols]

[0209] 1. Jet Impingement Reactor 2. Reaction Chamber 3 First fluid inlet 4 Second fluid inlet 5 nozzles 6 Fluid outlet 7 First fluid conduit 8 Second fluid conduit 9 Third fluid conduit 121,171,181 First Piece 132,172,182 Second Piece 16 Part of the reaction chamber wall 21 First Gap 22 Second Gap 23 The Third Gap 24 upstream end of second piece 25 downstream end of second piece 28 Lumen of fluid conduit 29a Upstream part of lumen 29b Middle part of the lumen 29c Downstream of the lumen 31,319 Planar walls of reaction chamber 32,329 recesses 33,73,83 Connecting piece 34, 74, 84 Upstream end of connecting piece 35,75,85 Downstream end of connecting piece 744,844 Upstream part of connecting piece 755,855 Downstream part of connecting piece 36, 76, 86 Fluid conduit of connecting piece 37, 77, 87 Connectors or fittings for connecting pieces 38,78,88 Circular groove 39,79 O-ring seal 10,40,80 Housing 11,41,81 First housing piece 12,42,82 Second housing piece 13 Lumen of first fluid conduit 14 lumen of second fluid conduit 15 Lumen of third fluid conduit 51, 52, 91, 92, 109a, 109b Insertion guide 26,36,56,76,96,116 Fastening means 27,37,57,97 Connectors 98,108 Snap-fit ​​or press-fit mechanisms x First central axis y Second central axis

Claims

1. 1. A jet impingement reactor comprising a reaction chamber, the chamber having a substantially spherical shape, the spherical shape comprising: (a) first and second fluid inlets, the first and second fluid inlets being positioned at opposite positions on a first central axis of the reaction chamber such that the first and second fluid inlets face each other, each of the first and second fluid inlets being provided by a nozzle; (b) a fluid outlet disposed on a second central axis of the chamber, the second central axis being perpendicular to the first central axis; is interrupted by the reactor further comprises first, second and third fluid conduits, the first and second fluid conduits configured to direct a first fluid to the first fluid inlet and a second fluid to the second fluid inlet, and the third fluid conduit configured to direct a third fluid downstream from the fluid outlet, the third fluid being formed by the mixing or reaction of the first and second fluids in the reaction chamber; The reactor comprises at least two pieces secured to one another, a first piece of which is made from a polymeric material and comprises at least a portion of the first or second fluid conduit and at least a hemispherical portion of the reaction chamber, and a second piece of which is at least partially insertable into the first piece and comprises the fluid outlet.

2. 10. The reactor of claim 1, wherein the first piece is molded with a first void for receiving the second piece by insertion, and the second piece is molded and adapted to be insertable into the first void.

3. 3. The reactor of claim 1 or 2, wherein the first gap is cylindrical, columnar, or tapered.

4. the second piece comprises: an upstream end comprising the fluid outlet and a portion of the reaction chamber; - downstream end; - a third fluid conduit fluidly connecting said upstream end and said downstream end.

5. 5. The reactor of claim 1, wherein the second piece is fully insertable into the first cavity.

6. 6. The reactor of any one of claims 1 to 5, wherein the first piece is formed at least primarily from a thermoplastic polymer material, preferably comprising polytetrafluoroethylene (PTFE), polyamide, polycarbonate (PC), polyetheretherketone (PEEK), polyethylene (PE), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polyoxymethylene (POM), polyphenylsulfone (PPSF or PPSU), or polyetherimide (PEI).

7. 7. The reactor of claim 1, wherein the first and second fluid conduits each have a central longitudinal axis that coincides with the first central axis of the reaction chamber, and the third fluid conduit has a central longitudinal axis that coincides with the second central axis of the reaction chamber.

8. 8. The reactor of any one of claims 1 to 7, wherein the first and / or second fluid conduits have a lumen with an upstream portion and a downstream portion, the upstream portion being cylindrical or columnar and having a substantially larger diameter than the downstream portion.

9. 9. The reactor of claim 8, wherein the downstream portions of the first and second fluid conduits each have downstream ends that define or are coincident with the first and second fluid inlets, respectively.

10. 10. The reactor of claim 9, wherein the downstream sections are tapered toward their downstream ends.

11. 9. The reactor of any one of claims 1 to 8, wherein the downstream section is substantially cylindrical.

12. 12. The reactor of claim 1, wherein the lumen of each of the first and second fluid conduits further comprises an intermediate section between the upstream section and the downstream section, the intermediate section tapering toward the downstream section.

13. 13. The reactor of claim 12, wherein the tapered intermediate section and the tapered downstream section have different taper angles.

14. 14. The reactor of any one of claims 1 to 13, wherein the nozzle is provided by a downstream section.

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

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

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

18. 18. The reactor of any one of claims 1 to 17, wherein the first and second fluid inlets have diameters in the range of about 50 μm to about 600 μm.

19. 19. The reactor of any one of claims 1 to 18, wherein the diameter of the first fluid inlet is different from the diameter of the second fluid inlet.

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

21. 21. The reactor of 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 and the fluid outlet.

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

23. 23. The reactor of claim 22, wherein the planar wall is provided by the first piece as a protrusion on the first piece, and the second piece has a recess for receiving the protrusion.

24. 21. The reactor of any one of claims 1 to 20, wherein the spherical shape of the reaction chamber is interrupted only by at least two planar wall portions, each having an area that is independently smaller than an area of ​​the first and second fluid inlets, the fluid outlet, and the fluid outlet, and the first planar wall portion and the second planar wall portion are disposed at opposite positions on the first central axis of the reaction chamber.

25. 25. The reactor of claim 24, wherein the at least two planar walls are provided by the first piece as protrusions of the first piece, and the second piece has first and second recesses adapted to receive the protrusions.

26. 26. The reactor of any one of claims 1 to 25, wherein the first piece comprises a second cavity and a third cavity, each of the second cavity and the third cavity being shaped to receive a connecting piece for conducting the first fluid or the second fluid from an upstream fluid source to the first fluid conduit or the second fluid conduit, respectively.

27. 27. The reactor of claim 26, wherein the connecting piece has an upstream end, a downstream end, and a fluid conduit extending from the upstream end to the downstream end, and at least the downstream end is insertable into the second or third gap such that the fluid conduit of the connecting piece is in fluid communication with the lumen of the first or second fluid conduit of the reactor.

28. 28. The reactor of claim 27, wherein the upstream end of the connecting piece has a connector for securing a tube or pipe, such as a luer fitting or a barbed connector or fitting.

29. 29. The reactor of any one of claims 26 to 28, wherein the connecting piece features an outer circular groove at or near its downstream end for retaining an O-ring seal to seal the connecting piece to the first piece of the reactor.

30. 30. A first piece of a reactor according to any one of claims 1 to 29.

31. 31. A method of manufacturing a first piece 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 piece.

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

33. 32. The method of claim 31 , wherein the first and second fluid inlets are formed by a step of micro-drilling or laser drilling.

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

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

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

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

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