EP4065265A1

EP4065265A1 - Reactor and method for producing a formulation

Info

Publication number: EP4065265A1
Application number: EP20828848.0A
Authority: EP
Inventors: Christoph Englert; Marc Lehmann
Original assignee: Smartdyelivery GmbH
Current assignee: Smartdyelivery GmbH
Priority date: 2019-11-27
Filing date: 2020-12-11
Publication date: 2022-10-05
Also published as: DE102019218404A1; JP2023507713A; WO2021105971A1

Abstract

The invention relates to a reactor for producing a formulation, wherein the reactor comprises at least two ports, a base and at least one sidewall extending flush from same. The base and sidewall together define a mixing chamber with a height h_Μ and at least one axis of symmetry largely perpendicular to the base and disposed at least at a distance r from the sidewall. A first port is arranged in the base or at a height h_ö ranging from 0.6 to 0.0 h_M adjacent to the base in the sidewall of the mixing chamber to introduce flowable substances and/or substance mixtures into the mixing chamber. The first port is designed with an adjacent backflow preventer arranged therein or thereon, wherein the backflow preventer allows the introduction of flowable substances into the mixing chamber through the port, but prevents the escape of flowable substances out from the mixing chamber through the port. Furthermore, the first port is designed with a port area extending in a range between a minimum and a maximum, wherein the minimum area is 0.05 mm² and the maximum area is defined as a value determined from V_{mixing chamber}[cm³]/area_{first port} [cm²] ≈ 5500.

Description

REACTOR AND METHOD FOR PREPARING A FORMULATION

Field of invention

The invention relates to a reactor for producing a formulation according to the subject matter of claim 1, a reactor system according to the subject matter of claim 12 and a method for producing a formulation using a reactor system according to the subject matter of claim 15.

Technical background

Industrial processes that require effective stirring and mixing of fluids or of flowable substances are known from a wide variety of industrial sectors. These range from mining to hydrometallurgy, the petroleum industry, the food, pulp and paper industries, to the pharmaceutical and chemical industries. In general, the term “stirring” refers to a process in which mechanical means cause a fluid to move in a vessel. “Mixing”, on the other hand, describes a process in which two or more separate phases or fluids are randomly distributed into one another through the mixing process. Fluids can be stirred, for example to accelerate the mixing of two miscible fluids, to dissolve solids in liquids, to distribute gas in a liquid in the form of small gas bubbles, etc. The mixing of liquids in reaction vessels or reactors can, for example to obtain optimal operational conditions for chemical systems be important if such systems require, for example, a uniform temperature or a uniform substance concentration within the reactor.

There are no uniform requirements for the design of the reaction vessel for the various processes, since vessels of different designs often meet the specifications of the process. Standard reactors are usually used to simplify the design and minimize costs. Transferring the scale is often difficult when test results are to be transferred to large-scale systems on a laboratory scale (“upscaling”). Starting with small-scale test systems, gradually enlarged systems are built and tested, through pilot systems to the large-scale systems mentioned. While this approach represents a possibility of process development, which offers a relatively high transmission reliability with regard to suitable apparatus dimensioning and process conditions, it is disadvantageously associated with a high expenditure of time and costs. In the field of pharmaceutical nanotechnology, upscaling in the production of complex particles, such as multi-component, nanostructured carrier systems, is associated with considerable problems, especially when there are specifications regarding a defined particle composition and / or a defined particle size.

The present invention advantageously provides a reactor for the production of formulations which can be used in discontinuous production processes (“batch process”). In a discontinuous process, an amount of material limited by the capacity of a production vessel (e.g. reactor, mixer) is fed as a whole to the work system and removed from it as a whole after the production process has been completed. The reactor according to the invention for producing formulations, in particular formulations from the field of nanotechnology, advantageously offers the possibility of inexpensive and rapid upscaling compared with the prior art. The reactor according to the invention can also be used for the production of a large number of very different formulations.

Presentation of the invention, task, solution, advantages

In a first aspect, the invention relates to a reactor for producing a formulation, the reactor comprising at least two openings, a base and at least one side wall extending flush therefrom. The base and the side wall together define a mixing chamber with a height IΊM and at least one symmetry axis that is largely perpendicular to the base and at least a distance r from the side wall, with a first opening in the base or at a height ho in the range of 0, 6 to 0.0 IΊM is arranged adjacent to the base in the side wall of the mixing chamber in order to introduce flowable substances and / or mixtures of substances into the mixing chamber. The first opening is formed with a check valve arranged therein or adjacent thereto, the check valve allowing flowable substances to enter the mixing chamber through the opening, but preventing flowable substances from flowing out of the mixing chamber through the opening. The first opening is with one in an area between one Minimum and a maximum extending opening area formed, the minimum area at 0.05 mm ² and the maximum area at a value that is determined from V mixing chamber [cm ³ ] / area of first opening [OTI ² ] ^« 5500.

In the technical sense, a formulation is a mixture which consists of one or more active substances and auxiliaries and which is produced according to a recipe by mixing together defined amounts of ingredients. The formulation can, for example, be a medicinal substance, comprising low molecular weight substances, in particular inhibitors, inducers or contrast agents, or also higher molecular weight substances, in particular potentially therapeutically useful nucleic acids (e.g. short interfering RNA, short hairpin RNA, micro RNA, plasmid DNA) and / or proteins (eg antibodies, interferons, cytokines), the formulation can also be a varnish, a dispersion paint or a plastic. The mixing chamber for producing this formulation is defined by a base and the side wall that is flush with it. The base is not subject to any particular restrictions in terms of its shape. B. just complete the interior of the mixing chamber (training in the form of a plate), with respect to the interior convex or concave (training as a Ku gel segment), or be conical. Accordingly, the at least one side wall, which is flush with the base, can be delimited from the base or merge smoothly into the base; this can be the case, for example, with a largely round mixing chamber. The height IΊM of the mixing chamber is preferably calculated on the basis of the geometric center of gravity of the base. The term “geometric center of gravity” is understood to mean a particularly distinguished point which is mathematically calculated from the averaging of all points within the figure. The axis of symmetry of the mixing chamber, which is arranged at least ei nem distance r from the side wall, is in the operating state preferably in a vertical position with respect to a corresponding environmental coordinate system. A “backflow stop” is understood to mean a backflow preventer which only allows flow in one direction. A conventional backflow preventer closes automatically when the defined flow direction is reversed and also opens automatically when the flow direction is permitted. In its simplest form, the non-return valve can be a septum or a slotted membrane, e.g. B. a silicone membrane, or a puncture membrane, which, for example, after a Puncture closes. In an alternative embodiment, the non-return valve can be a valve in the narrower sense, in which a closure part (e.g. plate, cone, ball or needle) is moved approximately parallel to the direction of flow of a fluid and in which an interruption of the Flow occurs when the sealing surface of the closing part is pressed against a suitably shaped opening, the valve or sealing seat. The first opening arranged in the base or adjacent to the base in the side wall at the height is also not restricted in terms of its shape, preferably the opening is largely round, the first opening having a range between a minimum and a dimension ximum extending area is formed, the minimum being 0.05 mm ² . This area corresponds to the area of a cannula with an outer diameter of> 30 G (outer diameter <0.3 mm, with an area of 0.05 mm ² , outer diameter = 0.25 mm). The unit G (for "gauge") is borrowed from the US-American unit for the classification of wires; the corresponding outer diameters of the cannulas in millimeters are also standardized in EN ISO 6009. The higher the gauge, the smaller the outside diameter of the cannula. The area of the first opening is therefore dimensioned in the minimal area so that it can accommodate a cannula with an outer diameter of 0.25 mm. With increasing volume of the mixing chamber, the surface of the first opening is adjusted accordingly, so that the maximum area is a value [crn ^3] from VMischkammer / _e irst surface opening [cm ^2] ^"5500 is determined. In the case of large-scale implementations with mixing chambers of several hundred or thousand liters in volume, it may be expedient to distribute the area of the first opening over several openings, with these further openings expediently also in the base or at a height in the range of 0, 6 to 0.0 IΊM are arranged adjacent to the base in the side wall of the mixing chamber. The reactor designed in this way for the production of a formulation is advantageously easily scalable and enables the targeted introduction of flowable substances via the at least 2 openings.

In a preferred embodiment of the reactor, the first opening can be arranged adjacent to the base in the side wall of the mixing chamber at a height height in the range from 0.4 to 0.1 lm, preferably in the range from 0.25 to 0.15 hM.

In a further implementation of the reactor according to the invention, the side wall can be cylindrical. The reactor designed in this way largely corresponds to the reactors used in many industrial processes (“standard reactor”). These Form is characterized by its simple design, which means that costs can be minimized. Furthermore, conventional software applications can be used to calculate mixing processes for low-viscosity fluids without having to adapt the geometric parameters accordingly.

In an advantageous development, a feed pipe can be formed around the first opening on the side of the side wall facing away from the mixing chamber, the feed pipe being designed as a receiving connector with an end thread for receiving the non-return valve. The feed pipe can particularly advantageously be designed as a threaded closure with an internal thread. The feed tube can be largely adapted to the opening area of the first opening in terms of its base area. In this way, only a small amount of dead space is created in the area of the opening area of the first opening. The dimensioning of the feed tube, which is designed to accommodate the non-return valve, depends on the type of non-return valve to be received (for example screw-on cover with a piercing membrane / septum). When used on an industrial scale, it is advantageous to secure the non-return valve against inadvertent detachment from the opening. A feed tube designed with an internal thread can be designed, for example, as a conventional Luer system. A conventional Luer system is a standardized connec tion system for a combined use of syringes and infusion sets in the me medical field. A conventional cannula, for example, can be screwed over its edge into the female connector with the Luer internal thread, locked with the feed tube and thus secured against inadvertent loosening.

In an advantageous implementation, the first opening and the feed pipe can be dimensioned in relation to the mixing chamber in such a way that back-mixing of the flowable substance from the mixing chamber into the feed pipe is prevented. This is achieved in particular when the supply pipe has the smallest possible volume and is largely adapted to the area of the first opening in terms of its base area. This arrangement advantageously results in a small dead space volume (dead space volume), as a result of which the efficiency of the mixing process is increased (small proportion of areas with little to no mixing). In addition, only a small dead space has an advantageous effect with regard to the use of material.

In a further embodiment of the reactor according to the invention, the second opening can be used as a closable tube for the introduction and / or discharge of flowable Substances and / or mixtures of substances can be formed into / out of the mixing chamber of the reactor. In a particularly preferred implementation, the second opening can be designed as a tube arranged largely along the at least one axis of symmetry of the mixing chamber in the base. A tube arranged in this way in the base made possible the simple discharge of flowable substances and / or substance mixtures from the mixing chamber according to their gravity in conventional operation of the reactor. Such a tube can also be used for introducing flowable substances and / or mixtures of substances; This advantageously simplifies the manufacture of the reactor by reducing the openings to be introduced and the feed and discharge lines that may be connected to them.

In a further embodiment of the reactor, a further opening of the reactor can be arranged opposite the base. This embodiment is particularly advantageous if the second opening is designed as a tube for discharging flowable substances and / or mixtures of substances in the base, and if flowable substances and / or mixtures of substances to be introduced are introduced via the further, oppositely arranged (= "opposite") opening become.

In a preferred development, the mixing chamber can be designed with at least one deflector plate arranged on the side wall. A deflector plate is understood to mean a plate which, when mixing, causes a fluid flow to be interrupted along the side wall in the mixing chamber by stirring. Without a corresponding baffle plate, flowable substances are moved le diglich without mixing, especially at low stirring speed. A cylindrical “standard reactor”, as used in industrial processes and in many mathematical modeling and simulation processes (computational fluid dynamics), is normally designed with four deflection plates at a distance of 90 °.

In a further implementation of the reactor according to the invention, the formulation to be produced can be selected from the group comprising nanostructured carrier systems, polyxplex, nanoparticles, liposomes, micelles, microparticles. A “nanostructured carrier system” refers to a nanoscale structure that is smaller than 1 pm and can be made up of several molecules. Advantageously, formulations in the pm range can also be produced in the reactor according to the invention, for example microparticles. If the nanostructured carrier system comprises polymers, it can also be referred to as "nanoparticles", if it comprises lipids, as a "liposome" (a "micelle") In contrast to the liposome, it only has a simple lipid layer). The fiction, contemporary nanostructured carrier system comprises polymers and lipids and is used to transport ("carrier") of active ingredients and / or other molecules, such as. B. Antibodies or dyes. A polyplex is defined as a nanoparticulate carrier system, which consists of a cationic polymer (e.g. polyethyleneimine, PEI) and negatively charged genetic material, e.g. DNA or RNA, with the positive charges of the cationic polymer (e.g. protonated amino groups) interact with the phosphate groups of the genetic material during the assembly of the particle in such a way that the genetic material is protected. With the reactor according to the invention, particulate formulations with a particle size in the nm to pm Be can advantageously be produced. For example, using the reactor according to the invention, regardless of the size of the reactor or the mixing chamber of the reactor, particles of a defined size with only a small range of variance (approx. +/- 5 nm) can be reproducibly produced within a selected size range.

In a second aspect, the present invention relates to a reactor system for producing a formulation, comprising a reactor as described above ben and a stirring tool, wherein the stirring tool is arranged in the mixing chamber of the reactor that it is in operation in the flowable substance and / or a mixture of substances generates an axis of rotation which is largely congruent with the axis of symmetry of the mixing chamber. A stirring tool refers to a tool for mixing flowable substances or mixtures of substances. Conventional stirring tools generally include a shaft which can be set in rotation by a motor and to which stirring blades are often attached so that the rotation of the shaft directly causes the movement of the stirring blades. Alternatively, a stirring tool can also consist of a stirrer and a stirring drive which are not directly connected to one another, for example a magnetic stirring tool. In a further alternative, the mixing can take place via an ultrasonic stirring tool, the ultrasonic stirring tool being able to act on the flowable substance and / or the substance mixture directly within the mixing chamber or from outside the mixing chamber. Such stirring tools are known from the prior art. By means of the stirring tool, an axis of rotation is generated in the flowable substance and / or mixture of substances during operation (e.g. a stirred liquid rotates around an axis of rotation), an axis of rotation being a straight line that defines or describes a rotation or rotation. In a preferred development of the reactor system, the stirring tool can be selected from the group comprising axial flow mixers, radial flow mixers, magnetic mixers, dispersers. In practice, a distinction is made between “laminar” and “turbulent” stirring and mixing systems. The stirring tool according to the invention belongs to the turbulent stirring and mixing systems which include, for example, propeller, turbine, disc, basket (or cyclone), bar and / or cross bar stirrer. Among the different types of mixers that generate a turbulent flow, a distinction is made between axial flow mixers and radial flow mixers. In a radial flow mixer, the flowable substance (hereinafter: fluid) is moved radially by the impeller (s) against the side wall, with the fluid flow splitting along the wall and approx. 50% of the fluid flow in one direction (towards the surface) and the rest circulates in the opposite direction (towards the ground). The speed of the fluid is highest in the immediate vicinity of the impeller along a horizontal line which runs through the center of the impeller. The group of radial flow mixers includes, for example, the Rushton turbine with straight agitator blades and turbines with curved agitator blades. In the axial flow mixer, the fluid is moved in the axial direction Rich, ie parallel to the stirrer shaft; overall, the fluid is pumped through the stirrer. The fluid flow is directed towards the bottom by the agitator blades, where it splits in the radial direction in order to rise in the vicinity of the side wall. The group of axial flow mixers includes, for example, propellers of the ship's propellers type. Magnetic mixers cause both radial and axial movement of the fluid in low-viscosity fluids, depending on the vessel geometry. According to the invention, the magnetic mixer is operated in such a way that it generates an axis of rotation during operation which is largely congruent with the axis of symmetry of the mixing chamber. The term “dispersing” means the mixing of at least two substances that do not or hardly dissolve in one another or that combine chemically with one another. During the dispersing process, the disperser distributes one substance (disperse phase) in another substance (continuous phase); the disperser according to the invention is preferably based on the rotor-stator arrangement. The rotor causes the fluid to be sucked axially into the head of the disperser, deflected therein and pressed radially through the slots of the rotor-stator arrangement. The acceleration forces act on the material with very strong shear and shear forces. In addition, the tower mixes bulence in the shear gap between rotor and stator is the suspension or emulsion. In accordance with the invention, the disperser is operated in such a way that, during operation, it generates an axis of rotation which is largely congruent with the axis of symmetry of the mixing chamber.

In a preferred development of the reactor system, this can furthermore comprise an insertion aid and / or pumping device connected to the first opening and / or the feed pipe. The insertion aid is used to supply flowable substances into the mixing chamber and can, for example, be designed as an injection syringe. The supply of flowable substances can be precisely regulated with regard to time and quantity via a pump device. Such insertion aids and / or pump devices (also: syringe pump, metering pump, perfusor) are known from the prior art.

In a third aspect, the invention relates to a method for producing a formulation, comprising the following steps: in a first step (a) a first fluid is added to a mixing chamber of a reactor system as described above. Preferably, after the addition, the first fluid completely covers the opening area of the first opening. The first fluid is then mixed to generate a vortex. In fluid mechanics, a vortex or vortex is a rotating movement of fluid elements around a straight or curved axis of rotation. In accordance with the invention, a vortex or vortex can be created by a variety of available techniques. In a third step, a second fluid is supplied to the first fluid from a reservoir. In this case, a substance or a substance mixture is dissolved in the second fluid, which is largely insoluble in the first fluid, while the second fluid dissolves completely in the first fluid, the second fluid being supplied to the mixing chamber via the first opening that the second fluid enters the first fluid in the region of the vortex in which the velocity of the fluid elements is highest.

The term fluid refers to substances that continuously deform under the influence of shear forces; In physics, this term is used to summarize gases and liquids. In connection with the invention, the first fluid is a liquid, preferably an aqueous solution; According to the invention, the second fluid is also preferably a liquid in which a substance or a substance mixture is homogeneously distributed which is largely insoluble in the first fluid. Preferably, the method of making a formulation is one Precipitation reaction (precipitation), where in a precipitation reaction the reactants are dissolved in the solvent and at least one product of the reaction is insoluble or sparingly soluble in this solvent and precipitates out as a precipitate. Particularly preferred is the precipitation reaction, a so-called nanoprecipitation, ie the precipitated structures are so small that one can speak of micro- or even nanoparticulate structures. These structures can be recognized or even invisible to the eye in the form of a cloudiness. This process is known as nanoprecipitation.

The reservoir according to the invention can be an insertion aid (for example an injection syringe connected to a cannula), which in turn can be connected to a pump device.

The process according to the invention allows the efficient production of a formulation in the discontinuous “batch” process, the process being scalable in a simple manner in accordance with the reactor system selected and enabling production on a small and large-scale industrial scale.

In an advantageous development of the method, a stirring tool with stirring blades can be used in step b to generate the vortex in the first fluid.

In a further embodiment of the method, in step c, the second fluid can enter the first fluid in the area of the agitating tool in which vtip is highest, where: vti _P oc pNϋ, with vti _P = speed at the tip of the respective agitating fluid gels, N = agitation speed in RPM (RPM = rounds per minute) and D = propeller diameter of the stirring tool. By adding in the area of the highest shear (maximum shear occurs in the area of the highest speed, i.e. at the tip of the impeller), a high initial shear load is applied to the added substances or mixtures of substances. Particularly for the production of nanostructured carrier systems, the particle size of the nanostructured carrier systems can advantageously be set precisely by defining the number of passages through the region of high shear stress in the vicinity of the impeller tip.

In a preferred implementation of the method according to the invention, the second fluid can be supplied via a pump device. This type of supply light advantageously enables precise control with regard to the point in time and the amount of the fluid supplied. In a further embodiment of the method, the formulation to be produced can be selected from the group comprising nanostructured carrier systems, polyplex, nanoparticles, liposomes, micelles, microparticles.

Brief description of the figures

In the following, some special embodiments of the invention are described by way of example and not in an exhaustive manner with reference to the accompanying figures.

The particular embodiments are only used to explain the general inventive concept, but they do not limit the invention.

FIG. 1 shows a schematic view of the reactor according to the invention.

FIG. 2 shows a detailed view of the reactor according to the invention in the area of the first opening.

FIG. 3 shows an alternative embodiment of the reactor with an introduced stirring tool.

FIG. 4 shows in tabular form the properties of various formulations (here: nanostructured carrier systems) which were produced in different sizes with the reactor according to the invention.

Preferred embodiment of the invention

In Figure 1, the reactor (1) for producing a formulation is shown. The reactor (1) comprises a mixing chamber (2) which is defined by a base (3) and at least one side wall (4) extending flush therefrom. The mixing chamber (2) is characterized by a height IΊM (vertical dotted line) and an axis of symmetry (5, dash-dot line) arranged in the present embodiment perpendicular to the base (3) at a distance r (horizontal dotted line) from the side wall (4) Line). In the present case, the mixing chamber (2) is largely designed as a cylinder (basically corresponding to a "standard reactor"), with the base (3) as a convex spherical segment with a centrally arranged flat (6) with regard to the interior of the mixing chamber (2) is trained. A first opening (7) is formed in the side wall (4) at a height of 0.18 hM adjacent to the base (3) and is used to introduce flowable substances and / or mixtures of substances into the mixing chamber (2). The first opening (7) is in a range between a minimum and a maximum extending opening area formed. The minimum area of the first opening (7) is 0.05 mm ² , corresponding to the area of a conventional cannula with an outer diameter of 0.25 mm. As part of a scaling process, the opening area can be adapted to the volume of the mixing chamber, the maximum area being a value determined from V mixing chamber [cm ³ ] / area of first opening [cm ² ] «5500. The first opening (7) is formed with a feed pipe (8). The reactor (1) also has a second opening (9) which is arranged in the centrally arranged flat (6) of the base (3) along the axis of symmetry (5) of the mixing chamber (2) and is designed as a closable tube. In conventional operation of the reactor, the tube can be used to simply discharge flowable substances and / or substance mixtures from the mixing chamber (2) according to their gravitational force, but flowable substances and / or substance mixtures can also be introduced via the tube. In the present case, the pipe adjoining the second opening (9) has a branch (10) via which reaction products can be separately discharged. The reactor (1) is formed with a third opening (11) opposite the base (3), which in the present embodiment is closed with a cover (12). For example, further flowable substances and / or substance mixtures and / or tools such as a stirring tool (13) can be introduced into the mixing chamber (2) via the third opening (11). Conventional stick mixers from the group of axial flow mixers, radial flow mixers, dispersers can be used as stirring tools; alternatively, mixing can also be carried out using a magnetic stirrer (13, shown here) or other stirrers which can be operated without a stirrer shaft. In the case of a magnetic stirrer, for example, no shaft is required because a rotating magnetic field acting from the outside on the stirring rod located in the mixing chamber drives the stirrer. The lid (12) arranged over the third opening (11) enables a formulation to be opened under defined ambient conditions, with measuring devices such as a thermometer or a pFH meter being inserted into the mixing chamber (14, 15, 16) through additional openings (14, 15, 16). 2) can be introduced.

The detailed view shown in FIG. 2 is limited to the area of the first opening (7) of the reactor shown in FIG. 1, which is formed with a feed pipe (8) arranged in the area adjacent to the opening. The first opening (7) is z with a diameter. B. formed according to a cannula diameter, for example 11 G (3.0 mm); the feed pipe (8) arranged around the first opening (7) is in With respect to the mixing chamber (2), it is dimensioned in such a way that back-mixing of the liquid from the mixing chamber (2) into the feed pipe (8) is prevented. With this arrangement, the dead space volume (dead space volume) is kept as low as possible, which increases the efficiency of the mixing process. Likewise, the amount of material available for the mixing process, which is fed via the first opening, is kept as low as possible, so that the formulation can be produced inexpensively. The feed pipe (8) is designed with a terminal external thread (not shown in FIG. 2). Via the external thread, the non-return valve according to the invention can seal off the first opening (7) and thus the mixing chamber (2) with respect to the environment. In the embodiment shown, the non-return valve is designed as a screw cap (18) which can be screwed to the external thread (17) of the feed pipe (8) via its internal thread. The non-return valve also comprises a puncture membrane (19), which is preferably made of an elastic material (e.g. bromobutyl rubber), so that self-sealing is ensured after piercing with a needle.

FIG. 3 shows an alternative embodiment of the reactor with an introduced stirring tool. The stirring tool (13) shown is a rod stirrer introduced through the opening 15 with an agitator shaft (13a), which is advantageously arranged along the axis of symmetry (5) of the mixing chamber (2) of the reactor (1). At the end of operation of the agitator shaft (13a) there are agitator blades (13b); For example, it can be a radial flow mixer or an axial flow mixer. A second fluid (not shown) is added to the first fluid (not shown) in the mixing chamber (2) through the first opening (7) via a screw cap (18) with a puncture membrane (not shown). The addition takes place in the area of the agitator blades (13b) of the agitator tool (13). The speed of the fluid elements is highest in the area of the vortex generated in the first fluid by the stirring tool (13). Further measuring instruments or probes (for example temperature / pFI probes) can be introduced via the further openings (14, 16) of the cover (12); a temperature probe inserted into opening (14) is shown here as an example.

FIG. 4 shows, in tabular form, properties of various formulations (here: nanostructured carrier systems) which were produced with reactors according to the invention in different sizes (500 ml, 2 l). The nanostructured carrier systems were investigated with regard to particle size and polydispersity index (PDI). The Z-Average indicates the mean particle diameter, which is based on the intensity distribution of the scattered light signal; the polydispersity evaluates the breadth of the distribution. Statistically, the z-average is an intensity-based average total that is based on a specific fit to the data of the raw correlation function. The fit is also known as the cumulative method and can be viewed as a forced fit of the result to a simple Gaussian distribution where the z-average is the mean and the PDI is related to the width of this simple distribution (assuming a single mean). Particle sizes varied in the range from 78 to 160 nm, it being possible, for example, to achieve desired particle sizes of approx. 160 nm in both the 500 ml and the 2 l reactor. With regard to the width, all the nanostructured carrier systems produced were, as desired, with a polydispersity index of <0.2. Accordingly, all formulations were characterized by an excellent homogeneity of the particles produced, regardless of the size of the reactor used.

List of reference symbols

1 reactor

2 mixing chambers (with height hwi)

3 base

4 side wall

5 axis of symmetry

6 centrally located flattening of the base

7 first opening (with height height)

8 feed tube

9 second opening

10 junction

11 third opening

12 lids

13 stirring tool

13a agitator shaft

13b impeller

14 Lid opening

15 Lid opening

16 Lid opening

17 External thread of the feed tube

18 screw caps

19 puncture membrane

20 Introducer

Claims

Expectations

1. Reactor for producing a formulation, wherein the reactor comprises at least two openings, a base and at least one side wall extending flush therefrom, wherein the base and the side wall together form a mixing chamber with a height IΊM and at least one largely perpendicular to the base and at least a distance r from the side wall defined axis of symmetry, wherein a first opening in the base or at a height ho in the range of 0.6 to 0.0 hM adjacent to the base in the side wall of the mixing chamber is arranged for flowable substances and / or mixtures of substances into the mixing chamber, and wherein the first opening is designed with a non-return valve arranged therein or adjacent thereto, the non-return valve allowing flowable substances to be introduced into the mixing chamber through the opening, flowable substances to flow out of the However, mixing chamber prevented through the opening, and wherein d The first opening is formed with an opening area extending in a range between a minimum and a maximum, where the minimum area is 0.05 mm ² and the maximum area is a value that is derived from the mixing chamber [cm ³ ] / area _e First opening [cm ² ] «5500 determined.

2. Reactor according to claim 1, wherein the first opening is arranged at a height height in the range from 0.4 to 0.1 hM, preferably in the range from 0.25 to 0.15 hM, adjacent to the base in the side wall of the mixing chamber.

3. Reactor according to one of claims 1 or 2, wherein the side wall is cylindrical.

4. Reactor according to one of the preceding claims, wherein on the side facing away from the mixing chamber of the side wall around the first opening to a guide tube is formed, wherein the supply tube is designed as a receiving connector with a terminal thread for receiving the backflow stop.

5. Reactor according to claim 4, wherein the feed pipe is designed as a threaded closure with egg nem internal thread.

6. Reactor according to one of claims 4 or 5, wherein the first opening and the feed pipe are dimensioned in relation to the mixing chamber so that back-mixing of the flowable substance from the mixing chamber into the feed pipe is prevented.

7. Reactor according to one of the preceding claims, wherein the second opening is designed as a closable tube for the entry and / or discharge of flowable substances and / or mixtures of substances into / from the mixing chamber.

8. Reactor according to claim 7, wherein the second opening is designed as a pipe angeord largely along the at least one axis of symmetry of the mixing chamber in the base.

9. Reactor according to one of the preceding claims, wherein a further opening of the reactor Publ is arranged opposite the base.

10. Reactor according to one of the preceding claims, wherein the mixing chamber is formed with at least one baffle arranged on the side wall.

11. Reactor according to one of the preceding claims, wherein the formulation to be produced is selected from the group comprising nanostructured carrier systems, polyplex, nanoparticles, liposomes, micelles, microparticles.

12. Reactor system for producing a formulation, comprising a reactor according to one of claims 1 to 11, and a stirring tool, wherein the stirring tool is arranged in the reactor that it generates an axis of rotation in the flowable substance and / or mixture of substances during operation, which is largely congruent with the axis of symmetry of the mixing chamber.

13. Reactor system according to claim 12, wherein the stirring tool is selected from the group comprising axial flow mixers, radial flow mixers, magnetic mixers, dispersers.

14. Reactor system according to claim 12 or 13, further comprising an insertion aid and / or pumping device connected to the first opening and / or the feed pipe.

15. A method for producing a formulation, comprising the steps of a. Adding a first fluid to a mixing chamber of a reactor system according to one of claims 12 to 14, b. Mixing the first fluid to create a vortex, c. Feeding a second fluid from a reservoir to the first fluid, where in the second fluid a substance or a substance mixture is dissolved which is largely insoluble in the first fluid, while the second fluid dissolves completely in the first fluid, the second fluid is supplied via the first opening of the mixing chamber in such a way that the second fluid enters the first fluid in the region of the vortex in which the velocity of the fluid elements is highest.

16. The method according to claim 15, wherein in step b a stirring tool with Rührflü geln is used to generate the vortex in the first fluid.

17. The method according to claim 16, wherein in step c the second fluid in the Be rich of the stirring tool enters the first fluid, in which the following applies: vtip oc pNϋ, where vti _P = speed at the tip of the respective impeller, N = agitation speed , D = propeller diameter of the stirring tool.

18. The method according to any one of claims 15 to 17, wherein the second fluid is supplied via a pump device.

19. The method according to any one of claims 15 to 18, wherein the formulation to be produced is selected from the group comprising nanostructured carrier system, polyplex, nanoparticles, liposomes, micelles, microparticles.