Reactor and method for producing formulation

Abstract

To provide a cost-effective, easy-to-scale-up reactor for the preparation of formulations in a batch process.SOLUTION: There is provided a reactor 1 comprising at least two ports and a mixing chamber 2, wherein the mixing chamber has a height hM and a substantially perpendicular axis of symmetry 5, and wherein the first port 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 into the mixing chamber, and wherein the first port has a backflow prevention device located inside or adjacent to the top of the mixing chamber, and wherein the backflow prevention device allows the substance to flow into the mixing chamber through the port, but prevents the substance from flowing out of the mixing chamber through the port, and wherein the first port is designed with a port area extending in a range between a minimum and a maximum, where the minimum area is 0.05 mm2 and the maximum area is defined as the value determined from Vmixingchamber [cm3 ] / areafirstport [cm2 ]≒5500.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to a reactor for preparing a formulation according to the subject matter of claim 1, to a reactor system according to the subject matter of claim 12 and to a method for preparing a formulation using the reactor system according to the subject matter of claim 15. [Background technology]

[0002] Industrial processes are known in a wide variety of industrial sectors that require effective stirring and mixing of fluids or free-flowing substances. These sectors range from mining, hydrometallurgy, petroleum, food, pulp and paper to pharmaceutical and chemical industries. In general, the term "stirring" refers to processes in which the movement of fluids in a vessel occurs by mechanical means. "Mixing", on the other hand, refers to processes in which two or more separate phases or fluids are randomly distributed with respect to each other. Fluids may be stirred, for example, to accelerate the mixing of two miscible fluids, to dissolve solids in a liquid, to disperse gas in a liquid in the form of fine bubbles, etc. For example, mixing of liquids in a reaction vessel or reactor may be important in chemical systems to provide optimal operating conditions, for example, when the chemical system requires a uniform temperature or a uniform concentration of substances in the reactor.

[0003] There is no uniform requirement for reactor design for different processes, because different shapes of vessels often match the process requirements. Usually, standard reactors are used to simplify the design and minimize costs. When transferring laboratory-scale experimental results to industrial-scale systems ("scale-up"), the adjustment of scale is often difficult. Starting from small-scale pilot equipment, reactors of increasing size are constructed and tested, from pilot plants to the above-mentioned industrial-scale systems. While this approach is a representative approach for process development that offers a relatively high transferability in terms of equipment dimensioning and process conditions, it has the disadvantage of being time-consuming and expensive. In the field of pharmaceutical nanotechnology, the scale-up process of the production of complex particles, such as multi-component nanostructured carrier systems, is associated with significant problems, especially when defined particle composition and / or particle size are required.

[0004] The present invention advantageously provides a reactor for preparing formulations, which can be used in discontinuous manufacturing processes ("batch processes"). In discontinuous processes, substances are fed into the system in an amount limited by the volume of the manufacturing vessel (e.g., reactor, mixer) and removed from the system at the completion of the manufacturing process. The reactor for preparing formulations according to the present invention, especially the reactor for preparing formulations in the nanotechnology field, advantageously offers the possibility of cost-effective and rapid scale-up compared to known reactors of the prior art. The reactor according to the present invention can further be used for the manufacture of a variety of different formulations. Summary of the Invention

[0005] Objects, Solutions, and Advantages of the Invention In a first aspect, the present invention relates to a reactor for preparing a formulation, the reactor comprising at least two apertures, a base, and at least one sidewall extending flush from the base. The base and the sidewall together define a mixing chamber, the mixing chamber having a height h Mand at least one axis of symmetry substantially perpendicular to the base and disposed at least a distance r from the sidewall, and the first aperture is disposed within the base or adjacent the base and at least a distance r from the sidewall of the mixing chamber for introducing free-flowing substances and / or mixtures into the mixing chamber. M The height of the range h A The first aperture is configured with a check valve disposed therein or adjacent thereto that allows free flowing material to flow through the aperture into the mixing chamber but prevents free flowing material from flowing out of the mixing chamber through the aperture. The first aperture is formed to have an aperture area that extends between a minimum and a maximum, the minimum area being 0.05 mm 2 and the maximum area is the volume 混合室 [cm 3 ] / area 第1の開孔部 [cm 2 ] ≒ 5500.

[0006] Technically, a formulation is defined as a mixture containing one or more active ingredients and excipients, and the formulation is prepared by mixing the ingredients in defined amounts according to the formulation recipe. The formulation may be a drug, for example a low molecular weight substance, in particular an inhibitor, an inducer or an imaging agent, or a high molecular weight substance, in particular a drug containing nucleic acids (e.g. small interfering RNA, short hairpin RNA, microRNA, plasmid DNA) and / or proteins (e.g. antibodies, interferons, cytokines) that may be therapeutically useful, and the formulation may be a varnish, an emulsion paint, or a synthetic substance. The mixing chamber for preparing this formulation is defined by a base and a side wall flush with it. The base is not particularly limited with respect to its shape. For example, the base may close the interior of the mixing chamber in the form of a flat plate, may present a convex or concave shape with respect to the interior of the mixing chamber (if formed as a part of a sphere), or may be conical. Thus, at least one side wall that ends flush with the base may be bounded from the base or may transition smoothly to the base. The latter situation may occur, for example, when moving to a substantially circular mixing chamber. Mis preferably calculated based on the geometric center (centre of gravity) of the base. The term "geometric center" refers to a defined point in a plan view which is the arithmetic mean position of all points in the view. The axis of symmetry of the mixing chamber, located at least a distance r from the side wall, is in a vertical position with respect to the corresponding geographic coordinate system during operation. The term "non-return valve" refers to a valve (backflow prevention device) that prevents backflow, allowing flow in only one direction. A typical backflow prevention device automatically closes when reversing from a given flow direction and automatically opens to allow flow in the permitted direction. In its simplest design, a non-return valve may be a diaphragm, or a membrane with a slit, e.g. a silicone membrane, or a puncturable membrane that closes (sealed) after puncturing. In an alternative embodiment, the non-return valve may be a valve in the narrower sense, where a closure member (e.g. a plate, cone, ball or needle) moves substantially parallel to the direction of fluid flow and the flow is blocked when the sealing surface of the closure member is pressed into a valve seat, which is an aperture of suitable shape. In the base or at a height h A The first aperture, which is disposed in the sidewall adjacent to the base at 0.05 mm 2 , is also not limited as to its shape. Preferably, the first aperture is substantially circular and is formed to have an area extending in a range between a minimum and a maximum value, the minimum being 0.05 mm 2 . 2 This area is for diameters greater than 30G (i.e., diameter ≦0.3 mm, surface area 0.05 mm 2 , outer diameter = 0.25 mm). The unit G (for "gauge") corresponds to the unit of the American wire gauge classification. The respective outer diameter in millimeters of the cannula is also standardized in the European standard EN ISO 6009. The higher the gauge number, the smaller the outer diameter of the cannula. The area of ​​the first aperture is therefore minimally dimensioned to allow the insertion of a cannula with an outer diameter of 0.25 mm through the aperture. As the volume of the mixing chamber increases, the maximum area increases accordingly. 混合室 [cm 3 ] / area 第1の開孔部 [cm 2For industrial-scale plants with mixing chambers with volumes exceeding hundreds or thousands of liters, it may be advantageous to distribute the area of ​​the first aperture among several apertures. These further apertures may also be located adjacent to the base, in the base or on the side walls of the mixing chamber, with an area of ​​0.6 to 0.0 h. M The height of the range h A Advantageously, a reactor for preparing the formulation so designed can be easily scaled and allows the intended introduction of free-flowing substances through at least two openings.

[0007] In a further embodiment of the reactor, the first aperture is adjacent to the base and has a diameter of 0.4 to 0.1 h. M in the range of 0.25 to 0.15 h M The height of the range h A The mixing chamber may be provided with a side wall.

[0008] In a preferred implementation of the reactor according to the invention, the side wall may be cylindrical. Reactors designed in this way usually correspond to reactors used in many industrial processes ("standard reactors"). This type of reactor is advantageously characterized by a simple design that allows costs to be kept to a minimum. Furthermore, standard software applications can be used to calculate the mixing operations of low-viscosity fluids without the need to adjust the respective geometric parameters.

[0009] In a preferred embodiment, the supply conduit can be arranged around the first aperture on the side of the side wall facing away from the mixing chamber. The supply conduit is designed as a receiving connector with a terminal thread for receiving the check valve. In a particularly advantageous embodiment, the supply conduit can be designed as a screw-on closure with a female thread. The supply conduit can be aligned with the aperture face of the first aperture with respect to its lower end. This type of alignment results in only a small volume of dead space in the vicinity of the aperture face area of ​​the first aperture. The dimensioning of the supply conduit designed to insert the check valve depends on the type of check valve (e.g. a screw-on lid with a pierceable membrane / septum). When used in industrial-scale applications, it is advantageous to ensure that the check valve is not inadvertently removed from the respective aperture. The supply conduit with a female thread can be designed, for example, as a conventional Luer system. The conventional Luer system is a standardized connection system to which syringes and infusion sets can be easily connected in the medical field. For example, a regular cannula may be threaded by its end with a receiving connector having a female Luer thread, thereby locking it to the supply conduit and thus securing it against inadvertent removal.

[0010] In a further implementation, the first aperture and the supply conduit can be dimensioned relative to the mixing chamber so as to prevent back-mixing of the free-flowing material from the mixing chamber into the supply conduit. This is achieved in particular when the supply conduit has the smallest possible volume and its lower end is substantially aligned with the aperture face of the first aperture. In this arrangement, the volume of dead space (interstitial volume) created is advantageously small, thereby increasing the efficiency of the mixing process (i.e. there are only a small proportion that is hardly or not mixed at all). Furthermore, a small volume of dead space is advantageous with regard to the efficient use of material.

[0011] In a further embodiment of the reactor according to the invention, the second aperture may be arranged as an openable conduit for introducing and discharging free-flowing substances and / or substance mixtures into and from the mixing chamber of the reactor. In a particularly preferred embodiment, the second aperture may be arranged as a conduit positioned at the base of the mixing chamber substantially along at least one axis of symmetry of the mixing chamber. During normal operation of the reactor, such a conduit arranged at the base allows easy drainage by gravity of the free-flowing substances and / or substance mixtures from the mixing chamber. Such a conduit may also be utilized for introducing free-flowing substances and / or free-flowing substance mixtures. Thus, by limiting the number of apertures to be incorporated and the possible inlets and outlets to be attached thereto, the manufacture of the reactor is advantageously simplified.

[0012] In a preferred embodiment of the reactor, the further opening of the reactor can be arranged on the opposite side to the base. This embodiment is particularly advantageous if the second opening is formed in the base as a conduit for discharging the free-flowing substances and / or mixtures and if the free-flowing substances and / or mixtures are introduced via the further opening arranged on the opposite side.

[0013] In further embodiments, the mixing chamber may include at least one baffle plate disposed along the side wall. A "baffle plate" refers to a plate that interrupts the flow of fluid along the side wall of the mixing chamber during mixing by stirring. Without a suitable baffle plate, especially at low stirring speeds, the free-flowing material simply moves and does not actually mix. A cylindrical "standard reactor" used in industrial processes and many computational fluid dynamics modeling techniques typically has four baffles spaced 90° apart.

[0014] In a further embodiment of the reactor according to the invention, the formulation prepared may be selected from the group comprising nanostructured carrier systems, polyplexes, nanoparticles, liposomes, micelles, microparticles. "Nanostructured carrier systems" refers to nanoscale structures of less than 1 μm that may be composed of multiple molecules. In the reactor according to the invention, formulations in the μm range, such as microparticles, may also be advantageously prepared. When the nanostructured carrier system comprises a polymer, it may be called a "nanoparticle", and when it comprises a lipid, it may be called a "liposome" (in contrast to liposomes, "micelles" are characterized by a lipid monolayer). The nanostructured carrier systems of the invention comprise polymers and lipids and have the function of transporting ("carrying") active ingredients and / or other molecules, such as antibodies or dyes. Polyplexes are defined as nanoparticle carrier systems that are essentially composed of cationic polymers (e.g., polyethyleneimine, PEI) and negatively charged genetic material, e.g., DNA or RNA, where the positive charges of the cationic polymer (e.g., protonated amino groups) interact with the phosphate groups of the genetic material during particle assembly, thus protecting the genetic material. Using the reactor according to the invention, particulate formulations with particle sizes in the nm-μm range can be prepared. By utilizing the reactor according to the invention, particles of defined dimensions can be reproducibly prepared within a given size range, regardless of the dimensions of the reactor or the mixing chamber of the reactor, and the particles exhibit a small variation (approximately + / - 5 nm).

[0015] In a second aspect, the present invention relates to a reactor system for preparing a formulation, comprising a reactor as described above and a stirring tool, the stirring tool being arranged in the reactor such that during operation it generates an axis of rotation in the free-flowing substance and / or mixture, which axis of rotation substantially coincides with the axis of symmetry of the mixing chamber. In this specification, the term "stirring tool" refers to a device for mixing a free-flowing substance or substance mixture. Conventional stirring tools generally comprise a shaft rotatable by a motor, most often a shaft on which an impeller blade is attached, so that the rotation of the shaft directly influences the movement of the impeller blade. However, alternatively, the stirring tool may also consist of a stirrer and a stirring drive that are not directly connected to each other (e.g., a magnetic stirrer). As a further alternative, stirring may be achieved by utilizing an ultrasonic stirrer, which acts on the free-flowing substance and / or substance mixture from either inside or outside the mixing chamber. Such stirring tools are known in the prior art. During operation, the stirring tool generates an axis of rotation in the free-flowing substance and / or mixture thereof (e.g., the stirred liquid rotates about the axis of rotation). Here, a rotation axis is a line that defines or describes rotational motion.

[0016] In a preferred embodiment of the reactor system, the stirring tool may be selected from the group comprising axial mixers, centrifugal mixers, magnetic mixers, dispersers. In practice, a classification 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, propellers, pitched blade turbines, disk-type flat blade turbines (Rushton impellers) and curved blade turbines. Among the various types of mixers that generate turbulence, a further classification is made between axial mixers and centrifugal mixers. In centrifugal mixers, the free-flowing material (hereinafter fluid) is driven radially towards the side wall by an impeller, the fluid flow is divided along the wall, and about 50% of the fluid is circulated in one direction (towards the surface) while the rest is circulated in the opposite direction (towards the bottom). The velocity of the fluid is highest in the immediate vicinity of the impeller along a horizontal line passing through the center of the impeller. The group of centrifugal mixers includes, for example, Rushton turbines with straight impellers and turbines with curved impellers, as mentioned above. In an axial mixer, the fluid is driven axially, i.e. parallel to the impeller axis. In general, the fluid is pushed by the impeller blades. The flow is directed by the impeller to the bottom of the reactor, where it splits radially and rises near the side wall. Axial mixers include, for example, marine propellers. In low-viscosity fluids, the magnetic stirrer induces both radial and axial movements of the fluid as a function of the geometry of the vessel. The magnetic stirrer according to the invention operates to generate an axis of rotation that, during operation, substantially coincides with the axis of symmetry of the mixing chamber. A "disperser" disperses a substance (dispersed phase) in another substance (continuous phase) in the process of dispersion. The disperser according to the invention is preferably of rotor-stator configuration. The term "disperse" is understood to refer to the mixing of at least two substances that are not (or barely) soluble in each other or do not chemically bond. During operation of the disperser rotor, the fluid is drawn axially into the disperser head, redirected within the head, and forced radially through slots in the rotor-stator assembly. The acceleration forces impart very strong shear and thrust forces to the material.Also, the turbulence generated in the gap between the rotor and the stator mixes the suspension or emulsion being dispersed. The disperser according to the invention operates so as to generate an axis of rotation which, during operation, substantially coincides with the axis of symmetry of the mixing chamber.

[0017] In a further implementation of the reactor system, the system may further comprise an introduction device and / or a pump device connected to the first aperture and / or the supply conduit. The introduction device may be utilized to supply the free-flowing substance to the mixing chamber and may be configured as a conventional syringe. Advantageously, the pump device can be utilized to precisely regulate the supply of the free-flowing substance in terms of time and amount. Such introduction devices and / or pump devices (also drip pumps) are known in the prior art.

[0018] In a third aspect, the present invention relates to a method for preparing a formulation, comprising the following steps: In a first step (a), a first fluid is added to the mixing chamber of the above reactor system. Preferably, the first fluid completely blocks the open surface of the first opening after addition. The first fluid is then stirred to generate a vortex. In fluid mechanics, a vortex is a rotational movement of a fluid element around a straight or curved axis of rotation. According to the present invention, a vortex can be generated by various available techniques. In a third step, a second fluid is fed from a container to the first fluid. In this case, a substance or mixture of substances that is substantially insoluble in the first fluid is dissolved in the second fluid, while the second fluid is completely dissolved in the first fluid. The second fluid is fed to the mixing chamber through the first opening so that the second fluid enters the first fluid in the region of the vortex that exhibits the highest speed of the fluid element.

[0019] According to the invention, such substances are called fluids and are continuously deformed under the influence of shear forces. In physics, this term encompasses gases and liquids. In the context of the invention, the first fluid is a liquid, preferably an aqueous solution. According to the invention, the second fluid is preferably a liquid in which a substance or a mixture of substances is uniformly dispersed, said substance or mixture of substances being substantially insoluble in the first fluid. Preferably, the method for preparing the formulation is a precipitation reaction, in which the reactants are dissolved in a solvent, but at least one reaction product is completely insoluble or poorly soluble in this solvent and precipitates. When the precipitation reaction is a nanoprecipitation reaction, it is particularly preferred that the precipitated structures are so small that they are called microparticle structures or even nanoparticle structures. These structures may be visible as turbidity or may even be invisible. This process is called nanoprecipitation.

[0020] The container of the present invention may be an introduction device (eg, a hypodermic syringe connected to a cannula), which in turn may be connected to a pump device.

[0021] The method of the present invention advantageously allows for the efficient preparation of formulations in a discontinuous "batch" process, which can be scaled in a straightforward manner according to the reactor system selected, thereby making small-scale and industrial-scale preparations equally possible.

[0022] In a further implementation of the method, in step b, a stirring tool equipped with a stirring blade may be used to generate a vortex in the first fluid.

[0023] In a further embodiment of the method, in step c, the second fluid is tip can enter the first fluid at a region of the stirring tool where v tip ∝πND, where v tip= tip speed of the respective impeller blade, N = stirring speed (RPM = revolutions per minute), and D = impeller diameter of the stirring tool. By adding in the area of ​​highest shear (maximum shear occurs in the area of ​​highest speed, i.e., the impeller tip), a high initial shear stress is applied to the added substance or mixture. Predetermining the number of passages through the area of ​​high shear stress near the impeller tip to prepare the nanostructured support system advantageously allows precise setting of the particle size of the respective nanostructured support system.

[0024] In a preferred implementation of the method according to the invention, the second fluid may be delivered via a pump device. This type of delivery advantageously allows precise control of the timing and amount of delivered fluid.

[0025] In a further embodiment of the method, the formulation prepared may be selected from the group comprising nanostructured carrier systems, polyplexes, nanoparticles, liposomes, micelles, microparticles.

[0026] Specific embodiments of the invention will now be described, by way of non-limiting examples, with reference to the accompanying drawings, in which:

[0027] The specific embodiments are merely illustrative of the general inventive concept and do not limit the invention in any way. [Brief description of the drawings]

[0028] [Figure 1] 1 is a schematic, substantial diagram of a reactor according to the present invention; [Diagram 2] FIG. 2 is a detailed view of the region of the first opening of the reactor according to the invention. [Diagram 3] FIG. 13 shows an alternative embodiment of a reactor with an agitation tool inserted. [Figure 4] 1 is a table showing the properties of various formulations (in this case nanostructured support systems) prepared utilizing reactors according to the invention of different dimensions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Figure 1 shows a reactor (1) according to the invention for preparing a formulation. The reactor (1) comprises a mixing chamber (2) defined by a base (3) and at least one side wall (4) extending flush therefrom. The mixing chamber (2) has a height h M (vertical dotted line) and an axis of symmetry (5, dashed dotted line) which in this embodiment is arranged perpendicular to the base (3) at a distance r (horizontal dotted line) from the side wall (4). The mixing chamber (2) is arranged as a substantially cylindrical shape (corresponding to a "standard reactor") and the base (3) is configured with respect to the interior of the mixing chamber (2) as a convex spherical segment with a flattened area (6) located in the middle. The side wall (4) is formed with a first aperture (7) adjacent to the base (3), the first aperture having a diameter of 0.18h for the introduction of free-flowing substances and / or mixtures into the mixing chamber (2). M Height h A The first aperture (7) is configured with an aperture area that extends between a minimum and a maximum value. The minimum area of ​​the first aperture (7) is 0.05 mm 2 which corresponds to the area of ​​a conventional cannula having an outer diameter of 0.25 mm. As part of the scaling process, the aperture area can be adapted to the volume of the mixing chamber, with the maximum area being 0.001 mm. 混合室 [cm 3 ] / area 第1の開孔部 [cm 2]≈5500. The first aperture (7) is arranged together with a feed conduit (8). The reactor (1) further comprises a second aperture (9), which is arranged along the axis of symmetry (5) of the mixing chamber (2) in the centrally arranged flattened area (6) of the base (3), the second aperture (9) being designed as an openable conduit. During normal operation of the reactor, the freely flowing substances and / or mixtures can be discharged from the mixing chamber (2) via the conduit according to gravity, but the inflow of the freely flowing substances and / or substance mixtures can also take place via the conduit. In this case, a branch (10) is formed in the conduit leading from the second aperture (9), through which the reaction products can be removed separately. The reactor (1) is formed with a third opening (11) opposite the base (3), which in this embodiment is sealed by a lid (12). Through this third opening (11) further free-flowing substances and / or substance mixtures and / or instruments such as stirring tools (13) can be introduced into the mixing chamber (2). Conventional mixers selected from the group of axial mixers, centrifugal mixers and dispersers may be considered to carry out the mixing operation, but alternatively mixing may be performed by utilizing a magnetic stirrer (13, shown) or other stirrers that can be operated without a stirring shaft. For example, in the case of a magnetic stirrer, a stirring shaft is not required, since a rotating magnetic field outside the mixing chamber drives a stirrer located in the mixing chamber. The lid (12) located above the third opening (11) allows the preparation of the formulation under defined environmental conditions, and measuring devices such as a thermometer or a pH meter can be introduced into the mixing chamber (2) through further openings (14, 15, 16).

[0030] The detailed view shown in FIG. 2 is limited to the region of the first aperture (7) of the reactor shown in FIG. 1, where a supply conduit (8) is formed, which is arranged in the region adjacent to the aperture. The first aperture (7) is configured, for example, with a diameter corresponding to the diameter of the cannula, for example 11G (3.0 mm). The supply conduit (8) arranged around the first aperture (7) is dimensioned with respect to the mixing chamber (2) so as to prevent back-mixing of liquid from the mixing chamber (2) into the supply conduit (8). This arrangement keeps the dead space volume (gap volume) as small as possible, thereby increasing the efficiency of the mixing process. Also, the amount of material required for the mixing process, which is fed through the first aperture, is kept as small as possible, which allows for a high cost-effectiveness in the preparation of the formulation. The supply conduit (8) is formed with a terminal male thread (not shown in FIG. 2). The check valve according to the invention can utilize the male thread to close and seal the first aperture (7) and thus the mixing chamber (2) from the environment. In the embodiment shown, the check valve is designed as a screw cap (18) which can be screwed onto the male thread (17) of the supply conduit (8) with a corresponding female thread. The check valve further comprises a pierceable membrane (19), preferably made of an elastic material (e.g. bromobutyl rubber), to ensure self-sealing after puncture with a needle.

[0031] In FIG. 3 an alternative embodiment of the reactor is shown with a stirring tool inserted in the mixing chamber. The stirring tool (13) shown is a rod mixer introduced through an opening 15, which advantageously has a stirring shaft (13a) arranged along the axis of symmetry (5) of the mixing chamber (2) of the reactor (1). At the working end of the stirring shaft (13a) a stirring blade (13b) is arranged. Here, the mixer can be a centrifugal mixer or an axial mixer. A second fluid (not shown) is added to the first fluid (not shown) present in the mixing chamber (2) through the first opening (7) by means of an introduction device (20) used to pierce a pierceable membrane (not shown) arranged in the screw cap (18). The introduction takes place in the area of ​​the stirring blade (13b) of the stirring tool (13). In the area of ​​the vortex generated in the first fluid by the stirring tool (13), the velocity of the fluid elements is maximum. Additional measuring instruments or probes (e.g. temperature probe / pH probe) may be introduced through additional openings (14, 16) in the lid (12). A temperature probe is shown here by way of example introduced in opening (14).

[0032] FIG. 4 shows a table summarizing the characteristics of various formulations (here nanostructured carrier systems) prepared using reactors according to the invention of different dimensions (500 mL, 2 L). The nanostructured carrier systems were investigated in terms of particle size and polydispersity index (PDI). The Z-average indicates the average particle size based on the intensity distribution of the scattered light signal. Polydispersity evaluates the width of the distribution. Statistically, the z-average is an average based on the intensity by a specific fitting to the raw correlation function data. The fitting, also called the cumulative method, can be considered as a forced fitting of the results to a simple Gaussian distribution, the z-average is the average value, and the PDI is related to the width of that simple distribution (assuming a single average value). Here, the particle size varies in the range of 78 nm to 160 nm, and for example, the desired particle size of about 160 nm could be achieved in both 500 mL and 2 L reactors. In terms of the distribution width, all the nanostructured carrier systems prepared had a polydispersity index of less than 0.2, as desired. From the above, all the formulations, regardless of the dimensions of the reactor used for the preparation, were characterized by excellent uniformity of the particles. [Explanation of symbols]

[0033] 1. Reactor 2 Mixing chamber (height h M ) 3 base 4 side wall 5 Axis of Symmetry 6 Flat area located in the center of the base 7 First opening (height h A ) 8 Supply conduit 9 Second opening 10 Branch 11 Additional opening 12 Lid 13 Stirring tool 13a Stirring tool shaft 13b Agitator blade 14 Lid opening 15 Lid opening 16 Lid opening 17 Male thread of supply conduit 18 Screw Cap 19 Punctureable membrane 20 Introduction device

Claims

1. A reactor for preparing a pharmaceutical product in a batch process, the reactor comprising at least two openings, a base, and at least one side wall extending flush from the base, wherein the base and the side wall together define a mixing chamber, the mixing chamber having a height h Ｍ It has at least one axis of symmetry that is substantially perpendicular to the base and positioned at a distance r from the side wall, To introduce a free-flowing substance and / or mixture into the mixing chamber, the first opening is located 0.6 to 0.0 h adjacent to the base. Ｍ Height h of the range Ａ It is positioned on the side wall of the mixing chamber, The first opening is configured to include a check valve located inside or adjacent to it, which allows the introduction of a free-flowing substance into the mixing chamber through the opening, but prevents the outflow of the free-flowing substance from the mixing chamber through the opening, and the minimum area of ​​the first opening is 0.05 mm². ２ And, The preparations to be prepared are selected from the group including nanostructured carrier systems, polyplexes, nanoparticles, liposomes, micelles, and microparticles, and are used in the reactor.

2. The first opening is located in the side wall of the mixing chamber, adjacent to the base, at a distance of 0.4 to 0.1 h. Ｍ range, preferably 0.25 to 0.15 h Ｍ Height h of the range Ａ The reactor according to claim 1, arranged as follows.

3. The reactor according to claim 1 or 2, wherein the side walls are cylindrical.

4. The reactor according to any one of claims 1 to 3, wherein a supply conduit is positioned around a first opening on the side of a side wall facing away from the mixing chamber, and the supply conduit is designed as a receiving connector having terminal threads for receiving a check valve.

5. The reactor according to claim 4, wherein the supply conduit is designed as a threaded closure having a female thread.

6. The reactor according to claim 4 or 5, wherein the first opening and the supply conduit are sized relative to the mixing chamber to prevent back-mixing of liquid from the mixing chamber into the supply conduit.

7. The reactor according to any one of claims 1 to 6, wherein the second opening is arranged as an openable and closable conduit for introducing a free-flowing substance and / or a mixture of substances into and / or discharging it from the mixing chamber of the reactor.

8. The reactor according to claim 7, wherein the second opening is arranged as a conduit positioned at the base of the mixing chamber substantially along one axis of symmetry of the mixing chamber.

9. The reactor according to any one of claims 1 to 8, wherein a further opening of the reactor is located on the opposite side from the base.

10. The reactor according to any one of claims 1 to 9, wherein the mixing chamber comprises at least one baffle plate positioned on the side wall.

11. The reactor according to any one of claims 1 to 10, wherein the preparation to be prepared is a nanostructured support system.

12. A reactor system for preparing a formulation, comprising a reactor according to any one of claims 1 to 11 and a stirring tool, wherein the stirring tool is positioned in the reactor such that a rotational axis substantially coincides with the axis of symmetry of the mixing chamber is created in the substance and / or mixture that flows freely during operation.

13. The reactor system according to claim 12, wherein the stirring tool is selected from the group including an axial flow mixer, a centrifugal mixer, a magnetic mixer, and a disperser.

14. The reactor system according to claim 12 or 13, further comprising an introduction device and / or a pump device connected to a first opening and / or a supply conduit.

15. A method for preparing a pharmaceutical product, a. A step of adding a first fluid to the mixing chamber of the reactor system according to any one of claims 12 to 14, b. A step of stirring the first fluid in such a way that it generates a vortex, c. A step of supplying a second fluid from a container to a first fluid, wherein a substance or mixture of substances substantially insoluble in the first fluid is dissolved in the second fluid, while the second fluid is completely soluble in the first fluid, and the second fluid is supplied to a mixing chamber through a first opening such that the second fluid enters the first fluid within the region of a vortex exhibiting the highest velocity of the fluid elements. A method that includes this.

16. The method according to claim 15, wherein in step b, the stirring tool is used to generate vortices in the first fluid using stirring blades.

17. In process c, the second fluid enters the first fluid in the region of the agitation tool where v ｔｉｐ is highest, where v ｔｉｐ ∝πND, where v ｔｉｐ = the velocity at the tip of each impeller blade, N = the agitation speed, and D = the diameter of the impeller of the agitation tool, the method according to claim 16.

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 prepared is selected from the group comprising nanostructured carrier systems, polyplexes, nanoparticles, liposomes, micelles, and microparticles.

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