Reactor for the preparation of a formulation

Abstract

The invention discloses a reactor for preparing a formulation. The reactor comprises at least two apertures, a base and at least one sidewall extending flush therefrom, wherein the base and the sidewall together define a mixing chamber with a height h.sub.M and at least one axis of symmetry arranged substantially perpendicular to the base and at least one distance r from the sidewall. A first aperture is arranged within the base or adjacent to the base in the sidewall of the mixing chamber at a height h.sub.A ranging from 0.6 to 0.0 h.sub.M in order to introduce free-flowing materials and/or mixtures to the mixing chamber. The first aperture is configured with a non-return valve disposed therein or adjacent thereto, the non-return valve permitting the introduction of free-flowing materials to the mixing chamber through the aperture, but preventing outflow of free-flowing materials from the mixing chamber through the aperture. The first aperture is formed with an aperture area extending in a range between a minimum and a maximum, the minimum area being 0.05 mm.sup.2 and the maximum area being determined by a value resulting from Volume.sub.mixing chamber [cm.sup.3]/Area.sub.first aperture [cm.sup.2]≈5500.

Claims

1. Reactor for preparing a formulation, wherein the reactor comprises at least two apertures, a base and at least one sidewall extending flush therefrom, wherein the base and the sidewall together define a mixing chamber with a height h.sub.M and at least one axis of symmetry arranged substantially perpendicular to the base and at least one distance r from the sidewall, wherein a first aperture is arranged within the base or adjacent to the base in the sidewall of the mixing chamber at a height h.sub.A ranging from 0.6 to 0.0 h.sub.M in order to introduce free-flowing materials and/or mixtures to the mixing chamber, and wherein the first aperture is configured with a non-return valve disposed therein or adjacent thereto, the non-return valve permitting the introduction of free-flowing materials to the mixing chamber through the aperture, but preventing outflow of free-flowing materials from the mixing chamber through the aperture; and wherein the first aperture is formed with an aperture area extending in a range between a minimum and a maximum, the minimum area being 0.05 mm.sup.2 and the maximum area being determined by a value resulting from Volume.sub.mixing chamber [cm.sup.3]/Area.sub.first aperture [cm.sup.2]≈5500.

2. Reactor according to claim 1, wherein the first aperture is arranged adjacent to the base in the sidewall of the mixing chamber at a height h.sub.A ranging from 0.4 to 0.1 h.sub.M, preferably ranging from 0.25 to 0.15 h.sub.M.

3. Reactor according to claim 1, wherein the sidewall is cylindrical.

4. Reactor according to claim 1, wherein a supply conduit is arranged around the first aperture on the side of the sidewall facing away from the mixing chamber, wherein the supply conduit is designed as a receiving connector with a terminal thread for receiving the non-return valve.

5. Reactor according to claim 4, wherein the supply conduit is designed as a threaded closure having an internal thread.

6. Reactor according to claim 4, wherein the first aperture and the supply conduit are dimensioned with respect to the mixing chamber such as to prevent re-mixing of the liquid from the mixing chamber into the supply conduit.

7. Reactor according claim 1, wherein the second aperture is arranged as a closable conduit for the introduction of free-flowing materials and/or mixtures of materials into the mixing chamber of the reactor and/or their discharge therefrom.

8. Reactor according to claim 7, wherein the second aperture is arranged as a conduit positioned in the base of the mixing chamber substantially along its at least one axis of symmetry.

9. Reactor according to claim 1, wherein an additional aperture of the reactor is arranged opposite of the base.

10. Reactor according to claim 1, wherein the mixing chamber is provided with at least one baffle arranged on the sidewall.

11. Reactor according to claim 1, wherein the formulation to be prepared is selected from the group comprising nanostructured carrier system, polyplex, nanoparticles, liposome, micelle, microparticles.

12. A reactor system for preparing a formulation comprising a reactor according to claim 1, and a stirring tool, wherein the stirring tool is arranged in the reactor such that it generates an axis of rotation within the free-flowing material and/or mixture during operation, which axis of rotation 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 mixer, radial flow mixer, magnetic mixer, disperser.

14. Reactor system according to claim 12, further comprising an introduction device and/or a pumping device connected to the first aperture and/or the supply conduit.

15. A method of preparing a formulation comprising the steps a. adding a first fluid to a mixing chamber of a reactor system according to claim 12, b. stirring the first fluid such as to generate a vortex, c. supplying a second fluid to the first fluid from a reservoir, wherein a material or mixture of materials substantially insoluble in the first fluid is dissolved in the second fluid, while the second fluid is completely soluble in the first fluid, wherein the second fluid is supplied to the mixing chamber via the first aperture such that the second fluid enters the first fluid in the region of the vortex exhibiting the highest speed of the fluid elements.

16. The method according to claim 15, wherein in step b, a stirring tool is used with stirring blades for generating the vortex in the first fluid.

17. The method according to claim 16, wherein in step c, the second fluid enters the first fluid in the region of the stirring tool where v.sub.tip is the highest, with: v.sub.tip∝πND, wherein v.sub.tip=speed at the tip of the respective impeller blade, N=agitation velocity, D=diameter of the impeller of the stirring tool.

18. The method according to claim 15, wherein the second fluid is supplied via a pumping device.

19. The method according to claim 15, wherein the formulation to be prepared is selected from the group comprising nanostructured carrier system, polyplex, nanoparticles, liposome, micelle, microparticle.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0028] Hereinafter, by way of example and not limiting, certain particular embodiments of the invention will be described with reference to the accompanying drawings.

[0029] The particular embodiments are merely illustrative of the general inventive concept, but do not limit the invention in any way.

[0030] FIG. 1 depicts a schematic view of the reactor according to the invention.

[0031] In FIG. 2, a detailed view of the reactor according to the invention in the region of the first aperture is shown.

[0032] FIG. 3 illustrates an alternative embodiment of the reactor with an inserted stirring tool.

[0033] In FIG. 4 the characteristics of various formulations (in this case: nanostructured carrier systems) which were prepared utilizing differently sized reactors according to the invention are presented in a table.

PREFERRED EMBODIMENT OF THE INVENTION

[0034] FIG. 1 depicts a reactor (1) for preparing a formulation according to the present invention. The reactor (1) comprises a mixing chamber (2) which is defined by a base (3) and at least one sidewall (4) extending flush therefrom. The mixing chamber (2) is characterized by a height h.sub.M (vertical dotted line) and an axis of symmetry (5, dash-dotted line), which in the present embodiment is arranged perpendicular to the base (3) at a distance r (horizontal dotted line) of the sidewall (4). The mixing chamber (2) is arranged substantially as a cylinder (corresponding to a “standard reactor”), wherein the base (3) is configured, with respect to the interior of the mixing chamber (2), as a convex spherical segment with a centrally disposed flattened region (6). The sidewall (4) is formed with a first aperture (7) adjacent to the base (3), wherein the first aperture is located at a height h.sub.A of 0.18 h.sub.M in order to allow the introduction of free-flowing materials and/or mixtures into the mixing chamber (2). The first aperture (7) is configured with an aperture area extending in a range between a minimum and a maximum. The minimum area of the first aperture (7) is 0.05 mm.sup.2, corresponding to the area of a conventional cannula having an outer diameter of 0.25 mm. As part of a scaling process, the aperture area may be adapted to the volume of the mixing chamber, with the maximum area determined by a value resulting from Volume.sub.mixing chamber [cm.sup.3]/Area.sub.first aperture [cm.sup.2]≈5500. The first aperture (7) is arranged with a supply conduit (8). The reactor (1) furthermore comprises a second aperture (9) arranged in the centrally disposed flattened region (6) of the base (3) along the axis of symmetry (5) of the mixing chamber (2), wherein the second aperture (9) is designed as a closable conduit. During regular operation of the reactor, free-flowing materials and/or mixtures may be discharged from the mixing chamber (2) via the conduit in accordance with gravity, the entry of free-flowing materials and/or mixtures of materials, however, may also be effected via the conduit. In the present case, the conduit extending from the second aperture (9) is formed with a branch (10), allowing for separate removal of reaction products. Opposite the base (3) the reactor (1) is formed with a third aperture (11), which in the present embodiment is sealed by a lid (12). Via this third aperture (11), further free-flowing materials and/or mixtures of materials and/or tools such as a stirring tool (13) may be introduced into the mixing chamber (2). Conventional mixers selected from the group of axial flow mixers, radial flow mixers, and dispersers may be considered for performing the mixing operation, alternatively, however, mixing may also be accomplished by utilizing a magnetic stirrer (13, shown here) or other stirrers operateable without an agitator shaft. In the case of a magnetic stirrer, for example, no agitator shaft is required since a rotating magnetic field outside of the mixing chamber drives the stir bar located within the mixing chamber. The lid (12) arranged above the third aperture (11) enables the preparation of a formulation under defined ambient conditions, wherein measuring devices, such as a thermometer or a pH meter, may be introduced into the mixing chamber (2) via additional apertures (14, 15, 16).

[0035] The detailed view shown in FIG. 2 is limited to the region of the first aperture (7) of the reactor as depicted in FIG. 1, which is formed with a supply conduit (8) arranged in the region adjacent to the aperture. The first aperture (7) is configured with a diameter which e.g. corresponds to the diameter of a cannula, for example, 11 G (3.0 mm). The supply conduit (8) arranged around the first aperture (7) is dimensioned with respect to the mixing chamber (2) such as to prevent re-mixing of the liquid from the mixing chamber (2) into the supply conduit (8). By this arrangement, the volume of dead space (clearance volume) is kept as low as possible, thereby increasing the efficiency of the mixing process. Also, the amount of material required for the mixing process, which is supplied through the first aperture, is kept as low as possible, thus enabling cost efficiency in the preparation of the formulation. The supply conduit (8) is formed with a terminal external thread (not shown in FIG. 2). Utilizing the external thread, the non-return valve according to the invention may close off sealingly the first aperture (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 supply conduit (8) via its corresponding internal thread. The non-return valve further comprises a pierceable membrane (19), which preferably consists of an elastic material (e.g. bromobutyl rubber), such that self-sealing is ensured after a puncture with a needle.

[0036] In FIG. 3 an alternative embodiment of the reactor is shown wherein a stirring tool is inserted into the mixing chamber. The stirring tool (13) as illustrated is a rod mixer introduced via opening 15, having an agitator shaft (13a) advantageously arranged along the axis of symmetry (5) of the reactor's (1) mixing chamber (2). The operating end of the agitator shaft (13a) is arranged with stirring blades (13b); herein, the mixer may be a radial flow mixer or an axial flow mixer. A second fluid (not shown) is added to the first fluid (not shown) present in the mixing chamber (2) via the first aperture (7) by means of an introduction device (20) used for puncturing a pierceable membrane (not shown) located in a screw cap (18). The introduction is effected in the region the stirring blades (13b) of the stirring tool (13). In the region of the vortex generated in the first fluid by the stirring tool (13), the velocity of the fluid elements is highest. Additional measuring instruments or probes (for example temperature/pH probes) may be introduced via the additional apertures (14, 16) in the lid (12); a temperature probe introduced into the aperture (14) is shown here by way of example.

[0037] FIG. 4 depicts a table summarizing properties of various formulations (here: nanostructured carrier systems), which were prepared with differently sized reactors (500 ml, 2 l) according to the invention. The nanostructured carrier systems were examined with respect to particle size and polydispersity index (PDI). The Z-average indicates the average particle diameter based on the intensity distribution of a scattered light signal; polydispersity evaluates the width of the distribution. Statistically, the z-average is an intensity-based average based on a specific fit to raw correlation function data. The fit is also referred to as cumulative method and may be regarded as forced fitting of the result to a simple Gaussian distribution, where the z-mean is the mean and the PDI is related to the width of that simple distribution (assuming a single average). Here, particle sizes varied ranging from 78 nm to 160 nm, wherein, for example, in both the 500 ml and in the 2 l reactor, desired particle sizes of about 160 nm could be achieved. With regard to the width, all nanostructured carrier systems prepared were at a polydispersity index of <0.2, as desired. Accordingly, all formulations were characterized by excellent homogeneity of the particles, regardless of the size of the reactor utilized for preparation.

REFERENCE SIGNS

[0038] 1 reactor [0039] 2 mixing chamber (height NO [0040] 3 base [0041] 4 sidewall [0042] 5 axis of symmetry [0043] 6 centrally disposed flattening of the base [0044] 7 first aperture (a height h.sub.A) [0045] 8 supply conduit [0046] 9 second aperture [0047] 10 branch [0048] 11 additional aperture [0049] 12 lid [0050] 1 stirring tool [0051] 13a shaft of the stirring tool [0052] 13b stirring blade [0053] 14 lid aperture [0054] 15 lid aperture [0055] 16 lid aperture [0056] 17 external thread of the supply conduit [0057] 18 screw lid [0058] 19 pierceable membrane [0059] 20 introduction device