Abstract:
A mixing container has a wall enclosing a mixing volume, an anchor fixed at the wall of the mixing container inside the mixing volume, and at least one mixing plate movably mounted to the anchor to allow a relative movement of the at least one mixing plate along a stir direction perpendicular to the extension of the mixing plate. Each of the at least one mixing plates is provided with at least one magnet.

Description:
BACKGROUND 
       [0001]    1. Field of the Invention 
         [0002]    The invention relates to a mixing container and a mixing system. 
         [0003]    2. Description of the Related Art 
         [0004]    The pharmaceutical industry has a need for a low cost single-use mixing technology that operates over a large scale range of container volume, for example for containers from 3 liters volume to 3000 liters volume. The mixing technology should be capable to mix two or more liquids or at least one solid with at least one liquid. Because disposable containers are preferred in various applications the mixing container should be easy and inexpensive to manufacture and should perform a reliable mixing operation. Additionally, because the material to be mixed has high purity requirements, the mixing technology should be ultraclean, i.e. should not generate particulates or create a risk of leakage of fluid through seals. 
       SUMMARY OF THE INVENTION 
       [0005]    One aspect of the invention relates to a mixing container comprising a wall enclosing a mixing volume, an anchor fixed at the wall of the mixing container inside the mixing volume, and at least one mixing plate movably mounted to the anchor to allow a relative movement of the at least one mixing plate along a stir direction having a component perpendicular to the extension of the mixing plate. Each of the at least one mixing plate is provided with at least one magnetic device. 
         [0006]    Herein “at least one mixing plate movably mounted to the anchor” is synonymous with a connection between the mixing plate and the anchor that allows a movement of the mixing plate relative to the anchor, including, but not limited to a hinge, flexure material, a mechanical linkage or by pivotally mounting the mixing plate to the anchor. 
         [0007]    The mixing volume may be substantially identical to the volume of the container. 
         [0008]    Alternatively, the container may be partially filled with a gas, i.e. may contain a headspace, to provide a wider range of working volumes or to provide stabilization of the liquid material (e.g. with an inert gas such as nitrogen). 
         [0009]    The anchor can be mounted from the inside of the mixing container to the wall. The anchor is not able to move laterally and/or rotatably relative to the part of the wall surrounding the anchor. Thus, the anchor is not a movable element. 
         [0010]    One or more mixing plates are movably, preferably pivotally, mounted to the anchor. The mounting may be provided by means of a hinge or a flexible region of the mixing plate and/or the anchor allowing a relative movement of each mixing plate along a stir direction perpendicular to the extension of the mixing plate. The mixing plate has generally a lateral extension along two dimensions which is much larger than the thickness of the mixing plate. The thickness direction is generally identical to the stir direction. 
         [0011]    The mixing or stirring of a liquid and/or solid in the mixing container is performed by vibrating the mixing plates. In order to actuate the at least one mixing plate, each mixing plate is provided with at least one magnetic device, such as a piece of ferromagnetic material (for example steel), a permanent magnet, a superconducting magnet or an electromagnet. Thus, the mixing plate can be actuated by applying a variant external magnetic field to the mixing container, preferably near the mixing plate. In case the external magnetic field is time variant, the magnetic device and thus the mixing plate can be induced to perform a vibrating motion, which is beneficial for performing the mixing operation. 
         [0012]    Optionally, each of the at least one mixing plates is mounted to the anchor by means of a flexure hinge. The anchor and the at least one mixing plate may be made of the same material and/or made as one piece. As example, the anchor and the at least one mixing plate can be made of thermoplastic resin, preferably by injection molding. In this case anchor, mixing plate and the connecting flexure hinge can be easily formed. 
         [0013]    As a further option, each of the at least one mixing plates comprises a proximal end movably, preferably pivotally, mounted to the anchor and a distal end comprising the at least one magnetic device. The flexure hinge may be located at the proximal end of the at least one mixing plate. 
         [0014]    In an alternative embodiment, each of the at least one mixing plates comprises a proximal end movably, preferably pivotally, mounted to the anchor, a distal end and a magnetic device, wherein the magnetic device is located in a part of the mixing plate between the proximal end and the distal end. Preferably, the magnetic device is located in the middle part of the mixing plate between the proximal end and the distal end. 
         [0015]    These embodiments offer the advantage that the magnetic actuator positioned outside of the container and containing the magnets of the drive unit (which interact with the corresponding magnets of the magnetic devices of the mixing plates inside the container) can have a smaller, more space-saving size than a larger magnetic actuator adapted to interact with magnetic devices which are placed at the distal ends of the mixing plates. 
         [0016]    Optionally, the at least one magnetic device is located at a side or a surface of the mixing plate directed to the wall of the mixing container. In other words the side or surface of the mixing plate comprising the magnetic device is directed away from the center of the mixing volume or to the outside of the container. 
         [0017]    According to another embodiment of the invention, the magnetic device is embedded in the interior of the mixing plate, in case the magnetic device is made of a material which is not compatible with the contents to be mixed in the mixing container. 
         [0018]    In all of the aforementioned embodiments, the gap between the mixing plate, respectively the magnetic device, and the wall of the container should be minimized in order to maximize the coupling between the at least one magnetic device of the mixing plate and a corresponding magnetic device outside the container. However, an undersized gap undesirably limits the travel distance of the mixing plate, hence a gap in the range of 5 mm to 10 mm is preferred. 
         [0019]    In an embodiment of the invention, the anchor is fixed and the mixing plates are set in vibrating motion by application of an external driving magnetic field. However, it is also possible for an internal magnetic field in the mixing plates (e.g. by an electromagnet disposed in each mixing plate and a fixed permanent magnet disposed outside the container) to create an internal driving magnetic field. 
         [0020]    As an option the wall of the mixing container comprises a flexible material. Generally the wall can be formed as a flexible bag, particularly when used as a disposable bioreactor, e.g. for mixing and for culturing organisms. As a further option the wall can be formed as a rigid container. In both cases the wall can be at least partially made of at least one of plastic, metal such as (stainless) steel, and glass. The wall can be made of a gamma-ray sterilizable polymer, particularly when used as a bioreactor. 
         [0021]    Anchor and wall are assembled in a fluid (liquid and/or gas) tight manner. As an option the anchor is welded to the wall of the mixing container. Particularly, in case the anchor and the wall are made of the same or different thermoplastic polymers the welding of anchor and wall is a convenient way to mount both together in a fluid tight manner. 
         [0022]    Optionally, the mixing container comprises a plurality of mixing plates and the magnetic devices of neighbouring mixing plates are of opposite orientation. For example, two, three, four, five, six, seven, eight or more mixing plates may be connected to the anchor. The mixing plates can be identical or different from each other. 
         [0023]    Each mixing plate can comprise one or more mixing orifices, i.e. holes through the mixing plate in order to allow a fluid flow from one side of the mixing plate to the other. Optionally, each mixing orifice is a tapered orifice through which a net fluid flow can be generated when the orifice moves up and down during the vibrating motion of the mixing plate which leads to a better mixing result. The flow of fluid is a net fluid flow caused by flow in one direction being higher than flow in the opposite direction. The facilities provided in the mixing-plate openings can be tapered upwards or downwards, although a combination is possible. In other words all tapered orifices can be oriented in one direction or the tapered orifices may be partially directed in one direction and partially in the opposite direction. The orifices can have other geometries, such as orifices with round entrances or ellipse entrances or diffuser nozzles. In order to perform the mixing each of the mixing plates is moved periodically along and against the stir direction, which extend substantially perpendicular to the areal extension of the mixing plate. In other words, the mixing plates perform longitudinal vibrations along the stir direction. 
         [0024]    The invention also relates to a mixing system comprising the above-described mixing container, a container receptacle adapted to at least partially receive the mixing container, and a magnetic actuator comprising at least one magnetic device adapted to induce a time-variant magnetic field which actuates the at least one magnetic device of the mixing container in order to move the corresponding mixing plate along the stir direction. 
         [0025]    Optionally, the magnetic actuator comprises a turntable to which the at least one magnetic device is mounted. Particularly, the arrangement pattern of the magnetic devices mounted to the turntable can be congruent or identical to the pattern of the magnetic devices of the mixing plates mounted to the anchor. As an option, the turntable comprises a plurality of magnetic devices wherein neighbouring magnetic devices are of opposite orientation. Optionally, the stir direction is substantially parallel to the axis of rotation of the turntable. 
         [0026]    In a particularly preferred embodiment the magnetic devices of neighboring mixing plates have opposite polarity, i.e. N, S, N, S, N, etc., whereas the turntable comprises a plurality of magnetic devices wherein neighboring magnetic devices are of the same orientation, i.e. N, N, N, N, N, etc. or S, S, S, S, S, etc. In other words, the magnetic devices of the turntable have all the same polarity. By means of this embodiment half of the mixing plates are moving in one direction (for example upward movement), while the other half of the mixing plates are moving in the opposite direction (for example downward movement). This arrangement pattern of the magnetic devices of the mixing plates and of the turntable creates a balanced movement of the mixing plates which avoids potentially damaging reaction forces which may be caused by a unbalanced movement of the mixing plates wherein all mixing plates move in the same direction simultaneously. 
         [0027]    The invention further relates to a mixing container comprising a wall enclosing a mixing volume, an anchor fixed at the wall of the mixing container inside the mixing volume, and at least one mixing plate movably mounted to the anchor to allow a relative movement of the at least one mixing plate along a stir direction perpendicular to the extension of the mixing plate. Each of the at least one mixing plates is provided with at least one mixing orifice and wherein each of the at least one mixing plates is provided with at least one magnetic device. 
         [0028]    Further features and advantages are described with references to the figures. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0029]      FIG. 1  shows a top view of an anchor with a mixing plate connected thereto. 
           [0030]      FIG. 2  shows a section view to the embodiment shown in  FIG. 1 . 
           [0031]      FIG. 3(   a ),  3 ( b ) and  FIG. 3(   c ) show various arrangements of mixing plates. 
           [0032]      FIG. 4  shows a top view of a mixing system. 
           [0033]      FIG. 5  shows a section view to the mixing system taken along line  5 - 5  in  FIG. 4 . 
           [0034]      FIG. 6  shows an exploded section view of the whole mixing system. 
           [0035]      FIG. 7  shows a further section view to the mixing system shown in  FIG. 6  when in use. 
           [0036]      FIGS. 8(   a ) and  8 ( b ) show perspective views of the mixing system while  FIG. 8(   c ) is a side elevational view of mixing plate. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0037]      FIGS. 1 and 2  show an embodiment of a mixing container  1 . While  FIG. 1  shows a top view of the mixing container  1 ,  FIG. 2  shows a section view along the section line  2 - 2  shown in  FIG. 1 . As shown in  FIGS. 1 and 2 , the mixing container  1  includes a mixing head  2  comprising an anchor  3  with at least one mixing plate  13  connected thereto. 
         [0038]    The mixing container  1  may be a single use container. The anchor  3  is attached to the wall  7  of the mixing container  1  via a welding flange  9  of the anchor  3  which is welded to a welding zone  11  of the wall  7 . One or more (not shown) mixing plates  13  are movably, preferably pivotally connected to the anchor  3  via a flexure hinge  15  (shown in  FIG. 2 ). The wall  7  may be rigid or flexible, such as a bag. As an advantage a flexible, bag-like wall  7  allows to fold and collapse the mixing container  1  prior to use and after use for disposal. 
         [0039]    Each mixing plate  13  is formed as a planar plate comprising one or more mixing orifices  17 , which can have a tapered shape, for example a cone shape, as shown for example in the figures. This allows the generation of a net fluid flow through the mixing orifices  17  leading to an improved mixing result. 
         [0040]    The mixing plate  13  contains one or more embedded magnetic devices or magnets  19 , which can be for example formed of a NdFeB disc made of an alloy of neodynium, iron and boron and which are used as drivers. A ferromagnetic material such as ferritic stainless steel could be substituted for the permanent magnet  19  to reduce costs. However, the driving force would be reduced by approximately the half. The magnets  19  may also be mounted to the surface of the mixing plate  13 . Alternatively, the magnets  19  can be embedded in the interior of the mixing plate  13 . 
         [0041]    The mixing plate can be actuated by applying an external magnetic field to the mixing container  1 , preferably near one or more magnets  19  of the one or more mixing plates  13 . By varying the external magnetic field over the time the magnets  19  and thus the mixing plates  13  are induced to perform a vibration motion along a stir direction S. A magnetic actuator comprising at least one magnetic device or magnet  21  can be located near the mixing container  1  in order to induce a time-variant magnetic field which actuates the at least one magnet  19  of the mixing plate  13 , and thus, cause a vibration of the mixing plate  13  along the stir direction S. 
         [0042]    The transient actuation of the magnets  19  can be obtained by using a magnet  21  providing a variable magnetic field, such as an electromagnet, or by moving the position of magnet  21 .  FIG. 1  indicates that magnet  21  is moving along a circular path C around anchor  3  in order to periodically actuate magnet  19 . In order to maximize the actuating force applied to magnet  19  by magnet  21  the gap  23  or distance between both should be minimized. For example the distance may range between 5 mm and 10 mm. In other words, the permanent magnet  19  should be located as close to the wall  7  of the mixing container  1  as is possible without causing collisions between the mixing plate  13  and the wall  7 . The permanent magnet  19  need not to be in the plane of the mixing plate  13 . It may be advantageous to have a clearance between the mixing plate  13  and the wall  7 , so that the net fluid flow induced by the motion of the mixing plate  13  is not hindered. 
         [0043]    The orifices  17  located in the mixing plate  13  need not be of circular shape, but they may also have the shape of a slot or any other convenient shape. Each mixing plate  13  may be connected to the anchor  3  at one or more locations via linkages or hinges  15 . These linkages may be rigid, thereby creating a bending cantilever beam, or flexible, such as a living hinge. The motion of the mixing plate  13  is determined by the geometry, material properties, fluid properties, and the temporal variation of the external magnetic field. The anchor  3  and the at least one mixing plate  13  may be formed integrally, e.g. by injection molding, from a polymeric material suitable for product contact, and thus, forming a mixing head  2 . The mixing head  2  is ideally contoured such that the top surface is smooth and does not have any sharp edges that could potentially damage the opposite interior wall  7  of the mixing container  1  when the mixing container  1  is collapsed. 
         [0044]      FIGS. 3(   a ),  3 ( b ) and  3 ( c ) show various arrangements of mixing plates  13 . As shown in  FIG. 3(   a ) eight mixing plates  13  could be assembled to or formed integrally with the anchor  3 . All mixing plates  13  have an identical pattern of orifices  17 . As shown in  FIG. 3(   b ), it is also possible to perform the mixing operation with two mixing plates  13  connected to the anchor  3 , or as shown in  FIG. 3(   c ), with four mixing plates  13 . 
         [0045]      FIGS. 4 and 5  show an embodiment of a drive unit  5 . While  FIG. 4  shows a top view of the drive unit  5 ,  FIG. 5  shows a section view along the section line  5 - 5  shown in  FIG. 4 . As shown in  FIGS. 4 and 5 , the drive unit  5  comprises a container receptacle  25  adapted to at least partially receive the mixing container  1  (shown in  FIGS. 1 and 2 ). The container receptacle  25  may be a flat area adapted to be in mechanical contact and/or magnetic contact with the anchor  3  and/or the wall  7  of the mixing container  1 . As an option the mixing container  1  can be placed with its bottom to the container receptacle  25 . The term “magnetic contact” describes the case when the wall  7  does not come into touch with the container receptacle  25 , but the drive unit  5  is close enough to actuate the magnets  19  of the mixing container  1 . Regardless whether mixing container  1  and drive unit  5  are in mechanical or magnetic contact with each other the container receptacle  25  may be formed congruent to a part of the wall  7  including the anchor  3 . 
         [0046]    The drive unit  5  includes a magnetic actuator  27  comprising at least one magnet  21  adapted to induce a time-variant magnetic field which actuates the at least one magnet  19  of the mixing container  1  in order to move the corresponding mixing plate  13  along the stir direction S. 
         [0047]    The magnetic drive unit  5  is external to the mixing container  1  and generates a variable magnetic field for example by motion of a permanent magnet  21  or by variable current through a fixed electromagnet (not shown). The preferred solution is to move one or more permanent magnets  21  in a circular path C that coincides with the position of the permanent magnets  19  embedded in the mixing plates  13 . The permanent magnets  21  may be mounted to a turntable  29  and are rotated by means of a conventional rotating motor  31 , such as a brushless DC motor  31 , powered via a power cord  33 . The turntable  29  can be coupled to the motor  31  via a gear  35  and a driving shaft  37 . 
         [0048]    The permanent magnets  21  can be arranged on the turntable in a way so that neighbouring magnets  21  are of opposite orientation. In other words the magnetic poles of adjacent magnets  21  are opposite—e.g. N, S, N, S, so that the rotation of the motor  31  generates alternating attraction and repulsion forces at each mixing plate  13  as the permanent magnet  21  in the drive unit  5  approaches the permanent magnet  19  embedded in the mixing plate  13 . In a preferred embodiment the magnets  19  of neighboring mixing plates  13  have opposite polarity—e.g. N, S, N, S, whereas the magnets  21  of the drive unit  5  all have the same polarity, i.e. N, N, N, N or S, S, S, S, so that a balanced motion of the mixing plates  13  is created, wherein one half of the mixing plates  13  moves upward and the other half of the mixing plates  13  performs a downward motion or vice versa. 
         [0049]      FIGS. 6 and 7  show section views of the whole mixing system shown in  FIGS. 1 to 5 .  FIG. 6  shows the drive unit  5  and the mixing container  1  having a partially flexible wall  7  in a collapsed state, so that the mixing volume  39  inside the container  1  is minimized. Attached to the mixing container  1  is a reservoir  41  containing a liquid or solid substance  43  to be mixed with a solvent. The reservoir is separated from the mixing volume  39  by means of a seal  45 , particularly a sterile, hermetic seal. 
         [0050]    As shown in  FIG. 7  the mixing container  1  is expanded, the seal  45  is broken to release substance  43  from the reservoir  41  into the mixing container  1  and a solvent is added. The anchor  3  with the mixing plates  13  is coupled to the drive unit  5  and the drive unit  5  is activated in order to perform the mixing operation. 
         [0051]    The motion of each orifice  17  (as shown in  FIGS. 1 to 3 ) in the mixing plate  13  is adequate to generate a net flow of liquid inside the single-use mixing container  1 . The orifices  17  may be arranged in either direction. For low level applications a downward direction is preferred to avoid splashing at the surface  47  of the liquid. Although flow is primarily axial, the relative movement of magnets  19  in the mixing plates  13  combined with the flexibility of the linkages creates a wobble. This wobble may be exploited to generate fluid motion with a nonzero radial component. The drive unit  5  is fully isolated from the container and there are no seals or bearings in contact with the product inside the single-use mixing container  1 . The drive unit  5 , particularly the container receptacle  25 , may have a geometry which precisely locates the anchor  3  of the mixing container with respect to the moving magnets  19 . 
         [0052]    There are several parameters which may be adjusted in design or in operation to achieve a target performance. The number, size, spacing, and polarity of the magnets  19 ,  21  in the mixing plates  13  and the drive unit  5  may be adjusted to change the driving power. The power, speed, and gear ratio of the motor  31  may be adjusted to change the mixing power. It may be advantageous to operate near the resonant frequency of the mixing plate  13  to maximize the amplitude of response of the mixing plate  13 . 
         [0053]    The geometry of the mixing orifices  17  (e.g. diameter, angle, depth) may also be optimized to maximize mixing performance. 
         [0054]      FIG. 8(   a ) shows a perspective view of the mixing system, wherein the mixing container  1  is in an expanded state.  FIG. 8(   b ) shows the arrangement of mixing head  2  relative to the magnetic actuator  27 .  FIG. 8(   c ) shows a detailed view of a wobbling mixing plate  13 . The elements of  FIGS. 8(   a ),  8 ( b ) and  8 ( c ) are identical with the elements shown in the previous figure, and thus, are labelled with identical reference signs. The mixing system is operated as described with reference to  FIGS. 6 and 7  above. 
       LIST OF REFERENCE SIGNS 
       [0000]    
       
           1  mixing container 
           2  mixing head 
           3  anchor 
           5  drive unit 
           7  wall of the mixing container 
           9  welding flange of the anchor 
           11  welding zone of the wall 
           13  mixing plate 
           15  flexure hinge 
           17  mixing orifice 
           19  magnet of the mixing plate 
           21  magnet of the drive unit 
           23  gap 
           25  container receptacle 
           27  magnetic actuator 
           29  turntable 
           31  motor 
           33  power cord 
           35  gear 
           37  driving shaft 
           39  mixing volume 
           41  reservoir 
           43  substance 
           45  seal 
           47  surface of the liquid 
         S stir direction 
         C circular path around the anchor