EP2480323B1 - Method and device for mixing a heterogeneous solution to obtain a homogeneous solution - Google Patents

Method and device for mixing a heterogeneous solution to obtain a homogeneous solution Download PDF

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Publication number
EP2480323B1
EP2480323B1 EP20100769027 EP10769027A EP2480323B1 EP 2480323 B1 EP2480323 B1 EP 2480323B1 EP 20100769027 EP20100769027 EP 20100769027 EP 10769027 A EP10769027 A EP 10769027A EP 2480323 B1 EP2480323 B1 EP 2480323B1
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Prior art keywords
vessel
rotation
axis
container
support
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German (de)
French (fr)
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EP2480323A1 (en
Inventor
Tom Beumer
Wilco Brusselaars
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Biomerieux SA
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Biomerieux SA
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/10—Mixers with shaking, oscillating, or vibrating mechanisms with a mixing receptacle rotating alternately in opposite directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/20—Mixing the contents of independent containers, e.g. test tubes
    • B01F31/22—Mixing the contents of independent containers, e.g. test tubes with supporting means moving in a horizontal plane, e.g. describing an orbital path for moving the containers about an axis which intersects the receptacle axis at an angle
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/23—Mixing of laboratory samples e.g. in preparation of analysing or testing properties of materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2215/00—Auxiliary or complementary information in relation with mixing
    • B01F2215/04—Technical information in relation with mixing
    • B01F2215/0413—Numerical information
    • B01F2215/0418—Geometrical information
    • B01F2215/0422—Numerical values of angles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/50—Mixing liquids with solids

Definitions

  • the present invention relates to a method for mixing a heterogeneous solution containing a liquid and a solid entity or at least two different liquids and, optionally, a solid entity in order to obtain a homogeneous solution, in which method the heterogeneous solution is available in a container.
  • the method is particularly interesting because it proposes the combination of a circular or orbital non-circular movement of the container which has an axis of symmetry which is itself inclined with respect to gravity.
  • the invention also proposes a device allowing the implementation of such a method.
  • a mixture should not be performed with too much force that could create a suspension desired solutions to be mixed either by centrifugation, with phase separation, or in the form of aerosols or emulsion, which can generate, for example if one treats nucleic acids, cross-contamination detrimental to a reliable subsequent diagnosis .
  • a mixture must, in certain cases, be carried out within a defined period of time in order to prevent the solutions to be mixed from being subjected to temperature variations or else a secondary reaction to take place.
  • the mixing techniques used in the laboratory are more or less complex to implement.
  • One of the mixing techniques consists, when adding a second solution to a first solution present in a container, to alternately perform suction several times followed by a discharge in the container using a cone by the action of the piston of a pipette.
  • the disadvantage of this method is that it requires during its implementation a certain dexterity and delicacy on the part of the user. The repetitiveness of such an operation is also doubtful depending on this user and its state of fatigue, nervousness, etc. Indeed, too high frequency of suction / discharge related to a bad position of the cone in the container may cause the appearance of air bubbles within the mixture.
  • the enzymes, buffers and other reagents useful for the amplification reaction are added to the biological sample and a small volume of oil.
  • This volume of oil covers the amplification mixture and prevents the evaporation of the amplification reagents during the different heating cycles during the amplification.
  • the oily phase mixes with the aqueous phase creating an emulsion which will prevent the action of the enzyme.
  • the patent application US-2006/0177936 offers a universal tube holder that is configured to perform sample preparation.
  • An apparatus for centrifugally vortexing includes a motor with a rotating system on which the portable universal tube holder is mounted for rotation and oscillation thereof. This technique results in the ability to more effectively mix at least two liquids or at least one liquid and at least one solid entity, for example, consisting of magnetic particles. More effectively, it should be understood that this patent application advocates back-and-forth movements, called oscillations.
  • the prior art US Patent 5,921,676 also discloses a mixing technique using a mixing device whose platform is driven by an orbital movement horizontal and / or vertical.
  • This device makes it possible to mix volumes of large or medium quantity, that is to say of the order of milliliter.
  • it does not make it possible to effectively mix volumes smaller than one milliliter. Indeed, as the diameter of the container containing the solutions to be mixed is greater than the diameter of the orbital movement, the mixture of solutions will be effective.
  • the center of the container performs an orbital distance equivalent to the orbital distance of the platform, thereby generating centrifugal forces in the liquid that change diametrically direction at each half rotation and allow mixing of the solutions.
  • the document FR-A-2436624 apparatus for mixing a fluid material in a container comprising: a first container support means for rotating about a first axis; second means for supporting the container, allowing its rotation about a second axis which is not perpendicular to the first; first drive means connected to said second support means for rotating the container about said second axis; and a second driving means which is connected to said first support means for rotating the container about said first axis while the container is rotating about said second axis.
  • the problem with this type of device is that both axes of rotation are always intersected. There is therefore an area in the vicinity of this intersection that has almost no movement, so there will be a mixture that will be differential between the closest and the farthest points of this intersection point and therefore a non-homogeneous mixture at the intersection. within the liquid or liquids.
  • the devices of the prior art fail to mix small volumes of heterogeneous solutions into a homogeneous solution while preventing the formation of emulsions and / or aerosols (risk of contamination in the medical field for example) and wetting all the walls of the container. There is therefore still a need for a new mixing device counteracting the disadvantages of those of the prior art.
  • the Applicant proposes a new device for mixing heterogeneous solutions to obtain a homogeneous solution. Thanks to the device according to the invention, the solutions contained in the container undergo successive accelerations and decelerations whose sinusoidal intensity allows their gentle agitation while avoiding wetting of the entire walls of the container and / or a dispersion of the phases of the different solutions. This device also makes it possible to dispense with a centrifugation step after mixing.
  • heterogeneous solution means at least two liquids or fluids which are miscible in the aqueous phase and have different properties and viscosities. These fluids may contain solid entities or suspended particles. These liquids and possibly the solid entities that are contained in these liquids are unevenly and irregularly distributed in the container containing them.
  • homogeneous solution means a solution whose constituent elements are uniformly and regularly distributed in the container which contains them.
  • mixing in the sense of the present invention, means joining in a container at least two liquids having different properties so that they form a single liquid whose constituent elements are distributed uniformly and homogeneous. It can also be at least one liquid associated with at least one type of solid entities or particles in suspension.
  • solid entity is intended to mean particles which may be made of latex, glass (GPC), silica, polystyrene, agarose, sepharose, nylon, etc. These materials may possibly allow the confinement of magnetic material. It can also be a filter, a film, a membrane or a strip. These materials are well known to those skilled in the art.
  • rotation in the sense of the present invention defines a plane motion of a body where all the points of the body describe trajectories of the same geometrical shape but which have different centers, the centers being parallel to each other during the movement.
  • the trajectory can be in the form of a circle; the body rotates.
  • the trajectory can be elliptical; the body undergoes a elliptical translation.
  • the end of the cap is located at a distance L1 from the axis of the rotational movement (the position said to be closest to the axis) and the end of the bottom of the tube is at a distance L2 from the axis of the rotational movement (so-called position furthest from the axis).
  • L1 the position said to be closest to the axis
  • L2 the axis of the rotational movement
  • the end of the cap and the end of the bottom form a segment which moves in a parallel manner about this axis; the segment describing for example a trajectory in the form of a circle.
  • the end of the cap and the end of the circle are at the same distance L3 from the axis of the movement.
  • sufficient air volume denotes a portion of a space of the air-filled vessel allowing during the rotational movement the free movement of liquids within the container.
  • substantially vertical position is meant in the present invention, any position varying from an angle between 0 ° and ⁇ 2 ° with respect to an axis of gravity.
  • This method can also be applied to mixing a heterogeneous solution containing at least one liquid and at least one solid entity.
  • the longitudinal axis of the container crosses twice the axis of rotation of said support per revolution.
  • the container contains in addition to the heterogeneous solution a volume of air sufficient to allow agitation without all or part of said heterogeneous solution can not leave said container during mixing.
  • the container contains in addition to the heterogeneous solution a volume of air sufficient to allow agitation and is closed by a plug, so that all or part of said heterogeneous solution can not leave said container when mixing.
  • the inclination of the longitudinal axis of the container varies according to the speed of rotation and / or according to its position during rotation.
  • the movement of the support is circular.
  • the movement of the support is ellipsoidal.
  • the axis of rotation of the support is in a substantially vertical position and that the longitudinal axis of the container is not in a substantially vertical position.
  • an angle of inclination of the longitudinal axis of the container relative to the axis of rotation of the support exists, and when the two axes are intersected, the angle is between 1 and 60 °, preferably between 20 and 50 ° and even more preferably between 25 and 45 °.
  • the container is closed.
  • the mixer according to the invention essentially uses a known "orbital" mixing device, but instead of placing the tube with its axis of symmetry parallel to the axis of rotation, we place the axis of symmetry of the tube at a non-symmetrical angle. parallel with the axis of rotation of the device and with gravity.
  • the method can be used with reaction vessels of virtually any shape, and has the most benefit in cases where conventional orbital or vortex oscillation methods are not suitable.
  • the normal mechanical arrangement for orbital motion as a mixing medium for liquids is shown on the figure 1 .
  • a solid support for example a horizontal table 1, movements confined in small circles or rotation 2 having a radius 5 and an axis of symmetry / rotation 3 of the table 1, preferably parallel to the gravity.
  • Each container 7, the contents of which must be mixed, is placed vertically on said table 1 with its axis of symmetry 4 parallel to the axis of rotation 3.
  • axis of symmetry 4 parallel to the axis of rotation 3.
  • an orbital mixer 9 in which the container 7 containing the liquid 8 to be mixed is placed at an angle 6 with respect to the axis of rotation 3, itself parallel to gravity. More and this is represented on the figure 3 , the inclination of the container 7 is always the same relative to the horizontal or the vertical for an outside observer in lateral position. In other words, an observer in this position will have the feeling that the container 7 will move alternately left and right and vice versa, said container 7 which remains a stable inclination.
  • the quality of the blend was judged visually, using high-speed video images, recorded at 200 frames per second, providing a time resolution of approximately 5 milliseconds (ms).
  • a cylindrical tube 11 of constant radius is used; in this case, a low viscosity of relatively small amounts of liquid mixes well even at near-zero angles. But if the viscosity and / or volume increases or when the oil is added, the zero degree mixture becomes much more difficult.
  • the improvement of the mixture is detectable even at small angles ( figure 8 ). Even small changes help to reduce mixing time, but we see that the best performance is achieved for angles greater than 20 degrees and even with larger angles, mixing time is decreased to levels close to mixing times the fastest for small volumes.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Mixers With Rotating Receptacles And Mixers With Vibration Mechanisms (AREA)
  • Mixers Of The Rotary Stirring Type (AREA)

Description

La présente invention concerne un procédé de mélange d'une solution hétérogène contenant un liquide et une entité solide ou au moins deux liquides différents et, éventuellement, une entité solide afin d'obtenir une solution homogène, procédé dans lequel on dispose la solution hétérogène dans un récipient. Le procédé est particulièrement intéressant car il propose la combinaison d'un mouvement circulaire ou orbital non circulaire du récipient qui possède un axe de symétrie qui est lui-même incliné par rapport à la gravité.The present invention relates to a method for mixing a heterogeneous solution containing a liquid and a solid entity or at least two different liquids and, optionally, a solid entity in order to obtain a homogeneous solution, in which method the heterogeneous solution is available in a container. The method is particularly interesting because it proposes the combination of a circular or orbital non-circular movement of the container which has an axis of symmetry which is itself inclined with respect to gravity.

L'invention propose également un dispositif permettant la mise en oeuvre d'un tel procédé.The invention also proposes a device allowing the implementation of such a method.

Le traitement des échantillons biologiques ou de produits chimiques liquides dans les laboratoires nécessite que ces liquides soient mélangés ensemble et/ou à des composés pour effectuer différentes réactions, notamment des réactions de détection. Il est donc important que le mélange de ces différents mélanges dans un récipient soit optimal pour que là réaction puisse avoir lieu. Un mélange sera d'autant plus difficile à réaliser que les solutions contenant les échantillons biologiques ou les composés réactifs auront :

  • des densités différentes et/ou
  • des viscosités variées et/ou
  • des caractères miscibles très différents les unes des autres,
  • un volume des solutions qui sera petit,
  • etc.
The treatment of biological samples or liquid chemicals in laboratories requires that these liquids be mixed together and / or compounds to perform different reactions, including detection reactions. It is therefore important that the mixing of these different mixtures in a container is optimal for the reaction to take place. A mixture will be all the more difficult to achieve as the solutions containing the biological samples or the reactive compounds will have:
  • different densities and / or
  • varied viscosities and / or
  • miscible characters very different from each other,
  • a volume of solutions that will be small,
  • etc.

En outre, un mélange ne doit pas être effectué avec une force trop brutale qui pourrait créer une suspension non désirée des solutions à mélanger soit par centrifugation, avec séparation de phases, soit sous forme d'aérosols ou d'émulsion, ce qui peut générer, par exemple si l'on traite des acides nucléiques, des contaminations croisées préjudiciables à un diagnostic ultérieur fiable. Enfin, un mélange doit, dans certains cas, être effectué dans un laps de temps défini pour éviter que les solutions à mélanger subissent des variations de température ou bien qu'une réaction secondaire se mette en place.In addition, a mixture should not be performed with too much force that could create a suspension desired solutions to be mixed either by centrifugation, with phase separation, or in the form of aerosols or emulsion, which can generate, for example if one treats nucleic acids, cross-contamination detrimental to a reliable subsequent diagnosis . Finally, a mixture must, in certain cases, be carried out within a defined period of time in order to prevent the solutions to be mixed from being subjected to temperature variations or else a secondary reaction to take place.

Les techniques de mélange utilisées en laboratoire sont plus ou moins complexes à mettre en oeuvre.The mixing techniques used in the laboratory are more or less complex to implement.

Une des techniques de mélange consiste, lors de l'ajout d'une deuxième solution à une première solution présente dans un récipient, d'effectuer alternativement plusieurs fois une aspiration suivie d'un refoulement dans le récipient à l'aide d'un cône par action du piston d'une pipette. L'inconvénient de cette méthode est qu'elle nécessite lors de sa mise en oeuvre une certaine dextérité et délicatesse de la part de l'utilisateur. La répétitivité d'une telle opération est d'ailleurs douteuse en fonction de cet utilisateur et de son état de fatigue, d'énervement, etc. En effet, une fréquence trop élevée des aspirations/refoulements liée à une mauvaise position du cône dans le récipient peut provoquer l'apparition de bulles d'air au sein du mélange. De plus, si le refoulement est effectué avec une vitesse élevée, le volume prélevé sera éjecté avec une force trop importante, ce qui augmente le risque d'éclaboussures par ricochet contre la paroi du récipient et de sortie éventuelle de certaines gouttes. Il peut en résulter une perte de la quantité de solution à mélanger. Par ailleurs, cette perte peut aussi provenir d'une phase de refoulement incomplète au cours de laquelle l'utilisateur n'actionne pas dans sa totalité le piston permettant de chasser le liquide du cône. De plus, cette technique ne permet pas le mélange de solutions de viscosités élevées. Enfin, l'introduction répétée du cône dans le milieu à mélanger augmente sensiblement le risque d'introduire des contaminants.One of the mixing techniques consists, when adding a second solution to a first solution present in a container, to alternately perform suction several times followed by a discharge in the container using a cone by the action of the piston of a pipette. The disadvantage of this method is that it requires during its implementation a certain dexterity and delicacy on the part of the user. The repetitiveness of such an operation is also doubtful depending on this user and its state of fatigue, nervousness, etc. Indeed, too high frequency of suction / discharge related to a bad position of the cone in the container may cause the appearance of air bubbles within the mixture. In addition, if the discharge is carried out with a high speed, the volume taken will be ejected with too much force, which increases the risk of splashing ricochet against the wall of the container and possible exit of some drops. This can result in a loss of the amount of solution to be mixed. Moreover, this loss can also come from an incomplete phase of discharge during which the user does not actuate in its entirety the piston for driving the liquid from the cone. In addition, this technique does not allow the mixing of solutions of high viscosities. Finally, the repeated introduction of the cone into the medium to be mixed substantially increases the risk of introducing contaminants.

Une technique très répandue en laboratoire pour effectuer un mélange consiste à faire subir un vortex, action dite « vortexer », immédiatement après leur introduction dans un récipient des deux solutions. Le brevet US-A-4,555,183 décrit un appareil pour mettre en oeuvre cette technique. Cet appareil permet, lorsque le contact du tube avec l'évidemment du rotor est établi, de mettre en marche le moteur et d'entraîner le rotor à des vitesses de rotation très élevées. Les solutions contenues dans le tube subissent une rotation et un mouvement ascensionnel, l'ensemble créant un tourbillon permettant de mélanger les solutions. Cependant cette technique présente les deux inconvénients majeurs suivants. Tout d'abord, lorsque l'utilisateur retire le tube de l'évidement du rotor, le tourbillon cesse et une partie des solutions redescendent selon le principe de gravité, l'autre partie des solutions restant en contact avec les parois internes du tube, les mouillant, sur une hauteur correspondant à la hauteur du tourbillon. Il est donc nécessaire de procéder à une étape supplémentaire de centrifugation pour récupérer la partie des solutions en contact avec les parois internes du tube. De plus, cette technique ne permet pas de mélanger indépendamment l'une de l'autre deux solutions non miscibles. En effet, du fait de la vitesse de rotation élevée, il se crée une dispersion sous forme de gouttelettes d'une solution dans l'autre. Or dans certains cas, cette émulsion n'est pas désirée. En effet lorsqu'un échantillon biologique est préparé pour une réaction d'amplification par exemple, les enzymes, tampons et autres réactifs utiles à la réaction d'amplification sont ajoutés à l'échantillon biologique ainsi qu'un petit volume d'huile. Ce volume d'huile recouvre le mélange d'amplification et prévient de l'évaporation des réactifs d'amplification lors des différents cycles de chauffage au cours de l'amplification. Pour obtenir un bon rendement d'amplification, il est nécessaire de bien mélanger les différents réactifs de la phase aqueuse sans détruire la couche protectrice d'huile. Or en appliquant la technique décrite dans US-B-4,555,183 à un mélange pour une réaction d'amplification, du fait des fortes vitesses de rotations, la phase huileuse se mélange à la phase aqueuse en créant une émulsion qui empêchera l'action de l'enzyme.A common technique in the laboratory to perform a mixture is to undergo a vortex, action called "vortex", immediately after their introduction into a container of the two solutions. The patent US Patent 4,555,183 describes an apparatus for implementing this technique. This device makes it possible, when the contact of the tube with the rotor is established, to start the motor and to drive the rotor at very high speeds of rotation. The solutions contained in the tube undergo a rotation and an upward movement, all creating a vortex to mix solutions. However, this technique has the following two major drawbacks. Firstly, when the user withdraws the tube from the recess of the rotor, the vortex stops and some of the solutions descend according to the principle of gravity, the other part of the solutions remaining in contact with the inner walls of the tube, the wetting, on a height corresponding to the height of the vortex. It is therefore necessary to carry out an additional centrifugation step to recover the portion of the solutions in contact with the inner walls of the tube. In addition, this technique does not allow to mix independently of one another two immiscible solutions. Indeed, because of the high rotation speed, it creates a dispersion in the form of droplets of a solution in the other. But in some cases, this emulsion is not desired. Indeed, when a biological sample is prepared for an amplification reaction for example, the enzymes, buffers and other reagents useful for the amplification reaction are added to the biological sample and a small volume of oil. This volume of oil covers the amplification mixture and prevents the evaporation of the amplification reagents during the different heating cycles during the amplification. To obtain a good amplification yield, it is necessary to mix the various reagents of the aqueous phase without destroying the protective layer of oil. But by applying the technique described in US-B-4555183 to a mixture for an amplification reaction, because of the high rotational speeds, the oily phase mixes with the aqueous phase creating an emulsion which will prevent the action of the enzyme.

Sur la base de ce même principe, la demande de brevet US-A-2006/0177936 propose un support de tubes universel qui est configuré pour effectuer de la préparation d'échantillon. Un appareil permettant l'action d'un vortex par centrifugation inclus un moteur avec un système de mise en rotation sur lequel le support de tubes universel portable est monté pour permettre sa rotation et son oscillation. Cette technique aboutit à la possibilité de mélanger plus efficacement au moins deux liquides ou au moins un liquide et au moins une entité solide, par exemple, constituée par des particules magnétiques. Par plus efficacement il faut comprendre que cette demande de brevet préconise des mouvements de va-et-vient, dites oscillations. Cette technique a néanmoins quelques inconvénients notamment la formation d'émulsions et/ou d'aérosols, qui entraîne un risque de contamination dans le domaine médical par exemple) ainsi que le mouillage de l'ensemble des parois du récipient avec tous les risques de contamination croisée qui sont inhérentes à ce procédé d'oscillation.On the basis of this same principle, the patent application US-2006/0177936 offers a universal tube holder that is configured to perform sample preparation. An apparatus for centrifugally vortexing includes a motor with a rotating system on which the portable universal tube holder is mounted for rotation and oscillation thereof. This technique results in the ability to more effectively mix at least two liquids or at least one liquid and at least one solid entity, for example, consisting of magnetic particles. More effectively, it should be understood that this patent application advocates back-and-forth movements, called oscillations. This technique nevertheless has some disadvantages including the formation of emulsions and / or aerosols, which entails a risk of contamination in the medical field, for example) as well as the wetting of all the walls of the container with all the risks of contamination. which are inherent in this oscillation process.

L'art antérieur US-A-5,921,676 fait également état d'une technique de mélange mettant en oeuvre un dispositif de mélange dont la plateforme est animée d'un mouvement orbital horizontal et/ou vertical. Cet appareil permet de mélanger des volumes de quantité importante ou moyenne, c'est-à-dire de l'ordre de millilitre. En revanche, il ne permet pas de mélanger efficacement des volumes inférieurs au millilitre. En effet, tant que le diamètre du récipient contenant les solutions à mélanger est supérieur au diamètre du mouvement orbital, le mélange des solutions sera effectif. Le centre du récipient effectue une distance orbitale équivalente à la distance orbitale de la plateforme, générant ainsi des forces centrifuges dans le liquide qui changent diamétralement de direction à chaque demi-rotation et permettent le mélange des solutions. En revanche lorsque le diamètre du récipient est inférieur au diamètre du mouvement orbital, ce qui est le cas par exemple pour des tubes Eppendorf®, les solutions subissent des forces centrifuges qui les poussent contre la paroi pendant toute la durée du mouvement orbital. Il n'y a pas de contraintes de changements de direction des forces de centrifugation, donc le mélange ne peut se faire, les solutions ont le même parcours que la plateforme sur laquelle est posé le récipient. De plus la répétitivité du mouvement est tout à fait hypothétique.The prior art US Patent 5,921,676 also discloses a mixing technique using a mixing device whose platform is driven by an orbital movement horizontal and / or vertical. This device makes it possible to mix volumes of large or medium quantity, that is to say of the order of milliliter. On the other hand, it does not make it possible to effectively mix volumes smaller than one milliliter. Indeed, as the diameter of the container containing the solutions to be mixed is greater than the diameter of the orbital movement, the mixture of solutions will be effective. The center of the container performs an orbital distance equivalent to the orbital distance of the platform, thereby generating centrifugal forces in the liquid that change diametrically direction at each half rotation and allow mixing of the solutions. On the other hand, when the diameter of the container is smaller than the diameter of the orbital movement, which is the case, for example, for Eppendorf® tubes, the solutions undergo centrifugal forces which push them against the wall during the entire duration of the orbital movement. There are no constraints of direction changes of the centrifugation forces, so mixing can not be done, the solutions have the same path as the platform on which the container is placed. Moreover, the repetitiveness of the movement is quite hypothetical.

Le document FR-A-2.436.624 concerne un appareil permettant de mélanger une matière fluide dans un récipient, comprenant : un premier moyen de support du récipient, permettant sa rotation autour d'un premier axe ; un second moyen de support du récipient, permettant sa rotation autour d'un second axe qui n'est pas perpendiculaire du premier ; un premier moyen d'entraînement qui est raccordé audit second moyen de support pour faire tourner le récipient autour dudit second axe ; et un second moyen d'entraînement qui est raccordé audit premier moyen de support pour faire tourner le récipient autour dudit premier axe tandis que le récipient tourne autour dudit second axe. Le problème de ce type d'appareil est que les deux axes de rotation sont toujours intersectés. Il y a donc une zone au voisinage de cette intersection qui ne présente quasiment aucun mouvement, il y aura donc un mélange qui sera différentiel entre les points les plus proches et les plus éloignés de ce point d'intersection et donc un mélange non homogène au sein du ou des liquides.The document FR-A-2436624 apparatus for mixing a fluid material in a container, comprising: a first container support means for rotating about a first axis; second means for supporting the container, allowing its rotation about a second axis which is not perpendicular to the first; first drive means connected to said second support means for rotating the container about said second axis; and a second driving means which is connected to said first support means for rotating the container about said first axis while the container is rotating about said second axis. The problem with this type of device is that both axes of rotation are always intersected. There is therefore an area in the vicinity of this intersection that has almost no movement, so there will be a mixture that will be differential between the closest and the farthest points of this intersection point and therefore a non-homogeneous mixture at the intersection. within the liquid or liquids.

De plus les dispositifs de l'art antérieur ne parviennent pas à mélanger de petits volumes de solutions hétérogènes en une solution homogène tout en prévenant de la formation d'émulsions et/ou d'aérosols (risque de contamination dans le domaine médical par exemple) et du mouillage de l'ensemble des parois du récipient. Il existe donc toujours un besoin d'un nouveau dispositif de mélange contrecarrant les inconvénients de ceux de l'art antérieur.In addition, the devices of the prior art fail to mix small volumes of heterogeneous solutions into a homogeneous solution while preventing the formation of emulsions and / or aerosols (risk of contamination in the medical field for example) and wetting all the walls of the container. There is therefore still a need for a new mixing device counteracting the disadvantages of those of the prior art.

Pour ce faire, la Demanderesse propose un nouveau dispositif permettant le mélange de solutions hétérogènes afin d'obtenir une solution homogène. Grâce au dispositif selon l'invention, les solutions contenues dans le récipient subissent des accélérations et des décélérations successives dont l'intensité sinusoïdale permet leur agitation douce tout en évitant un mouillage de la totalité des parois du récipient et/ou une dispersion des phases des différentes solutions. Ce dispositif permet également de s'affranchir d'une étape de centrifugation après le mélange.To do this, the Applicant proposes a new device for mixing heterogeneous solutions to obtain a homogeneous solution. Thanks to the device according to the invention, the solutions contained in the container undergo successive accelerations and decelerations whose sinusoidal intensity allows their gentle agitation while avoiding wetting of the entire walls of the container and / or a dispersion of the phases of the different solutions. This device also makes it possible to dispense with a centrifugation step after mixing.

Par « solution hétérogène » au sens de la présente invention, on entend au moins deux liquides ou fluides miscibles en phase aqueuse ayant des propriétés et viscosités différentes. Ces fluides peuvent contenir des entités solides ou des particules en suspension. Ces liquides et éventuellement les entités solides qui sont contenues dans ces liquides sont répartis de manière non-uniforme et irrégulière dans le récipient qui les contient.For the purposes of the present invention, the term "heterogeneous solution" means at least two liquids or fluids which are miscible in the aqueous phase and have different properties and viscosities. These fluids may contain solid entities or suspended particles. These liquids and possibly the solid entities that are contained in these liquids are unevenly and irregularly distributed in the container containing them.

Le terme « solution homogène » selon l'invention signifie une solution dont les éléments constitutifs sont répartis de manière uniforme et régulière dans le récipient qui les contient.The term "homogeneous solution" according to the invention means a solution whose constituent elements are uniformly and regularly distributed in the container which contains them.

Le terme « mélanger », au sens de la présente invention, signifie réunir dans un récipient au moins deux liquides ayant des propriétés différentes de manière à ce qu'ils ne forment qu'un seul liquide dont les éléments constitutifs sont répartis de manière uniforme et homogène. Il peut également s'agir d'au moins un liquide associé à au moins un type d'entités solides ou de particules en suspension. Les termes « disperser » et « homogénéiser » peuvent être employés indifféremment en lieu et place du terme « mélanger ».The term "mixing", in the sense of the present invention, means joining in a container at least two liquids having different properties so that they form a single liquid whose constituent elements are distributed uniformly and homogeneous. It can also be at least one liquid associated with at least one type of solid entities or particles in suspension. The terms "disperse" and "homogenize" can be used interchangeably instead of "mix".

Par « entité solide », on entend au sens de la présente invention des particules qui peuvent être en latex, en verre (CPG), en silice, en polystyrène, en agarose, en sépharose, en nylon, etc. Ces matériaux peuvent éventuellement permettre le confinement de matière magnétique. Il peut s'agir également d'un filtre, d'un film, d'une membrane ou d'une bandelette. Ces matériaux sont bien connus de l'homme du métier.For the purposes of the present invention, the term "solid entity" is intended to mean particles which may be made of latex, glass (GPC), silica, polystyrene, agarose, sepharose, nylon, etc. These materials may possibly allow the confinement of magnetic material. It can also be a filter, a film, a membrane or a strip. These materials are well known to those skilled in the art.

Le terme « rotation » au sens de la présente invention définit un mouvement plan d'un corps où tous les points du corps décrivent des trajectoires de même forme géométrique mais qui ont des centres différents, les centres étant parallèles entre eux au cours du mouvement. La trajectoire peut avoir la forme d'un cercle ; le corps subit une translation rotative. Selon une autre forme de l'invention, la trajectoire peut être elliptique ; le corps subit une translation elliptique. Par exemple, si le corps est un tube Eppendorf® positionné initialement de la manière suivante : l'extrémité du capuchon se situe à une distance L1 de l'axe du mouvement de rotation (position dite la plus proche de l'axe) et l'extrémité du fond du tube se situe à une distance L2 de l'axe du mouvement de rotation (position dite la plus éloignée de l'axe). Lorsque le mouvement de rotation se met en marche autour de son axe, l'extrémité du capuchon et l'extrémité du fond forment un segment qui se déplace de façon parallèle autour de cet axe ; le segment décrivant par exemple une trajectoire en forme de cercle. Lorsque le segment a parcouru une distance d'un quart de cercle, l'extrémité du capuchon et l'extrémité du cercle se trouvent à la même distance L3 de l'axe du mouvement. Lorsque le segment a parcouru une distance d'un demi-cercle depuis la position initiale, à cause de ce déplacement parallèle du segment, l'extrémité du capuchon se situe à une distance L2 de l'axe du mouvement et l'extrémité du fond du tube se situe à la distance L1 de l'axe du mouvement. Ainsi la partie du tube initialement la plus proche de l'axe se retrouve dans la position la plus éloignée de cet axe après une demi rotation et vice-versa.The term "rotation" in the sense of the present invention defines a plane motion of a body where all the points of the body describe trajectories of the same geometrical shape but which have different centers, the centers being parallel to each other during the movement. The trajectory can be in the form of a circle; the body rotates. According to another form of the invention, the trajectory can be elliptical; the body undergoes a elliptical translation. For example, if the body is an Eppendorf® tube positioned initially as follows: the end of the cap is located at a distance L1 from the axis of the rotational movement (the position said to be closest to the axis) and the end of the bottom of the tube is at a distance L2 from the axis of the rotational movement (so-called position furthest from the axis). When the rotational movement starts about its axis, the end of the cap and the end of the bottom form a segment which moves in a parallel manner about this axis; the segment describing for example a trajectory in the form of a circle. When the segment has traveled a quarter circle distance, the end of the cap and the end of the circle are at the same distance L3 from the axis of the movement. When the segment has traveled a half-circle distance from the initial position, because of this parallel displacement of the segment, the end of the cap is at a distance L2 from the axis of the movement and the end of the bottom of the tube is at the distance L1 from the axis of the movement. Thus the part of the tube initially closest to the axis is found in the furthest position of this axis after half a rotation and vice versa.

Le terme « volume d'air suffisant » désigne une partie d'un espace du récipient occupé par de l'air permettant au cours du mouvement de rotation le libre déplacement des liquides à l'intérieur du récipient.The term "sufficient air volume" denotes a portion of a space of the air-filled vessel allowing during the rotational movement the free movement of liquids within the container.

Par « position sensiblement verticale » on signifie dans la présente invention, toute position variant d'un angle compris entre 0° et ±2° par rapport à un axe de gravité.By "substantially vertical position" is meant in the present invention, any position varying from an angle between 0 ° and ± 2 ° with respect to an axis of gravity.

La présente invention concerne un procédé de mélange d'une solution hétérogène contenant au moins deux liquides différents et, éventuellement, au moins une entité solide afin d'obtenir une solution homogène, le procédé comprenant les étapes suivantes :

  1. a) disposer tout ou partie de la solution hétérogène dans au moins un récipient ayant un axe longitudinal ;
  2. b) positionner le récipient au niveau d'un support mû autour d'un axe de rotation, l'axe longitudinal étant incliné par rapport à l'axe de rotation ;
  3. c) mettre en mouvement le support portant ledit récipient pour permettre à la partie du récipient la plus proche dudit axe de rotation de se retrouver dans la position la plus éloignée de cet axe après une demie-rotation, et à la partie du récipient la plus éloignée de l'axe de rotation de se retrouver en position la plus proche de celui-ci après une demie-rotation, afin de soumettre la solution contenue dans le récipient à des accélérations et décélérations successives dont l'intensité est sinusoïdale, ce qui permet l'agitation de ladite solution hétérogène qui devient homogène.
The present invention relates to a method for mixing a heterogeneous solution containing at least two different liquids and, optionally, at least one solid entity to to obtain a homogeneous solution, the process comprising the following steps:
  1. a) disposing all or part of the heterogeneous solution in at least one container having a longitudinal axis;
  2. b) positioning the container at a support rotated about an axis of rotation, the longitudinal axis being inclined relative to the axis of rotation;
  3. c) moving the support carrying said container to allow the part of the container closest to said axis of rotation to be in the position furthest from this axis after a half-rotation, and to the part of the container the most away from the axis of rotation to be in the closest position thereof after a half-rotation, to subject the solution contained in the vessel to successive accelerations and decelerations whose intensity is sinusoidal, which allows agitating said heterogeneous solution which becomes homogeneous.

Ce procédé peut également s'appliquer au mélange d'une solution hétérogène contenant au moins un liquide et au moins une entité solide.This method can also be applied to mixing a heterogeneous solution containing at least one liquid and at least one solid entity.

Quel que soit le mode de réalisation, lors de la mise en mouvement du support, l'axe longitudinal du récipient coupe par deux fois l'axe de rotation dudit support par tour de rotation.Whatever the embodiment, when moving the support, the longitudinal axis of the container crosses twice the axis of rotation of said support per revolution.

Quel que soit le mode de réalisation, le récipient contient outre la solution hétérogène un volume d'air suffisant pour permettre l'agitation sans que tout ou partie de ladite solution hétérogène ne puisse sortir dudit récipient lors du mélange.Whatever the embodiment, the container contains in addition to the heterogeneous solution a volume of air sufficient to allow agitation without all or part of said heterogeneous solution can not leave said container during mixing.

Selon une variante au mode de réalisation du paragraphe précédent, le récipient contient outre la solution hétérogène un volume d'air suffisant pour permettre l'agitation et est fermé par un bouchon, afin que tout ou partie de ladite solution hétérogène ne puisse sortir dudit récipient lors du mélange.According to a variant of the embodiment of the preceding paragraph, the container contains in addition to the heterogeneous solution a volume of air sufficient to allow agitation and is closed by a plug, so that all or part of said heterogeneous solution can not leave said container when mixing.

Quel que soit le mode de réalisation, l'inclinaison de l'axe longitudinal du récipient varie en fonction de la vitesse de rotation et/ou en fonction de sa position lors de la rotation.Whatever the embodiment, the inclination of the longitudinal axis of the container varies according to the speed of rotation and / or according to its position during rotation.

Toujours quel que soit le mode de réalisation précédemment décrit, le mouvement du support est circulaire.Still whatever the embodiment previously described, the movement of the support is circular.

Selon une variante au mode de réalisation du paragraphe précédent, le mouvement du support est ellipsoïdal.According to a variant of the embodiment of the preceding paragraph, the movement of the support is ellipsoidal.

La présente invention concerne également un dispositif permettant le mélange d'une solution hétérogène contenant au moins deux liquides différents et, éventuellement, au moins une entité solide, ou bien contenant au moins un liquide et au moins une entité solide, afin d'obtenir une solution homogène, qui est constitué de :

  1. i. un châssis statique pouvant, éventuellement, être posé sur une table ou tout autre surface,
  2. ii. un support mobile pouvant accueillir au moins un récipient ayant un axe longitudinal,
  3. iii. un moyen de motorisation fixé au châssis et apte à générer un mouvement de rotation, et
  4. iv. un moyen de transmission permettant la transmission du mouvement de rotation du moyen de motorisation vers le support mobile, l'action du moyen de transmission positionne le récipient afin que la partie du récipient la plus proche de l'axe de rotation se retrouve dans la position la plus éloignée de cet axe après une demie rotation, et que la partie du récipient la plus éloignée de l'axe de rotation se retrouve en position la plus proche de celui-ci après une demie rotation, afin de soumettre la solution contenue dans le récipient à des accélérations et décélérations successives dont l'intensité est sinusoïdale.
The present invention also relates to a device for mixing a heterogeneous solution containing at least two different liquids and, optionally, at least one solid entity, or containing at least one liquid and at least one solid entity, in order to obtain a homogeneous solution, which consists of:
  1. i. a static frame that can possibly be placed on a table or other surface,
  2. ii. a mobile support that can accommodate at least one container having a longitudinal axis,
  3. iii. motor means fixed to the frame and adapted to generate a rotational movement, and
  4. iv. transmission means for transmitting the rotational movement of the drive means to the movable support, the action of the transmission means positions the container so that the portion of the container closer to the axis of rotation is found in the position farthest from this axis after a half rotation, and that the part of the container farthest from the axis of rotation is found in the nearest position thereof after a half rotation, in order to subject the solution contained in the vessel to successive accelerations and decelerations whose intensity is sinusoidal.

Quel que soit le mode de réalisation du dispositif, l'axe de rotation du support est en position sensiblement verticale et que l'axe longitudinal du récipient n'est pas en position sensiblement verticale.Whatever the embodiment of the device, the axis of rotation of the support is in a substantially vertical position and that the longitudinal axis of the container is not in a substantially vertical position.

Quel que soit le mode de réalisation, un angle d'inclinaison de l'axe longitudinal du récipient par rapport à l'axe de rotation du support existe, et que lorsque les deux axes sont intersectés, l'angle est compris entre 1 et 60°, préférentiellement entre 20 et 50° et encore plus préférentiellement ente 25 et 45°.Whatever the embodiment, an angle of inclination of the longitudinal axis of the container relative to the axis of rotation of the support exists, and when the two axes are intersected, the angle is between 1 and 60 °, preferably between 20 and 50 ° and even more preferably between 25 and 45 °.

Quel que soit le mode de réalisation, le récipient est fermé.Whatever the embodiment, the container is closed.

La méthode que nous avons développée ne souffre d'aucun des susdits inconvénients. Les avantages de l'invention sur des méthodes de mélange disponibles actuellement sont :

  1. 1. Mouiller uniquement une zone limitée de la surface intérieure du récipient.
  2. 2. Permettre d'utiliser une gamme plus large de fréquences orbitales et des amplitudes au lieu d'une combinaison d'amplitude et de fréquence d'oscillation fermement définie.
  3. 3. Utiliser une gamme relativement large d'angles entre l'axe longitudinal du contenant et l'axe de rotation, en facilitant l'optimisation de ces paramètres plus simple et plus souple d'utilisation.
  4. 4. Autoriser un mouvement des liquides et ainsi le mélange qui soit suffisamment doux et lisse pour que le risque de formation d'aérosols soit beaucoup moins critique, voire inexistant, que dans le cas d'un mélange par vortex ou de type orbital, tel que décrit dans l'état de la technique.
  5. 5. Permettre ainsi le mélange efficace même sans fermeture du récipient et en diminuant fortement les risques de contamination.
The method we developed does not suffer from any of the above disadvantages. The advantages of the invention over currently available mixing methods are:
  1. 1. Wet only a limited area of the inner surface of the container.
  2. 2. Allow the use of a wider range of orbital frequencies and amplitudes instead of a combination of amplitude and oscillation frequency.
  3. 3. Use a relatively wide range of angles between the longitudinal axis of the container and the axis of rotation, facilitating the optimization of these parameters simpler and more flexible to use.
  4. 4. Allow a movement of liquids and thus the mixture which is sufficiently soft and smooth so that the risk of aerosol formation is much less critical or non-existent than in the case of vortex or orbital mixing, such as described in the state of the art.
  5. 5. Allow effective mixing even without closing the container and greatly reducing the risk of contamination.

Le mélangeur selon l'invention utilise essentiellement un dispositif de mélange « orbital » connu, mais au lieu de placer le tube avec son axe de symétrie parallèle à l'axe de rotation, nous plaçons l'axe de symétrie du tube avec un angle non parallèle avec l'axe de rotation du dispositif et avec la gravité.The mixer according to the invention essentially uses a known "orbital" mixing device, but instead of placing the tube with its axis of symmetry parallel to the axis of rotation, we place the axis of symmetry of the tube at a non-symmetrical angle. parallel with the axis of rotation of the device and with gravity.

L'amélioration de la performance de mélange est réalisée pour n'importe quel angle supérieur à zéro (zéro étant équivalent à deux axes parallèles). Bien entendu, cet angle peut varier en fonction des combinaisons spécifiques utilisées, basées sur :

  • la forme du récipient ou tube, et
  • des propriétés des liquides à mélanger,
pour lesquelles des gammes plus limitées d'angle peuvent être nécessaires.The improvement of the mixing performance is performed for any angle greater than zero (zero being equivalent to two parallel axes). Of course, this angle can vary depending on the specific combinations used, based on:
  • the shape of the container or tube, and
  • properties of the liquids to be mixed,
for which more limited ranges of angle may be required.

La méthode peut être utilisée avec des récipients de réaction de pratiquement n'importe quelle forme, et présente le plus d'avantages dans des cas où des méthodes classiques, à oscillation orbitale ou par vortex, ne sont pas adaptées.The method can be used with reaction vessels of virtually any shape, and has the most benefit in cases where conventional orbital or vortex oscillation methods are not suitable.

Les exemples et figures ci-joints représentent des modes particuliers de réalisation et ne peuvent pas être considérés comme limitant la portée de la présente invention.

  • La figure 1 représente un mélangeur orbital selon l'état de la technique.
  • La figure 2 présente un mélangeur selon la présente invention.
  • La figure 3 met en exergue le récipient dans deux positions différentes de son mouvement lorsqu'il est actionné par le mélangeur orbital selon l'invention ainsi que l'intensité des forces qui sont appliquées au liquide.
  • La figure 4 propose une représentation du mouvement le plus important subi par le liquide lors de la décélération montrée en figure 3.
  • La figure 5 représente les principaux flux liquides qui améliorent le mélange lors d'une rotation du mélangeur.
  • La figure 6 montre deux types différents de récipient utilisés par les inventeurs.
  • La figure 7 est un graphe avec en abscisse les vitesses du moteur, qui correspondent aux fréquences en tours par minute, et en ordonnée l'amplitude de rotation orbitale, exprimée en millimètre (mm).
  • La figure 8 est un graphe avec en abscisse l'angle d'inclinaison du récipient, mesuré en degré par rapport à la verticale, et en ordonnée la durée de mélange (MT exprimée en seconde) pour aboutir à l'homogénéité avec un récipient cylindrique selon la figure 6b.
  • La figure 9 est un graphe avec en abscisse l'angle d'inclinaison du récipient, mesuré en degré (Ang. (deg)) par rapport à la verticale, et en ordonnée la durée de mélange en seconde (MT (s)) pour aboutir à l'homogénéité avec un récipient Eppendorf® selon la figure 6a.
  • La figure 10 montre un graphe avec en abscisse la fréquence du mouvement de rotation du récipient cylindrique qui possède un angle d'inclinaison fixe de 45° par rapport à la verticale, et en ordonnée la durée de mélange en seconde pour aboutir à l'homogénéité avec un récipient cylindrique selon la figure 6b selon différentes concentrations d'un produit visqueux et en présence ou absence d'une couche d'huile.
The examples and accompanying figures show particular embodiments and can not be considered as limiting the scope of the present invention.
  • The figure 1 represents an orbital mixer according to the state of the art.
  • The figure 2 presents a mixer according to the present invention.
  • The figure 3 emphasizes the container in two different positions of its movement when actuated by the orbital mixer according to the invention as well as the intensity of the forces that are applied to the liquid.
  • The figure 4 proposes a representation of the most important movement undergone by the liquid during the deceleration shown in figure 3 .
  • The figure 5 represents the main liquid streams that improve the mixing during a rotation of the mixer.
  • The figure 6 shows two different types of containers used by the inventors.
  • The figure 7 is a graph with abscissa the engine speeds, which correspond to the frequencies in revolutions per minute, and ordinate the orbital rotation amplitude, expressed in millimeters (mm).
  • The figure 8 is a graph with the abscissa angle of inclination of the container, measured in degrees from the vertical, and the ordinate the mixing time (MT expressed in seconds) to achieve homogeneity with a cylindrical container according to the figure 6b .
  • The figure 9 is a graph with the abscissa angle of inclination of the container, measured in degrees (Ang (deg)) relative to the vertical, and the ordinate the mixing time in seconds (MT (s)) to reach the homogeneity with an Eppendorf® container according to figure 6a .
  • The figure 10 shows a graph with the abscissa the frequency of the rotational movement of the cylindrical container which has a fixed angle of inclination of 45 ° with respect to the vertical, and the ordinate the mixing time in seconds to achieve homogeneity with a container cylindrical according to figure 6b according to different concentrations of a viscous product and in the presence or absence of a layer of oil.

PRINCIPE OPERATOIREOPERATIVE PRINCIPLE Le schéma mécanique normal pour un mouvement orbital : The normal mechanical diagram for an orbital movement :

La disposition mécanique normale pour le mouvement orbital comme moyen de mélange pour des liquides est montrée sur la figure 1. Il y a un support solide, par exemple une table horizontale 1, des mouvements confinés dans de petits cercles ou rotation 2 ayant un rayon 5 et un axe de symétrie/rotation 3 de la table 1, préférentiellement parallèle à la gravité.The normal mechanical arrangement for orbital motion as a mixing medium for liquids is shown on the figure 1 . There is a solid support, for example a horizontal table 1, movements confined in small circles or rotation 2 having a radius 5 and an axis of symmetry / rotation 3 of the table 1, preferably parallel to the gravity.

Chaque récipient 7, dont le contenu doit être mélangé, est placé verticalement sur ladite table 1 avec son axe de symétrie 4 parallèle à l'axe de rotation 3. Dans l'état de la technique sur les mélangeurs orbitaux que la Demanderesse a identifiée cette même géométrie est utilisée.Each container 7, the contents of which must be mixed, is placed vertically on said table 1 with its axis of symmetry 4 parallel to the axis of rotation 3. In the state of the art on the orbital mixers that the Applicant has identified this same geometry is used.

Dans cette géométrie le mécanisme travaille pour générer un vortex. Ainsi le liquide (en fait les deux liquides que l'on souhaite mélanger, mais pour des raisons pratiques nous utiliserons le singulier par la suite) est accéléré et, dans un mouvement de type oscillation, commence à se déplacer de manière synchrone le long du mur vertical du récipient avec le centre de gravité du liquide à l'extérieur de l'orbite.In this geometry the mechanism works to generate a vortex. Thus the liquid (in fact the two liquids that we wish to mix, but for practical reasons we will use the singular later) is accelerated and, in an oscillation-like movement, begins to move synchronously along the vertical wall of the container with the center of gravity of the liquid outside the orbit.

Une supposition de base de cette méthodologie est que le liquide est en effet forcé dans un mouvement oscillant, qui exige une combinaison d'amplitude et la fréquence du mélangeur qui correspond à la combinaison du diamètre du récipient et des propriétés du liquide, comme la viscosité, densité et la tension de la surface. Avec les récipients de réaction non cylindriques, qui sont souvent utilisés dans biologie moléculaire, on peut supposer qu'il n'y a pas une combinaison d'amplitude de fréquence unique qui soit optimale : à une amplitude fixe la partie de fond étroit exige des fréquences plus hautes que la partie supérieure plus large du récipient. Cela est parfaitement illustré lors d'une expérimentation, qui montre que le mélange n'est pas complètement réalisé dans la partie la plus étroite du récipient la teinture du traceur étant absente.A basic assumption of this methodology is that the liquid is indeed forced in an oscillating motion, which requires a combination of amplitude and frequency of the mixer which corresponds to the combination of the diameter of the container and properties of the liquid, such as viscosity, density and surface tension. With non-cylindrical reaction vessels, which are often used in molecular biology, it may be assumed that there is not a combination of single frequency amplitude that is optimal: at a fixed amplitude the narrow bottom part requires frequencies higher than the wider upper part of the container. This is well illustrated in an experiment, which shows that the mixture is not completely made in the narrowest part of the container since the dye of the tracer is absent.

Une solution pour améliorer ce mélange serait simple, mais souffre de quelques inconvénients. Ainsi il faut augmenter la fréquence du mouvement orbital dans une telle mesure que, indépendamment du contenu du récipient, le liquide est mélangé. Un inconvénient clé de cette approche est qu'inévitablement le bouchon, qui cloisonne ledit récipient, est mouillé, avec une perte de liquide préjudiciable dans le domaine du diagnostique médical. En plus de cela, si une fine couche d'huile était présente sur le liquide, le mélange avec les liquides aqueux aboutirait à une émulsion, que l'on souhaite bien évidemment éviter.A solution to improve this mixture would be simple, but suffers from some disadvantages. Thus, the frequency of the orbital movement must be increased to such an extent that, independently of the contents of the container, the liquid is mixed. A key disadvantage of this approach is that inevitably the plug, which partitions said container, is wet, with loss of liquid detrimental in the field of medical diagnosis. In addition to this, if a thin layer of oil was present on the liquid, mixing with the aqueous liquids would result in an emulsion, which one obviously wishes to avoid.

Pour cette raison nous avons trouvé une façon différente d'utiliser le mélangeur orbital. Au lieu de chercher une façon d'introduire le vortex, nous avons décidé de chercher un autre modèle de mouvement des liquides qui induirait le mélange.For this reason we have found a different way to use the orbital mixer. Instead of looking for a way to introduce the vortex, we decided to look for another model of fluid movement that would induce mixing.

Géométrie préférée du dispositif de mélange : Preferred geometry of the mixing device :

Au lieu de placer le récipient 7 avec son axe de symétrie 4 parallèle à l'axe de rotation 3 du mélangeur 9, nous avons placé ledit récipient 7 sous un certain angle 6, comme cela est bien représenté sur la figure 2.Instead of placing the container 7 with its axis of symmetry 4 parallel to the axis of rotation 3 of the mixer 9, we placed said container 7 at an angle 6, as is well represented on the figure 2 .

Lors de la mise en application, un mélangeur orbital 9, selon l'invention, dans lequel le récipient 7 contenant le liquide 8 à être mélangé est placé sous un angle 6 par rapport à l'axe de rotation 3, lui-même parallèle à la gravité. De plus et cela est représenté sur la figure 3, l'inclinaison du récipient 7 est toujours la même par rapport à l'horizontale ou la verticale pour un observateur extérieur en position latérale. En d'autres termes, un observateur dans cette position aura la sensation que le récipient 7 bougera alternativement à gauche et à droite et inversement, ledit récipient 7 qui reste une inclinaison stable.During implementation, an orbital mixer 9, according to the invention, in which the container 7 containing the liquid 8 to be mixed is placed at an angle 6 with respect to the axis of rotation 3, itself parallel to gravity. More and this is represented on the figure 3 , the inclination of the container 7 is always the same relative to the horizontal or the vertical for an outside observer in lateral position. In other words, an observer in this position will have the feeling that the container 7 will move alternately left and right and vice versa, said container 7 which remains a stable inclination.

L'inspection visuelle, avec une caméra vidéo haut débit, du contenu du récipient 7 montre clairement deux différences saisissantes entre le mélange orbital classique et ce mode de mélange angulaire :

  1. 1. Sans bouger, la symétrie de la surface liquide est perdue et la circonférence du ménisque et l'angle de contact diffère avec l'angle du récipient 7.
  2. 2. En bougeant selon la flèche 2 sur le support 1, le mouvement de la surface du liquide 8 ressemble alors à des vagues, et en utilisant une teinture de traceur pour suivre sa redistribution spatiale pendant le mélange, il est facile d'observer un mouvement liquide comme présenté sur les figures 5a et 5b, selon la différence d'orientation de rotation.
Visual inspection, with a high-speed video camera, of the contents of the container 7 clearly shows two striking differences between the conventional orbital mixture and this mode of angular mixing:
  1. 1. Without moving, the symmetry of the liquid surface is lost and the circumference of the meniscus and the angle of contact differs with the angle of the container 7.
  2. 2. By moving according to the arrow 2 on the support 1, the movement of the surface of the liquid 8 then resembles waves, and by using a tracer dye to follow its spatial redistribution during the mixing, it is easy to observe a liquid motion as presented on the Figures 5a and 5b , depending on the rotation orientation difference.

C'est la combinaison de la distribution du liquide 8 qui est asymétrique, de la superficie accrue dudit liquide 8, de l'accélération sinusoïdale changeante avec de vraies accélérations, selon la flèche 9a et des ralentissements selon la flèche 9b (figure 3) qui facilite le flux, le reflux et donc le mélange. Ces accélérations selon la flèche 9a et ralentissements selon la flèche 9b correspondent respectivement aux mouvements observés dans les figures 5b et 5a. Au lieu de former un vortex, comme c'est le cas dans le mélange orbital classique à l'intérieur du liquide, et de retrouver le liquide enduit sur la surface intérieure du récipient 7, cette méthode conserve le liquide le plus groupé possible, tout en le balançant suffisamment pour que le liquide situé au fond dudit récipient 7 soit mis en mouvement également. Le mouvement interne du liquide est en fait une rotation autour d'un axe perpendiculaire aux deux autres axes, à savoir l'axe de gravité et l'axe de symétrie 4 du récipient 7.It is the combination of the distribution of the liquid 8 which is asymmetrical, the increased surface area of said liquid 8, the changing sinusoidal acceleration with real accelerations, according to the arrow 9a and slowdowns according to the arrow 9b ( figure 3 ) which facilitates the flow, the reflux and therefore the mixture. These accelerations according to the arrow 9a and slowdowns according to the arrow 9b respectively correspond to the movements observed in the Figures 5b and 5a . Instead of forming a vortex, as is the case in the conventional orbital mixture inside the liquid, and to find the liquid coated on the inner surface of the container 7, this method keeps the most grouped liquid possible, while by swaying it sufficiently so that the liquid located at the bottom of said container 7 is set in motion as well. The internal movement of the liquid is in fact a rotation about an axis perpendicular to the two other axes, namely the axis of gravity and the axis of symmetry 4 of the container 7.

EXEMPLESEXAMPLES 1 - Mode opératoire : 1 - Operating mode :

Nous avons utilisé et testé deux récipients ou tubes de formes géométriques différentes, tout d'abord un tube Eppendorf® 10 (figure 6a) et ensuite un tube plus classique, dit tube cylindrique 11 (figure 6b). Les tubes utilisés dans ces expériences ont donc un diamètre intérieur maximal de 5 millimètres (mm).We used and tested two containers or tubes of different geometrical shapes, first of all an Eppendorf® 10 tube ( figure 6a ) and then a more traditional tube, called a cylindrical tube 11 ( figure 6b ). The tubes used in these experiments therefore have a maximum inside diameter of 5 millimeters (mm).

Il y a d'autre part :

  1. 1. trois fluides différents de viscosité croissante, contenant soit 0, soit 1, soit 1,5 M de sorbitol,
  2. 2. avec pour chaque concentration la présence ou non d'huile sur la phase aqueuse,
  3. 3. avec une solution de teinture aqueuse ajoutée entre l'huile et la solution, contenant le sorbitol.
There is on the other hand:
  1. 1. three different fluids of increasing viscosity, containing either 0, 1 or 1.5 M sorbitol,
  2. 2. with for each concentration the presence or absence of oil on the aqueous phase,
  3. 3. with an aqueous stain solution added between the oil and the solution, containing the sorbitol.

On souhaite donc examiner :

  1. 1. A quel angle d'inclinaison le mélange est amélioré ?
  2. 2. A quelles gammes de fréquence le mélange est amélioré ?
  3. 3. Quel est l'effet de la viscosité et/ou de la couche d'huile sur le temps de mélange.
We therefore wish to examine:
  1. 1. At which angle of inclination is the mixture improved?
  2. 2. At which frequency ranges is the mixture improved?
  3. 3. What is the effect of the viscosity and / or the oil layer on the mixing time.

La qualité du mélange a été jugée visuellement, à l'aide d'images vidéo à haut débit, enregistrées à 200 images par seconde, fournissant une résolution de temps d'approximativement 5 millisecondes (ms).The quality of the blend was judged visually, using high-speed video images, recorded at 200 frames per second, providing a time resolution of approximately 5 milliseconds (ms).

2 - Impact de la forme du récipient, de la viscosité du liquide et présence ou non d'une couche d'huile : 2 - Impact of the shape of the container, the viscosity of the liquid and presence or absence of a layer of oil :

Pour une amplitude du dispositif 9 fixe, l'amplitude de la table 1 a toujours été constante quelque soit le réglage de vitesse de rotation. C'est ce que montre bien la figure 7, avec en abscisse les vitesses du moteur (qui correspondent aux fréquences) et en ordonnée l'amplitude de rotation orbitale. La figure 8 présente donc la réduction du temps nécessaire pour mélanger le liquide en changeant l'angle du tube cylindrique entre 0 degré (selon l'usage avec un mélange orbital classique) jusqu'aux valeurs de 50 degrés.For an amplitude of the fixed device 9, the amplitude of the table 1 has always been constant regardless of the speed setting. This is the proof of the figure 7 , with abscissa the engine speeds (which correspond to the frequencies) and ordinate the orbital rotation amplitude. The figure 8 therefore, the reduction in the time required to mix the liquid by changing the angle of the cylindrical tube between 0 degrees (depending on the use with a conventional orbital mixture) up to the values of 50 degrees.

Sur la figure 8, on utilise un tube cylindrique 11 de rayon constant ; dans ce cas, une faible viscosité d'assez petites quantités de liquide se mélange bien même aux angles proche de zéro. Mais si la viscosité et/ou le volume augmente ou quand l'huile est ajoutée, le mélange à zéro degré devient beaucoup plus difficile. En utilisant 60 µl de liquide aqueux dans un tube cylindrique 11, l'amélioration du mélange est détectable même à de petits angles (figure 8). Même de petits changements aident à réduire le temps de mélange, mais on voit que la meilleure performance est obtenue pour des angles supérieurs à 20 degrés et même avec des angles plus important, le temps de mélange est diminué à des niveaux proche des temps de mélange les plus rapides pour de petits volumes.On the figure 8 a cylindrical tube 11 of constant radius is used; in this case, a low viscosity of relatively small amounts of liquid mixes well even at near-zero angles. But if the viscosity and / or volume increases or when the oil is added, the zero degree mixture becomes much more difficult. By using 60 μl of aqueous liquid in a cylindrical tube 11, the improvement of the mixture is detectable even at small angles ( figure 8 ). Even small changes help to reduce mixing time, but we see that the best performance is achieved for angles greater than 20 degrees and even with larger angles, mixing time is decreased to levels close to mixing times the fastest for small volumes.

Cela signifie que dans un tube cylindrique 11, les liquides qui ne peuvent pas être mélangés à 0 degré, peuvent être parfaitement mélangés aux angles excédant 0 degré, avec des temps de mélange optimisés s'approchant de ceux de liquides semblables à l'eau à 0 degré.This means that in a cylindrical tube 11, the liquids that can not be mixed at 0 degrees, can be perfectly mixed at angles exceeding 0 degrees, with optimized mixing times approaching those of water-like liquids. 0 degree.

L'angle pour la meilleure performance de mélange dépend du volume du récipient et augmente de manière caractéristique avec la viscosité du liquide 8 (fluide) et de la présence d'huile sur le liquide aqueux. A des angles dépassant à sensiblement 30 degrés la plupart des configurations examinées ont permis le mélanges en quelques secondes, en général 5 secondes. Il est à noter que ceci est avéré pour un liquide ne contenant :

  • que 40 µl d'eau (H2O = courbe A), ou
  • 40 µl d'eau avec de l'huile (H2O + HUILE = courbe B), ou
  • 60 µl de sorbitol à 1,5M (SORB. = courbe C), ou enfin
  • 60 µl de sorbitol à 1,5M avec de l'huile (SORB. + HUILE = courbe D).
The angle for the best mixing performance depends on the volume of the container and typically increases with the viscosity of the liquid (fluid) and the presence of oil on the aqueous liquid. At angles exceeding substantially 30 degrees most of the examined configurations permitted mixing in seconds, usually 5 seconds. It should be noted that this is proven for a liquid containing:
  • that 40 μl of water (H 2 O = curve A), or
  • 40 μl of water with oil (H 2 O + OIL = curve B), or
  • 60 μl of sorbitol at 1.5M (SORB. = Curve C), or finally
  • 60 μl of sorbitol at 1.5M with oil (SORB + OIL = curve D).

3 - Impact de la forme du récipient et de la présence d'une couche d'huile : 3 - Impact of the shape of the container and the presence of a layer of oil:

Selon la figure 9, on a étudié l'effet de l'angle du tube 11 par rapport à la durée de mélange dans le cas de deux liquides stratifiés, à savoir aqueux avec deux viscosités (2 (= courbe E) et 20 (= courbe F) milliPascal par seconde ou mPas) couvertes par une couche d'huile.According to figure 9 the effect of the angle of the tube 11 with respect to the mixing time was studied in the case of two stratified liquids, namely aqueous with two viscosities (2 (= curve E) and 20 (= curve F) milliPascal per second or mPas) covered by a layer of oil.

Dans ce cas, en optimisant l'angle du récipient 10 qui est une forme de fiole conique de type Eppendorf®, nous avons constaté qu'il y a une transition plus nette entre le mélange lent et le mélange rapide, lorsqu'une couche d'huile est utilisée en plus du liquide. Dans ce cas à un angle compris entre 28 et 30 degrés, ainsi que pour les angles plus important, la durée de mélange est considérablement réduite. En fait plus la viscosité aqueuse augmente plus l'angle doit être important mais dans le cas présent lorsque la viscosité est augmentée (par augmentation fois dix de la quantité d'huile : 2 mPas pour la courbe délimitée par des carrés et 20 mPas pour la courbe délimitée par des triangles) l'augmentation de l'angle de 28 à 30 degrés permet d'obtenir un bon résultat de mélange.In this case, by optimizing the angle of the container 10 which is an Eppendorf® type conical flask shape, we have found that there is a clearer transition between the slow mixture and the rapid mixture, when oil is used in addition to the liquid. In this case at an angle of between 28 and 30 degrees, as well as for larger angles, the mixing time is considerably reduced. In fact, more aqueous viscosity increases the angle should be large but in the present case when the viscosity is increased (by increasing ten times the amount of oil: 2 mPas for the curve delimited by squares and 20 mPas for the curve delimited by triangles) the increase of the angle from 28 to 30 degrees makes it possible to obtain a good mixing result.

4 - Impact de la viscosité et de la présence d'une couche d'huile à forme et angle de positionnement constant pour le récipient :4 - Impact of the viscosity and the presence of an oil layer with constant shape and positioning angle for the container:

Dans le cas de la figure 10, et considérant la fréquence qui doit être appliquée pour des récipients cylindriques 11 à un angle de 45 degrés et qui a été choisie pour sa faculté à permettre un bon mélange, la fréquence optimale est de plus de 20 Hz. Cette fréquence dépendra de la géométrie du tube et doit néanmoins être optimisé pour chaque configuration. Cet effet de la fréquence (RPM) du récipient sur le temps de mélange pour les liquides « simples » avec viscosité croissante a été réalisé avec trois systèmes liquides stratifiés aqueux avec trois viscosités couvertes ou non par une couche d'huile :

  • 40 µl d'eau (0M) pour la courbe délimitée par des petits ronds (= courbe G),
  • 40 µl d'eau (1M) avec 1 M de sorbitol pour la courbe délimitée par des croix (= courbe H),
  • 40 µl d'eau (1.5M) avec 1,5 M de sorbitol pour la courbe délimitée par des gros carrés (= courbe I),
  • 40 µl d'eau et de l'huile (0M + HUILE) pour la courbe délimitée par des triangles (= courbe J),
  • 40 µl d'eau et de l'huile (1M + HUILE) avec 1 M de sorbitol pour la courbe délimitée par des petits carrés (= courbe K),
  • 40 µl d'eau et de l'huile (1.5M + HUILE) avec 1,5 M de sorbitol pour la courbe délimitée par des losanges (= courbe L).
In the case of figure 10 , and considering the frequency that must be applied for cylindrical containers 11 at an angle of 45 degrees and which has been chosen for its ability to allow a good mixture, the optimal frequency is more than 20 Hz. This frequency will depend on the geometry of the tube and must nevertheless be optimized for each configuration. This effect of the frequency (RPM) of the container on mixing time for "simple" liquids with increasing viscosity was achieved with three aqueous laminated liquid systems with three viscosities covered or not by a layer of oil:
  • 40 μl of water (0M) for the curve delimited by small circles (= curve G),
  • 40 μl of water (1M) with 1 M of sorbitol for the curve delimited by crosses (= curve H),
  • 40 μl of water (1.5M) with 1.5 M of sorbitol for the curve delimited by large squares (= curve I),
  • 40 μl of water and oil (0M + OIL) for the curve delimited by triangles (= curve J),
  • 40 μl of water and oil (1M + OIL) with 1 M of sorbitol for the curve delimited by small squares (= K curve),
  • 40 μl of water and oil (1.5M + OIL) with 1.5 M sorbitol for the curve delimited by diamonds (= curve L).

REFERENCESREFERENCES

  1. 1 - Support solide ou table1 - Solid support or table
  2. 2 - Mouvement de rotation du récipient 7 sur le support 12 - Rotation of the container 7 on the support 1
  3. 3 - Axe de rotation du mélangeur3 - Mixer rotation axis
  4. 4 - Axe de symétrie du récipient 74 - Symmetry axis of the container 7
  5. 5 - Rayon de la rotation5 - Radius of the rotation
  6. 6 - Angle entre l'axe de rotation 3 et l'axe de symétrie 46 - Angle between axis of rotation 3 and axis of symmetry 4
  7. 7 - Récipient contenant le liquide 87 - Container containing the liquid 8
  8. 8 - Liquide contenu dans le récipient 78 - Liquid contained in the container 7
  9. 9 - Dispositif mélangeur9 - Mixing device
  10. 10 - Tube Eppendorf®10 - Eppendorf® Tube
  11. 11 - Tube classique dit cylindrique11 - Classic cylindrical tube

Claims (11)

  1. Process for mixing a heterogeneous solution containing at least two different liquids and, optionally, at least one solid entity or else containing at least one liquid and at least one solid entity, so as to obtain a homogeneous solution, the process comprising the following steps:
    a) all or part of the heterogeneous solution is placed in at least one vessel having a longitudinal axis;
    b) the vessel is positioned on a support driven about a rotation axis, the longitudinal axis being inclined to the rotation axis; and
    c) the support on which said vessel stands is made to undergo a movement enabling that part of the vessel closest to said rotation axis to be found in the position furthest away from this axis after a half-rotation and that part of the vessel furthest away from the rotation axis to be found in the position closest to said axis after a half-rotation, so as to subject the solution contained in the vessel to successive accelerations and decelerations of sinusoidal intensity, thereby stirring said heterogeneous solution, which becomes homogeneous.
  2. Process according to Claim 1, characterized in that, during the movement of the support, the longitudinal axis of the vessel cuts the rotation axis of said support twice per rotation turn.
  3. Process according to either of Claims 1 and 2, characterized in that the vessel contains, apart from the heterogeneous solution, a volume of air sufficient to allow stirring without all or part of said heterogeneous solution being able to leave said vessel during mixing.
  4. Process according to either of Claims 1 and 2, characterized in that the vessel contains, apart from the heterogeneous solution, a volume of air sufficient to allow stirring and is closed by a stopper so that all or part of said heterogeneous solution cannot leave said vessel during mixing.
  5. Process according to any one of Claims 1 to 4, characterized in that the angle of inclination of the longitudinal axis of the vessel varies according to the rotation speed and/or according to the position of said vessel during rotation.
  6. Process according to any one of Claims 1 to 5, characterized in that the movement of the support is circular.
  7. Process according to any one of Claims 1 to 5, characterized in that the movement of the support is ellipsoidal.
  8. Device for mixing a heterogeneous solution containing at least two different liquids and, optionally, at least one solid entity, or else containing at least one liquid and at least one solid entity, so as to obtain a homogeneous solution, which consists of:
    i. a static frame which may, optionally, be placed on a table or any other surface;
    ii. a moveable support that can receive at least one vessel having a longitudinal axis;
    iii. a motor drive means fastened to the frame and capable of generating a rotational movement; and
    iv. a transmission means for transmitting the rotational movement of the motor drive means to the moveable support, the action of the transmission means positioning the vessel so that the part of the vessel closest to the rotation axis is found in the position furthest away from this axis after a half-rotation and that the part of the vessel furthest away from the rotation axis is found in the position closest to said axis after a half-rotation,
    so as to subject the solution contained in the vessel to successive accelerations and decelerations of sinusoidal intensity.
  9. Device according to claim 8, characterized in that the rotation axis of the support is in a substantially vertical position and in that the longitudinal axis of the vessel is not in a substantially vertical position.
  10. Device according to any one of Claims 8 to 9, characterized in that the longitudinal axis of the vessel is at an angle of inclination to the rotation axis of the support and in that, when the two axes intersect, the angle is between 1° and 60°, preferably between 20° and 50° and even more preferably between 25° and 45°.
  11. Device according to any one of Claims 8 to 10, characterized in that the vessel is closed.
EP20100769027 2009-09-25 2010-09-24 Method and device for mixing a heterogeneous solution to obtain a homogeneous solution Active EP2480323B1 (en)

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PCT/FR2010/052008 WO2011039453A1 (en) 2009-09-25 2010-09-24 Method and device for mixing a heterogeneous solution into a homogeneous solution

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WO2011039453A1 (en) 2011-04-07
FR2950541A1 (en) 2011-04-01
EP2480323A1 (en) 2012-08-01
US9084974B2 (en) 2015-07-21
FR2950541B1 (en) 2011-10-21
JP5683595B2 (en) 2015-03-11
US20120182829A1 (en) 2012-07-19
JP2013505821A (en) 2013-02-21

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