EP1883465B1 - Double-chamber mixing device for viscous pharmaceutical substances and method - Google Patents

Abstract

The invention concerns a double-chamber device for mixing at least two viscous substances, comprising: cylindrical and coaxial first and second communicating vessels, each hermetically sealed at one end by a mobile piston, and provided at its second end with a slightly conical bottom end, the two vessels being arranged, preferably vertically, in mirror symmetry relative to a meridian plane perpendicular to their common axis; a central mixing element connecting the two vessels at the two slightly conical bottom ends; and a high pressure hydraulic device for automatically activating the pistons in a coordinated reciprocating movement. A worm screw injection device in communication with one of the vessels or with the mixing element may be used to inject the substances. Mixing of substances may include driving the pistons in a coordinated reciprocal motion to collapse one vessel while expanding the other, forcing the substances through the central mixing element.

Description

Object of the invention

The present invention relates to a dual chamber mixing device for obtaining a very good homogeneity in the case of a mixture of viscous substances, in particular in the pharmaceutical field.

The invention also relates to the method of implementation of the device.

State of the art

Incorporation of pharmaceutical substances into high viscosity mixtures requiring perfect homogeneity is generally problematic with conventional mixing devices such as blade mixers, propeller mixers, kneaders, planetary mixers, rotor / stator mixers, and the like.

• pertes et sous-dosage des produits incorporés ;
• absence de mouvement dans le mélangeur car les produits à mélanger collent aux outils de mélange et à la paroi de la cuve ;
• augmentation néfaste de la température du mélange occasionnant la dégradation des produits mélangés ;
• pertes lors de la vidange de la cuve de mélange ou impossibilité de réaliser une vidange automatique.

The most common problems are:

• losses and under-dosing of the incorporated products;
• absence of movement in the mixer because the products to be mixed stick to the mixing tools and to the wall of the tank;
• harmful increase in the temperature of the mixture causing degradation of the mixed products;
• losses during the emptying of the mixing tank or inability to perform an automatic drain.

These problems all cause a lack of homogeneity of the mixture obtained incompatible with the stringent quality requirements of a pharmaceutical finished product, or simply the impossibility of achieving the desired mixture.
The document US 2004/0120217 A discloses a method according to the preamble of claim 1 and an apparatus according to the preamble of claim 2 for mixing a polymer with an agglomerate of one or more compounds in a pair of opposing pressure cylinders, communicated by an injector block located between the two cylinders, and using the two corresponding pistons to force the transfer of the polymer and the agglomerate from one cylinder to the other and vice versa, so as to divide and disperse the agglomerate in the mixture with the polymer.
The document US 3,353,918 A discloses an apparatus for mixing the polyurethane foam manufacturing ingredients, comprising: a mixing apparatus containing two chambers having adjacent ends interconnected by a wall having through-holes and two pistons, each slidably mounted in one of the respective two chambers, means for causing oscillation of the two pistons within the chambers so as to force the ingredients into the mixing apparatus in a back-and-forth movement through the orifices and to mix them, said wall comprising a discharge passage provided with a control valve and communicating with the orifices, the mixed ingredients being able to be unloaded, once the pistons converge towards the wall, provided that the valve is open. The wall also comprises means provided with valves and communicating with the orifices, for loading the ingredients into the mixing apparatus.
The document US 3,035,820 A discloses apparatus for emulsification and homogenization of a viscous solid or liquid suspension in a liquid (eg water / oil), wherein the suspension or mixture is forced through a high speed restriction and / or high pressure. The apparatus has a pair of opposed cylindrical syringes each having a piston slidably mounted in its cylinder, and operable to repetitively transfer the fluid reciprocally from one syringe to the other through the restriction which communicates the two cylinders.
The document US 6,062,722 A discloses a method of mixing a fluid in which one or two separate fluid reservoirs communicating with a static propeller mixer are used as the mixing apparatus. The fluid is forced from the tank to the static mixer and vice versa.

Goals of the invention

The present invention aims to provide a solution that makes it possible to overcome the disadvantages of the state of the art.

In particular, the present invention aims to provide a device and a mixing process that allow to obtain a perfectly homogeneous mixture of viscous pharmaceutical substances.

It is another object of the invention to provide a fully automatable device and mixing method.

It is an additional object of the invention to provide a mixing process which is satisfactory in less than 10 to 15 minutes.

The invention also aims to allow the mixture of heat-sensitive pharmaceutical substances.

Finally, the invention aims to provide a mixing device for the complete emptying of the tanks used.

Main characteristic elements of the invention

A first object of the present invention, indicated in claim 1, is to provide an automated process for mixing at least two viscous substances.

A second object of the present invention, indicated in claim 2, is to provide a device for mixing at least two viscous substances.

Preferred embodiments of the present invention are explained in claims 3 to 9.

Brief description of the figures

The figure 1 is a sectional view of the mixing device according to a preferred embodiment of the present invention.

The figure 2 schematically represents the different steps of the method of implementation of the device according to the figure 1 .

The figure 3 schematically represents the step of emptying the mixing device of the invention, which occurs once the desired homogeneity.

Description of a preferred embodiment of the invention

The present invention relates to a mixing unit which allows the incorporation and the automated and closed-loop mixing of pharmaceutical products to obtain a final mixture of high viscosity.

The invented mixing unit generally consists of two communicating tanks, vertical cylindrical, of the same axis and symmetrical with respect to a median horizontal plane (image of the tanks one of the other as in a mirror). These tanks are equipped with sealed pistons whose actuation by a hydraulic system allows the passage in successive cycles of the components to be mixed through a baffle mixing device. The assembly is fully automated using a PLC and can be thermostatically controlled for mixtures of heat-sensitive substances that require it.

1. 1) une première cuve supérieure 1, cylindrique d'axe vertical en acier inoxydable équipée :
   • d'une double enveloppe 3 dans laquelle un fluide de refroidissement ou de chauffage peut circuler ;
   • d'un fond 11 légèrement conique ;
   • d'un couvercle en acier inoxydable 12 faisant office de piston dont la forme, adaptée au fond conique de la cuve, et l'étanchéité permettent une vidange complète de la cuve ;
   • d'un dispositif hydraulique à haute pression permettant l'activation automatique du couvercle/piston (non représenté) ;
   • de connexions diverses 4, éventuellement munies de vannes, permettant la mesure de température, la mise sous vide ou la mise sous gaz inerte, la prise d'échantillons en cours de mélange, l'injection ou le prélèvement des substances, etc. ;
2. 2) une seconde cuve 2 inférieure, verticale et cylindrique en acier inoxydable, coaxiale et identique à la première cuve et disposée symétriquement en miroir par rapport à celle-ci ;
3. 3) un élément de mélange 5 également en acier inoxydable reliant les deux cuves 1, 2 équipé :
   • d'une double enveloppe 3 dans laquelle un fluide de refroidissement ou de chauffage peut circuler ;
   • d'un élément en acier inoxydable, muni de chicanes (mélangeur statique) permettant la création d'un flux turbulent de mélange au niveau des composants à mélanger ;
   • de connexions diverses 4 permettant la mesure de température, la mise sous vide ou la mise sous gaz inerte, la prise d'échantillons en cours de mélange, etc. ;
4. 4) un dispositif de contrôle (non représenté) permettant le contrôle et la synchronisation des différents mouvements des pistons, des cycles de mélanges ou encore de l'injection des composants par exemple à l'aide d'une vis sans fin.

According to a preferred embodiment of the invention shown in the figure 1 , the mixing unit consists of the following elements:

1. 1) a first upper vessel 1, cylindrical vertical axis stainless steel equipped with:
   • a double jacket 3 in which a cooling or heating fluid can circulate;
   • a slightly conical bottom 11;
   • a stainless steel lid 12 as a piston whose shape, adapted to the conical bottom of the tank, and the seal allow complete emptying of the tank;
   • a high pressure hydraulic device allowing the automatic activation of the lid / piston (not shown);
   • various connections 4, possibly equipped with valves, for temperature measurement, evacuation or putting in an inert gas, sampling during mixing, injection or removal of substances, etc. ;
2. 2) a second lower, vertical and cylindrical stainless steel tank 2, coaxial and identical to the first tank and arranged symmetrically in mirror relation thereto;
3. 3) a mixing element 5 also made of stainless steel connecting the two tanks 1, 2 equipped with:
   • a double jacket 3 in which a cooling or heating fluid can circulate;
   • a stainless steel element provided with baffles (static mixer) allowing the creation of a turbulent flow of mixture at the level of the components to be mixed;
   • various connections 4 for temperature measurement, evacuation or inert gas, sampling during mixing, etc. ;
4. 4) a control device (not shown) for controlling and synchronizing the various movements of the pistons, mixing cycles or even the injection of components for example using a worm.

The mixing and emptying processes according to the invention proceed as described below.

The mixing process whose steps (a) to (e) are represented on the figure 2 is carried out by pumping, in the form of successive cycles, the components to be mixed from the upper tank 1 to the lower tank 2 by passing through the static mixer 5 and vice versa. The number of cycles required is set by the type and viscosity of the components to be mixed.

Typically, with viscous pharmaceutical substances, this process is carried out between 5 and 10 cycles of about 30 seconds, which corresponds to a total process time of between 2 minutes and 5 minutes. According to the state of the art, a typical mixing time is 60 minutes.

The components of the mixture are introduced into the upper tank 1 before starting the mixing process by removing the lid 12 or are injected into the system being mixed by means of a sealed worm gear (not shown in FIG. the figures) which can be positioned indifferently on the upper tank 1 or on the central mixing element 5.

The mixing process is complete, the system allows a complete emptying of it as represented on the figure 3 . The mixture is transferred for this purpose completely into the upper tank 1 or lower 2 and then drained outwards.

Claims (9)

1. Automated method for mixing at least two viscous substances, preferably pharmaceutical, by means of a double-chamber mixing device, comprising:

   - a first tank (1) and a second tank (2), that are cylindrical, coaxial and communicating, each being sealingly closed at a first end with a moving piston (12,22) and provided at its second end with a slightly tapered bottom (11,21), both tanks (1,2) being positioned in mirror-image symmetry relative to a median plane that is perpendicular to their common axis;

   - a central static mixing element (5) connecting both tanks (1,2) at the level of the two slightly tapered bottoms (11,21);

   - a hydraulic device for automatically activating the pistons (12,22) according to a coordinated reciprocal motion,

   characterised by the following stages:

   - the substances to be mixed are injected into the first tank (1) or into the central static mixing element (5) by a sealed worm-screw injection;

   - a specified number of successive mixing cycles are achieved by pumping, said number being between 5 and 10 and the duration of each cycle being about 30 seconds, from the first tank (1) towards the second tank (2), passing through the central static mixer (5), and vice versa;

   - the final mixture is transferred to one of the two tanks (1,2), which is then emptied.
2. Double-chamber device for mixing at least two viscous substances comprising:

   - a first tank (1) and a second tank (2), that are cylindrical, coaxial and communicating, each being sealingly closed at a first end with a moving piston (12,22) and provided at its second end with a slightly tapered bottom (11,21), both tanks (1,2) being positioned in mirror-image symmetry relative to a median plane that is perpendicular to their common axis;

   - a central static mixing element (5) connecting both tanks (1,2) at the level of the two slightly tapered bottoms (11,21);

   - a hydraulic device for automatically activating the pistons (12,22) according to a coordinated reciprocal motion and for controlling and synchronising the motions of the pistons according to the mixing cycles and to the injection of the substances to be mixed

   characterised in that it also comprises a sealed injector in the form of a worm-screw device that is connected at the level of one of the tanks (1,2) or of the central static mixing element (5).
3. Device according to Claim 2, characterised in that the static mixing element (5) comprises a series of baffles or a labyrinth.
4. Device according to Claim 2 or 3, characterised in that the shape of each piston (12,22) is also slightly tapered and adapted to the shape of the corresponding tank, so as to allow the complete emptying of said tank.
5. Device according to Claim 2, 3 or 4, characterised in that both tanks (1,2), the two corresponding pistons (12,22) and the static mixing element (5) are made of stainless steel.
6. Device according to any one of Claims 2 to 5, characterised in that both tanks (1,2) and the static mixing element (5) are thermostatically controlled by a double external casing (3) in which a cooling or heating fluid may circulate.
7. Device according to any one of Claims 2 to 6, characterised in that the tapered shape of the bottom (11,21) of each tank (1,2) and of each respective piston (12,22) is between 5 and 15°.
8. Device according to any one of Claims 2 to 7, characterised in that at least one of the two tanks (1,2) and the static mixing element (5) are provided with a means (4) for injecting or removing the substances to be mixed, measuring the temperature, creating a vacuum or introducing an inert gas or taking samples during mixing.
9. Device according to Claim 8, characterised in that said means (4) comprises an injection or removal system of a luer-lock type and valves.

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