EP0589363A1 - Method and device for automatic mixing without contact of a reaction mixture in a analysing device - Google Patents

Abstract

Process for contactless automatic mixing of a liquid reaction mixture in an analytical instrument, in which the reaction mixture is situated in a vessel (4) accessible through the top via an orifice, with the aid of a gas jet coming out of an outlet orifice of a mixer element (1), a rapid, effective and reliable noninvasive mixing of the liquid is achieved in that the mixer element at the beginning of the mixing operation is lowered in the direction towards the liquid surface and the lowering movement is stopped in a lower final position in which the mixer element projects into the vessel but does not contact the liquid surface, the gas jet is turned on during the lowering of the mixer element, the gas jet is directed in such a way that it effects an asymmetric lowering of part of the liquid surface in the vicinity of the vessel wall and the gas jet has a rotary component of motion so that the lowered part of the liquid surface is set in rotation about the axis of the vessel. <IMAGE>

Description

The invention relates to a method for the contactless automatic mixing of a liquid reaction mixture in an analysis device and a device for carrying out the method.

Analyzes for medical purposes, in which body fluids, especially blood and urine, are examined for constituents (analytes) contained therein, have for many years been carried out predominantly with the aid of automatic analysis devices. Compared to manual methods, this not only reduces costs, but also improves the reliability and accuracy of the analyzes.

Various different types of automatic analyzers have been developed. The present invention is particularly suitable for so-called discrete analyzers, in which each individual analysis is carried out in a separate reaction vessel, which is in the Usually has a round (usually circular) cross-section, is transported in a vertical position through various processing stations of the device and is open at the top. The reaction vessel is fed computer-controlled with sample liquids and liquid reagents, the resulting reaction mixture is homogenized with the aid of a mixing device and after a predetermined reaction time, in many cases also after a multi-stage reaction in which several reagents are added in succession, one of the reactions of sample and Reagents resulting physically detectable measurable characteristic for the analysis determined. This measured variable can be, for example, a photometrically determinable extinction, a fluorescence signal or an electrochemical measured variable (voltage or current flow). The present invention is directed, regardless of the details of the method and the measured variable used for the detection, to automated analyzers of the most varied types, as long as they require the mixing of a reaction mixture in an elongated vessel with a vertical longitudinal central axis accessible from above through an opening.

The discrete automatic analyzers mentioned largely mimic the processing steps known from manual analyzes with the aid of mechanical, hydraulic and electronic means. It is therefore not surprising that machines of this type were among the first devices for automatic analysis. Although numerous other types of automatic analyzers, such as centrifugal analyzers and continuous flow analyzers, were subsequently developed, the discrete analyzers have not lost their importance in the long term. Rather, from today's perspective, they are by far the most important Group of automated analyzers. This success is essentially due to the fact that discrete automatic analyzers enable a completely selective, sample-oriented mode of operation, ie an individual program of different analytes can be determined in succession for each sample.

One of the fundamental problems that has accompanied the development of discrete automated analyzers from the beginning is the mixing of reaction mixtures in the reaction vessels. This task, which at first sight seems simple, proves to be difficult because a number of important requirements have to be met. In particular, the mixing should take place quickly and completely in order to ensure a high analysis speed and good accuracy. The accuracy, on the other hand, is significantly influenced by the fact that no foreign sample or reagent fractions get into a reaction vessel into which they do not belong during the machining process, including the mixing. This can be done in particular by transferring ("invasive") stirring elements which are immersed in the reaction mixture.

In order to avoid this so-called "carryover", proposals have long been made to mix the reaction mixture in a reaction vessel without touching the reaction liquid (non-invasively). For example, cylindrical reaction vessels with mixing elements fixed to their base were used, which were quickly rotated back and forth in the mixing device. In another known device, the reaction vessel is sonicated with ultrasound in a liquid bath in order to achieve the required homogenization.

It has also already been proposed to use a gas jet directed at the surface of the liquid in the vessel for mixing. In WO 85/03571 an air jet is used in connection with cuvettes with a rectangular cross-section, which flows from a stationary nozzle at the lowest possible angle to the liquid surface onto the edge of the liquid surface, i.e. is directed towards the meniscus at the boundary between the liquid and the wall of the vessel. It is important that both the nozzle and the vessel are stationary and exactly aligned during the mixing process, the jet running parallel to the longer dimension of the vessel cross section. The nozzle should preferably be located outside the vessel. In a less preferred embodiment, provision is also made to lower the nozzle into the vessel for the mixing process. However, this is considered disadvantageous because it reduces the throughput (i.e. the analysis performance) of the device and contaminates the nozzle from the liquid. Therefore, the nozzle must be rinsed between the mixing operations in this embodiment.

US Pat. No. 3,398,935 (which was filed in 1964, i.e. at the beginning of the development of automatic analysis devices) describes a mixing method which is based on generating a circular swirling gas mass above the surface of the liquid, the rotational movement of which is reduced to a liquid to be mixed Transmits viscosity and causes their mixing. Two practical realizations are described. 2 of the reference shows a gas line directed obliquely against the wall of the vessel, which is apparently rotated to produce the desired swirling gas mass above the surface of the liquid. In Figures 3 and 4 the reference is an embodiment shown in which a gas jet is directed centrally to the center of the surface. The rotating gas vortex is brought about in that the gas outlet channels at the lower end of the gas supply pipe run obliquely, so that a circulating movement component of the gas flow results.

These proposals for automatic contactless mixing using a gas jet have not been able to prevail in practice. Despite the known fundamental advantages of contactless mixing, invasive mixing elements which are immersed in the liquid are used almost exclusively in practice to homogenize the reaction mixture in automatic analyzers. The problem of carryover is solved as far as possible by washing the mixing element between the individual mixing processes. The associated expenditure in terms of equipment and time is accepted as inevitable.

The invention is based on the object of proposing a method and a device for automatically mixing a liquid reaction vessel in an analysis device which works without contact (non-invasively) and nevertheless enables the liquid to be mixed quickly, effectively and reliably.

The object is achieved in a method in which the reaction mixture is located in a vessel accessible from above through an opening, with the aid of a gas jet emerging from an outlet opening of a mixing element, in which the mixing element is lowered in the direction of the liquid surface at the beginning of the mixing process and the lowering movement in a lower end position, in which the mixing element protrudes into the vessel, However, the liquid surface is not touched, stopped, the gas jet is switched on during the lowering of the mixing element, the gas jet is oriented in such a way that it causes an unsymmetrical lowering of a part of the liquid surface in the vicinity of the vessel wall and the gas jet has a tangential component of motion so that the lowered part of the liquid surface is set in rotation around the axis of the vessel. Air is expediently used as the mixed gas for cost reasons.

The invention further relates to a device for carrying out the method, in which at least one and at most three gas jet outlet openings are provided in the vicinity of the lower end of the mixing element and are connected to a mixed gas source via a mixed gas line of the mixing element.

If the process condition according to the invention is observed, the reaction mixture is rapidly mixed without the mixing element or the surroundings of the vessel being contaminated by the liquid. In order to avoid liquid splashes and the resulting risk of carry-over, it is essential that the flow of the mixed gas is activated during the lowering of the mixing element into its lower end position. It should remain constant during the lowering of the mixing element or increase steadily up to a maximum value, which is then kept constant.

The lower end position in which the mixing element is stopped is selected so that the outlet opening of the gas jet is below the edge of the opening of the reaction vessel, but on the other hand the lower end of the mixing element does not touch the liquid surface. Within these limits, it can be determined empirically with knowledge of the present invention. In practice, distances of approximately 4 mm to 7 mm between the lowest boundary of the mixing element and the stationary liquid surface have proven themselves with a vessel diameter of approximately 9 mm.

The gas jet should be offset radially with respect to the axis of the vessel, i.e. it should hit the liquid surface at a point between the axis of the vessel and the wall of the vessel, although it does not have to be directed directly at the surface of the liquid, but can also be directed at a flat angle to the vessel wall and from there strikes the area of the liquid surface close to the wall. The jet of the mixed gas is dimensioned in its strength and spatial extent so that it causes an asymmetrical lowering of part of the liquid surface. The "strength" of the jet depends on the speed of the gas molecules and their flow rate. These quantities in turn depend on the gas pressure in the line through which the mixed gas is supplied in the mixing element and on the dimensions of the nozzle through which it is directed onto the liquid surface. Finally, the movement of the molecules of the gas jet has a rotational movement component, that is to say a movement component circulating around the longitudinal central axis of the vessel. This achieves a movement of the liquid in the reaction vessel which is characteristic of the invention. The liquid is rapidly set into a circulating movement, with liquid layers lying below the asymmetrical lowering of the liquid surface being set into a substantially horizontally circulating movement with almost no delay. The lower liquid areas in the central area of the circulation rise in a spiral up and mix very quickly with the upper liquid areas.

What is important here is the choice of the point of impact of the gas jet on the liquid surface in the radial direction. The beam is preferably directed in such a way that the radial distance of the deepest point of the asymmetrical depression from the wall is less than 10% of the largest vessel diameter.

The rotational movement component of the gas jet can be achieved in that the mixing element rotates with the outlet opening of the gas jet in the lower end position (about an axis coaxial to the central axis of the vessel). According to an alternative preferred embodiment, however, it can also be generated by appropriate alignment of the end section determining the jet direction of the mixed gas line leading to the outlet opening. This end section is referred to below as the nozzle. However, this expression should not be understood to mean that the end section of the line must have a nozzle-shaped, tapering shape. Rather, it can be cylindrical in shape with a constant cross section.

Fig. 1

Eine Schnittdarstellung eines in ein Reaktionsgefäß abgesenkten in der Endposition befindlichen Mischelementes,

Fig. 2

eine Ansicht einer ersten Ausführungsform eines Mischelementes von unten,

Fig. 3

eine Ansicht entsprechend Fig. 2 von einer alternativen Ausführungsform des Mischelementes.

The invention is explained in more detail below on the basis of an exemplary embodiment shown schematically in the figures; show it:

Fig. 1

3 shows a sectional illustration of a mixing element which is lowered into a reaction vessel and is in the end position,

Fig. 2

a view of a first embodiment of a mixing element from below,

Fig. 3

a view corresponding to FIG. 2 of an alternative embodiment of the mixing element.

The mixing element 1 shown in FIG. 1 protrudes with its lower end 2 into a circular-cylindrical reaction vessel 4 accessible from above through an opening 3, the vertical longitudinal axis of which is designated by A. There is a liquid 6 to be mixed in the vessel 4.

The mixing element 1 consists essentially of two coaxial tubes, namely an outer tube 8 and an inner tube 9. The walls of the outer tube 8 converge conically at the lower end 2 of the mixing element 1, so that the mixing element downwards (apart from in the wall 8a of the outer tube 8 existing holes, which serve as nozzles 12 and 13) is closed.

The lower end of the inner tube 9 is sealed at the annular line of contact 10 to the inside of the wall 8a of the outer tube 9, so that the interior of the tube 9 is separated from the annular space between the tube 9 and the tube 8.

The inner tube 9 serves as a mixed gas line 14, through which air is supplied from a mixed gas source 15 at a controllable pressure and, after passing through the nozzle 12, exits through an outlet opening 16. The annular space between the tubes 8 and 9 forms a line 18 which is separate from the mixed gas line 14 and which is connected to a gas source 19 in order to supply an additional gas stream which emerges from the outlet openings 20 through the bores 13 and - as will be explained in more detail below - serves as a protective gas. The gas sources 15, 19 and the connecting lines 15a, 19a to the mixing element 1 are only indicated symbolically. Suitable connection techniques, also in the case of a mixing element rotating about the vertical axis A, are known to the person skilled in the art.

In order to homogenize the liquid 6 in the vessel 4, the mixing element 1 is moved vertically downward in accordance with the arrow 21 and lowered into the upper part of the vessel 4, so that at least the lower end 2 projects into the vessel. The lowering movement is stopped in a defined lower end position, which is selected such that the outlet openings 16 and 20 are located below the edge 3a of the opening 3 and the mixing element 1 does not touch the surface of the liquid 6. During the lowering process, mixed gas is already supplied through line 14 and preferably also protective gas through line 18 and exits through outlet openings 16 and 20, respectively.

It is also essential for the function that the gas jet is oriented in such a way that an asymmetrical lowering of part of the liquid surface is brought about. In the figure, this lowered shape of the liquid surface 22 is shown as a solid line, while the rest position of the liquid surface is shown as a dashed line 23.

It is also important for the mixing effect according to the invention that the gas jet emerging from the outlet opening 16 has a rotational component with respect to the longitudinal central axis A of the vessel 4, in the preferred case of a round vessel cross section, that is, a component tangential to the wall 5 of the vessel 4. As mentioned, this can be done in two ways. On the one hand, the Nozzle 12, from which the mixed gas jet emerges, runs radially (that is, without a directional component tangential to the vessel wall). Such an embodiment is shown in FIG. 2. In this case, the tangential component of the gas jet movement is brought about by rotation of the mixing element 1 about the axis A. The rotation frequency should preferably be between 10 and 80 revolutions per minute, preferably between 20 and 30 revolutions per minute.

Another possibility for producing the tangential component is that the last section of the line of the mixed gas which determines the direction of the gas jet has a directional component tangential to a circle around the longitudinal central axis A of the vessel. Such an embodiment is shown in FIG. 3.

The embodiments according to FIGS. 2 and 3 also differ to the extent that only one outlet opening 16 is provided for the gas jet in FIG. 2, while FIG. 3 has three nozzles 12 ′ running obliquely with a tangential direction component with outlet openings 16 ′. The number of gas jet outlet openings is preferably between 1 and 3 regardless of the orientation of the nozzles.

In the embodiment according to FIG. 3, the mixing action occurs without the mixing element 1 being rotated, but of course both measures can also be combined, i.e. a mixing element with gas outlet openings according to FIG. 3 can also be set in rotation.

The movement of the liquid 6 during the mixing process is characterized in that on the one hand the liquid surface 22 is lowered relatively asymmetrically and that on the other hand this lowering of the liquid surface is set into a rotational movement. The difference d between the highest point of the liquid surface and the lowest point of its lowered part is preferably at least 25%, particularly preferably at least 50% of the diameter of the liquid surface (in the case of a non-circular cross section of its largest diameter). The reduction naturally depends on the flow of the gas jet, the gas pressure in the line 14 and the diameter of the at least one gas jet outlet opening. The gas flow is preferably between 10 ml / S and 70 ml / S, particularly preferably between 20 ml / S and 60 ml / S. The diameter of the gas jet outlet openings 16 should preferably be between 0.1 and 0.8 mm, particularly preferably between 0.5 and 0.7 mm. The gas pressure is preferably between 1.2 bar and 1.7 bar. The nozzles are preferably oriented at an angle α between approximately 30 ° and approximately 60 ° to the axis A, an angle of approximately 45 ° having proven particularly useful.

At the lower end 2 of the mixing element 1 protruding into the vessel 4, the additional outlet openings 20 are provided above the outlet openings 16, through which a second gas stream is supplied as a protective gas. The mixing element preferably has at least four such outlet openings 20, which form a ring which is uniformly distributed over the circumference of the mixing element 1.

The shape of the lower end 2 is also essential for a good mixing action and for reducing the risk that the mixing element 1 is contaminated by splashes of the liquid 6 during the mixing process of the mixing element 1 in relation to the cross section of the vessel 4 (in its upper region 4a, into which the mixing element 1 projects).

The largest horizontal cross-sectional area of the part of the mixing element 1 projecting into the vessel 4 in the lower end position should be at least 30% of the corresponding horizontal cross-sectional area of the vessel (measured at the same vertical height). It should be taken into account that the cross-sectional area to which this statement relates is square to the linear dimensions of the components. In the case of circular cross sections, for example, a ratio of the diameter of the mixing element 1 and the vessel 4 of 0.6: 1 corresponds to a cross section ratio of 0.36: 1. In other words, the cross section of the mixing element 1 should fill the vessel 4 relatively largely at least in a partial area of its height, so that only a considerably reduced cross section for the backflow of gas according to the arrows 25 past the mixing element 1 is available. As a result, the gas is stowed to a certain extent below the mixing element 1.

In order to reduce the risk of contamination, it is also advantageous if the lower boundary surface 26 slopes outwards and upwards from a deepest point 26a as shown. The lower boundary surface is to be understood as the surface closing the mixing element 1 downwards, i.e. the surface of the mixing element 1 below its largest cross-section immersed in the vessel 4.

Claims (12)

Method for the contactless automatic mixing of a liquid reaction mixture in an analysis device, in which the reaction mixture is located in a vessel accessible from above through an opening, with the aid of a gas jet emerging from an outlet opening of a mixing element,
in which
the mixing element is lowered towards the liquid surface at the beginning of the mixing process and the lowering movement is stopped in a lower end position in which the mixing element protrudes into the vessel but does not touch the liquid surface,
the gas jet is switched on while the mixing element is being lowered,
the gas jet is oriented in such a way that it causes an asymmetrical lowering of a part of the liquid surface with a deepest point in the vicinity of the vessel wall and
the gas jet has a rotational movement component, so that the lowest point of the lowered part of the liquid surface is set in rotation about the longitudinal central axis of the vessel. A method according to claim 1, wherein the flow of the gas jet is between 10 ml / s and 70 ml / s, preferably between 20 ml / s and 60 ml / s. Method according to one of the preceding claims, in which the angle between the direction of the gas jet as it emerges from the outlet opening of the mixing element and the longitudinal central axis of the vessel is between 30 ° and 60 °. Method according to one of the preceding claims, in which the gas jet is directed onto the liquid surface in such a way that the distance of the lowest point of the asymmetrical depression from the wall is less than 20% of the largest diameter of the liquid surface. Method according to one of the preceding claims, in which the lowest point of the asymmetrical depression produced by the gas jet is at least 25%, preferably at least 50% of the largest diameter of the liquid surface lower than the highest point of the liquid surface. Method according to one of the preceding claims, in which the mixing element rotates in the lower end position about an axis coaxial to the longitudinal central axis of the vessel. Method according to Claim 6, in which the rotation frequency of the mixing element is between 10 and 80 revolutions per minute, particularly preferably between 20 and 30 revolutions per minute. Device for carrying out the method according to one of the preceding claims, in which at least one and at most three gas jet outlet openings (16) are provided, which are via a mixed gas line (14) of the mixing element (1) are connected to a mixed gas source (15). Apparatus according to claim 8, wherein the diameter of each gas jet outlet opening (16) is between 0.1 and 0.8 mm, preferably between 0.5 and 0.7 mm. Device according to one of claims 8 or 9, wherein the mixing element (1) in the region of its lower end (2) above the at least one gas jet outlet opening (16) has at least one additional outlet opening (20) which is connected to the mixed gas line ( 14) separate line (18) is connected to a gas source (19) and through which an additional gas stream is supplied as a protective gas. Apparatus according to claim 9, wherein the line (18) for the splash protection gas in the gas supply element surrounds the mixed gas line (14) in a ring. Device according to one of Claims 7 to 10, in which the largest horizontal cross-sectional area of the part of the mixing element (1) which projects into the vessel in the lower end position is at least 30% of the corresponding horizontal cross-sectional area of the vessel (4).

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