EP1651341A2

EP1651341A2 - Reactor bottom

Info

Publication number: EP1651341A2
Application number: EP04741243A
Authority: EP
Inventors: Alexander Engel
Original assignee: Bavarian Nordic AS
Current assignee: Bavarian Nordic AS
Priority date: 2003-07-25
Filing date: 2004-07-23
Publication date: 2006-05-03
Also published as: US20060207682A1; CA2533487A1; WO2005011857A2; WO2005011857A3; DE10334371A1; JP2006528545A

Abstract

The invention relates to a bottom (2) for a reactor (1), comprising an upper side (5) in the form of a collector funnel (7), an opening (15) which is formed inside said collector funnel (7) and which is connected to a discharge channel (18) leading through the reactor bottom (2), and a closure part (16) for the opening (15), said closure part being movably arranged on the reactor bottom (2) and which can move between a closed position wherein it closes the opening (15) of the collector funnel (7) and a removal position wherein it is lowered into the reactor bottom (2), releasing a connection between the opening (15) and the discharge channel (18). The invention also relates to a method for separating a phase or capsules from a phase mixture or a hardening solution especially by means of sedimentation in a reactor provided with one such bottom.

Description

Reactor bottom of a reactor

The invention relates to a reactor base of a reactor, which is used in particular when encapsulating cells, and a method for separating a phase from a phase mixture in a reactor with such a reactor base.

Methods for encapsulating cells, e.g. B. microbial, plant or animal cells, or of biological and chemical substances are known. Merten et al. (A new method for the encapsulation of mammalian cells; Cytotechnolögy 7 121-130. 1991) describes a process for the encapsulation of mammalian cells, the capsules being produced from sodium cellulose sulphate (NaCS) and polydymethyldiailylammonium chloride (PDMDAAC); the cells are mixed with NaCS and the resulting mixture is dripped into the PDMDAAC solution. DD 217 821 A1 describes the mixing of Langerhans cells with NaCS and the dropping of the mixture into a precipitation bath which contains PDMDAAC. DD 217 821 A1 describes a method for producing a NaCS-PDMDAAC microcapsule system which contains hormone-producing cells. Microcapsules made of NaCS and PDADMAC are also known, inter alia, from DD 160 393 A, DD 219 795 A1, DD 217 821 A1 and DD 274 051 A1. An improved apparatus for the production of NaCS capsules is in Cho (process engineering design of an apparatus for the production of microencapsulated biocatalysts with separate supply of catalyst solution and capsule base substance, progress reports VDI, series 17, no. 108; VDI Verlag 1994; ISSN 0178-9600) described. Other processes in which a cell suspension or a medium containing particles flows through a nozzle, the droplets produced in the process with a layer or a coating, for example made of polyacrylate encased, placed in a hardening bath and removed or harvested therefrom after a specified hardening time, z. B. from DE 197 52 585 A1, US 5,656,469 A or EP 0 778 083 A1. Different encapsulation technologies are used in these processes.

In a known device for encapsulating cells (Encapsulator AP 'medical' from Inotech), the reactor or the reactor vessel must be removed from the device in order to harvest the capsules. By shaking and tilting the reactor vessel, the capsules are rinsed through a drain opening, which is located about 3 cm above a reactor base in the wall of the reactor vessel, into a collecting vessel or harvesting flask. This procedure is not very user-friendly and leads to an unusable residue of capsules in the reactor vessel.

It is the task of Effji.dung to create a reactor base of the type mentioned at the beginning of a reactor which, with a simple structure, is improved in terms of its use properties when used with the reactor, and to provide a method mentioned at the outset in which the reactor base according to the invention is used a desired phase or capsules can be removed from the reactor in a simple manner.

This object is achieved according to the invention by a reactor base with the features of claim 1 or by a method with the features of claim 14.

Advantageous embodiments of the invention are specified in the respective subclaims.

Since the reactor base of the reactor is formed as a collecting funnel, the phase of the phase mixture contained in the reactor or the capsules formed at the bottom or center of the funnel can Meltrichter formed harvest opening and the outlet channel are removed or harvested. A simple handling and operation results from the fact that a closure part is provided for the harvest opening, which is movably arranged on the reactor floor and between a closed position in which it closes the harvest opening of the collecting funnel and a removal position in which it is lowered into the reactor floor and releases a connection between the harvest opening and the outlet channel is adjustable. Thus, if necessary, the harvest opening can be released by adjusting the closure part and the phase to be separated or the capsules can be withdrawn through the outlet channel essentially without residues due to the collecting funnel. Dismantling of the reactor or reactor vessel for manual pouring out or pouring out the phase to be separated or the capsules is not necessary.

The surface or top of the closure part is preferably used as a diverting device for diverting the reactor! of? Phase mixture or the capsules formed from the harvest opening in the outlet channel. The Abieiteinrichtung thus supports the almost or completely loss-free draining.

In an expedient embodiment, the surface or top of the closure part has a collection area with a low level, the collection area being assigned to the outlet channel in the lowered removal position of the closure part. The collection area is in particular part of the drainage device and it can e.g. B. be formed approximately punctiform or linear. A circular or ring-shaped and thus approximately linear collecting area is formed on the periphery of the closure part, for example, in the case of a concavely curved upper side of the closure part. When lowering the closure part z. B. the capsules contained in the reactor on this peripherally limited by the wall of the outlet recess collection area, from which they then flow to the outlet channel. The harvest opening is expediently arranged in the region of the center of the collecting funnel in order to enable the phase or the capsules located above the harvest opening to be removed completely. The crop opening can be arranged both centrally and eccentrically to the central axis or to the center of the collecting funnel, which is formed symmetrically or asymmetrically. It is particularly preferred if the edge of the harvest opening runs through or touches the central axis of the collecting funnel and the surface of the closure part is inclined at the location of the harvest opening in accordance with the inclination of the funnel surface or has the corresponding funnel shape. Due to this shape of the surface, no particles or capsules remain on the lowered closure part, which opens the harvest opening. In its closed position, the surface of the closure part is then expediently arranged flush with the surface of the collecting funnel. When the closure part is open, the collecting funnel can be emptied without residue. In general, with a central or eccentric arrangement of the harvest opening or the closure part, the surface of the closure part can be beveled or spherical with respect to the central axis, so that no residues of particles or capsules can remain on the surface when they flow or flow out of the reactor ,

An outlet recess, which extends from the harvest opening in the reactor base and in particular parallel to the central axis of the collecting funnel, is preferably provided, which receives the closure part in a displaceable manner and into which the at least one outlet channel opens. The outlet recess can be a hole with a round cross-section or a non-circular one such as B. elliptical or rectangular cross section. Instead of the parallel and in particular central arrangement to the central axis of the collecting funnel, the outlet recess can also run at an acute angle to the central axis.

If, according to a preferred embodiment, an annular groove and / or a plurality of openings is or are formed in the wall of the outlet recess, the Communicate with the outlet channel, the draining or harvesting of the capsules can be done faster due to the larger drain cross-sections.

Furthermore, it is expedient if at least one drain channel covered by a sieve opens into the collecting funnel. A second liquid phase, in particular a liquid phase, can be drained or sucked out of the reactor via the discharge channel. A washing or rinsing liquid which has previously been fed to the reactor in order to rinse the capsules or generally the product formed in the reactor can also be drained off via the discharge channel. Such a rinsing process can be carried out once or several times.

The reactor base can be formed in one piece with the reactor or the reactor wall. On the other hand, it can be provided that the reactor and the reactor wall to the reactor bottom and is detachably connected to the top of the actuator bottom Re- the Samme! ^R trichte surrounding reactor wall can be fixed. The reactor floor is made of plastic such as. B. PTFE manufactured. The collecting funnel can also be attached to the reactor base as a separate sheet metal or plastic part.

The closure part can be adjustable both manually and by means of a drive device arranged on the reactor base.

In particular if the contents of the reactor can be mixed by means of a stirring device, the funnel angle of the collecting funnel is preferably essentially 130 ° to 170 ° and in particular 153 °. Otherwise, the funnel angle is selected as a function of the capsules or phases to be separated and their flow properties and can therefore have any suitable angle.

In the method according to the invention for separating a phase from a phase mixture in a reactor with a reactor base as described above, the phase mixture is introduced into the reactor, the phases are separated and the desired phase is removed by moving the closure part arranged in its closed position into its removal position and thereby releasing a connection between the harvest opening and the outlet channel, via the harvest opening and the outlet channel from the reactor. The advantages of this method result from the above explanations regarding the reactor floor. In principle, the phase mixture can contain two phases or more than two phases.

According to a preferred procedure, the phase mixture is a mixture of solid and liquid phases and the phases are separated by sedimentation of the solid phase, capsules in particular forming the solid phase. The phase separation by means of sedimentation is particularly expedient if the phase mixture is a hardening bath with capsules contained in the hardening bath as the phase to be separated and the capsules settle at the bottom of the collecting funnel, where they can be removed.

The capsules are, for example, ΝaCS capsules and they preferably contain biological cells, in particular animal, human or plant cells.

According to a further expedient process step, it can be provided that in the production of capsules, in particular ΝaCS capsules, the hardening bath is drained via the drain channel and flushing liquid is fed into the reactor and drained again via the drain channel, this process step being carried out one or more times can.

When separating a phase from a phase mixture with z. B. two or more liquid phases, the desired phase, which in the reactor z. B. forms a lower layer, can be removed through the harvesting opening and the outlet channel and the middle or the upper layer-like phase can, depending on the arrangement of the phase or layer, through the outlet channel or subsequently ßend to the lower phase through the harvest opening and the outlet channel.

An exemplary embodiment of the reactor base is explained in more detail below with reference to the drawing. It shows:

Figure 1 is a vertical sectional view of a reactor floor according to the invention with an outlet device.

FIG. 2 shows a plan view in a reduced representation of the reactor floor shown in FIG. 1; and

Fig. 3 in a vertical sectional view in an enlarged view an embodiment of the reactor floor with a modified outlet device.

A reactor 1 of a device for encapsulating cells, in particular microbial, plant or animal cells, or of biological and chemical substances contains a reactor base 2, which, for. B. is made of a circular or square plate made of PTFE and has on its underside 3 a support device with, for example, four feet 4, which are firmly attached to the underside 3 of the reactor base 2. Alternatively, the support device can be, for example, a support frame on which the reactor base 2 rests. The reactor base 2 is formed on its top 5 as a collecting funnel 7 having a central axis 6, which is surrounded by an edge region 8 of the top 5 and has a funnel angle of, for example, 153 °. The edge area 8 preferably contains a flat shoulder 9 for receiving a sealing ring 10 on which a reactor vessel, for. B. a glass cylinder 11 is arranged liquid-tight. Outside of the glass cylinder 11 or the paragraph 9, a holding device is preferably attached to the reactor base 2, which, for example, four distributed over the circumference of the reactor base 2 and on the Actuator floor 2 attached rods 12. The rods 12 preferably extend to the upper section of the glass cylinder 11 and fix a reactor head part (not shown) to the glass cylinder 11 by means of a releasable holding device and this to the reactor base 2.

The reactor base 2 also contains an outlet or harvest recess 13 which extends downward from the collecting funnel 7 into the reactor base 2 and is formed, for example, as a through-opening which connects the collecting funnel 7 to the underside 3 of the reactor base 2. The z. B. formed as a cylindrical bore outlet recess 13 or through opening is arranged eccentrically and in particular parallel to the central axis 6 that its wall 14, for example, touches the central axis 6 and thus runs through the deepest central point of the collecting funnel 7. A harvest opening 15 is thus formed in the inclined surface of the collecting funnel 7 by the outlet recess 13. A closure member 16 which, for. B. is piston-shaped and is vertically slidably received within the outlet recess 13, has a cross section corresponding to the outlet recess 13, so that it is tightly received in the outlet recess 13. The sealing of the closure part 16 takes place either due to the play-free fit of a plastic such as. B. PTFE manufactured closure member 16 in the outlet recess 13 and / or by a seal (not shown), for. B. an O-ring which is arranged on the circumference of the closure part 16 and bears sealingly on the wall 14 of the outlet recess 13 or alternatively is arranged in an annular groove formed in the wall 14. The closure part 16 is preferably received and guided in the outlet recess 13 in such a way that it cannot twist. This protection against rotation is provided, for example, by a non-round cross-sectional shape of the closure part 16 or the outlet recess 13 or by a corresponding guide which prevents the closure part 16, which is round in cross section, from rotating in the cylindrical outlet recess 13. The top or surface 17 of the closure part 16 is inclined and in particular is formed in accordance with the inclined surface of the collecting funnel 7 adjoining the upper harvest opening 15 of the outlet recess 13, so that the closure part 16 is arranged flush in the surface of the collecting funnel 7 when it is in it upper closed position.

The reactor base 2 also contains an outlet channel 18 which, for example, on the one hand in the wall 14 of the outlet recess 13 below the center or on the central axis 6 of the collecting funnel 7 and on the other hand on the underside 3 of the reactor base 2 z. B. opens into an outlet pipe or connector 19.

The closure part 16 is preferably movable or displaceable in the outlet recess 13 by means of a drive device. The drive device contains, for example, an electrically attached to the underside 3 of the reactor base plate 2. Drive motor 20, which is coupled via a gear and a screw device 21 to a spindle 22 connected to the closure part 16. In an alternative design, a manual stroke actuation or a manual displacement of the closure part 16 is provided.

The shape or shape of the top or surface 17 of the closure oil 16 forms a drainage device with a collecting area 26 at a low level, so that the reactor contents, e.g. B. a liquid or solids such as capsules or the like, is discharged from the surface 17 in the removal direction or in the direction of the outlet channel 18 substantially without residue. In the case of an inclined flat surface, the collecting area 26 extends around the lowest point of the surface 17 on the peripheral edge of the closure part 16.

The reactor base 2 also contains an additional drain channel 23, which preferably leads from the surface of the collecting funnel 7 to the underside 3 of the reactor base 2. The upper opening of the drain channel 23, which in the surface of the sam- Meltrichters 7 opens in particular adjacent to the outlet recess 13, is preferably covered by a sieve 24.

In an alternative design (see FIG. 3), the outlet recess or through hole is preferably arranged centrally to the central axis 6 of the collecting funnel 7. In the wall 14 of the outlet recess 13, a groove 25 is preferably formed as an annular channel into which the at least one outlet channel 18 opens. The surface 17 of the closure part 16 is preferably spherical or convex, so that in the lowered removal position of the closure part 16 (shown in broken lines in FIG. 3) the desired phase, in particular capsules formed, can be removed with little loss or without loss. The discharge device here forms an annular collecting area 26, which is lowered on the edge side, on the surface 17 of the closure part 16, in order to B. derive the capsules to the groove 25 or the ring channel.

The reactor is e.g. B. used in the encapsulation of cells. For example, a suspension of sodium cellulose sulphate and cells is dripped through a nozzle. The drops fall into a hardness bath made of PDADMAC contained in the reactor 1 or the reactor vessel 11. First, the closure part 16 is arranged in its upper closing division flush with the surface of the collecting funnel 7 and the drain channel 23 is blocked off. After the hardening time, the hardening bath is drained or pumped out via the drain channel 23, the sieve 24 holding back the encapsulated substances or capsules. A rinsing or washing liquid can then be filled into the reactor and, after washing the capsules, drained off via the drain channel 23. This washing process can be carried out once or several times. To harvest the capsules, the closure member 16 is moved downward until the opening of the outlet channel 18 in the wall 14 of the outlet recess 13 is exposed and thus the capsules can flow through the harvest opening 15 and the outlet channel 18 with little loss or loss-free, since no corners are present on the flow path in which capsules may remain. The upper side or surface 17 of the closure part 16 enables and thus supports the loss-free drainage of the capsules from the reactor 1.

Instead of encapsulating cells or the like, the reactor 1 with the described reactor bottom can be used very generally to separate a phase from a phase mixture with at least two phases, the phase located above the surface of the collecting funnel 7 through the harvest opening 15 with little loss or can even be deducted without loss.

LIST OF REFERENCE NUMBERS

Reactor 14 wall

Reactor floor 15 upper opening, harvest opening

Bottom 16 closure part

17 foot surface

Top 18 outlet duct

Central axis 19 connector

Hopper 20 drive motor

Edge area 21 screwing device

Paragraph 22 spindle

Seal ring 23 drain channel

Glass cylinder 24 sieve

Rod 25 groove

Outlet recess 26 collection area

Claims

claims

1. reactor bottom (2) of a reactor (1) with an upper side (5) formed as a collecting funnel (7), with a harvesting opening (15) formed in the collecting funnel (7), which has an outlet channel (18) leading through the reactor bottom (2) ) is connected, and with a closure part (16) for the harvest opening (15) which is movably arranged on the reactor base (2) and between a closed position in which it closes the harvest opening (15) of the collecting funnel (7) and a removal position , in which it is lowered into the reactor floor (2) and releases a connection between the harvest opening (15) and the outlet channel (18), is adjustable.

2. Reactor base according to claim 1, characterized in that the surface (17) of the closing cable (16) is formed as a drainage device for discharging a reactor content from the harvesting opening (15) into the outlet channel (18).

3. Reactor base according to claim 1 or 2, characterized in that the surface (17) of the closure part (16) has a collecting area (26) with a low level, the collecting area (26) in the lowered removal position of the closing part (16) the outlet channel ( 18) is assigned.

4. Reactor base according to claim 3, characterized in that the collecting area (26) on the surface (17) of the closure part (16) is formed approximately point-like or linear.

5. Reactor base according to one of claims 1 to 4, characterized in that the harvest opening (15) is arranged eccentrically to the central axis (6) of the collecting funnel (7) and that in particular the edge of the harvest opening (15) the central axis (6) of the collecting funnel (7) touched.

6. Reactor base according to one of claims 1 to 5, characterized in that the surface (17) of the closure part (16) with respect to the central axis (6) is chamfered or crowned.

7. Reactor base according to one of claims 1 to 6, characterized in that the surface (17) of the closure part (16) in its closed position is arranged flush with the surface of the collecting funnel (7).

8. Reactor base according to one of claims 1 to 7, characterized in that one of the harvest opening (15) in the reactor base (2) in particular parallel to the central axis (6) of the collecting funnel (7) extending outlet recess (13) the closure part (16th ) slidably receives and that the at least one outlet channel (18) opens into the outlet recess (13).

9. reactor base according to claim 8, characterized in that in the wall (14) of the outlet recess (13) an annular groove (25) and / or more openings is or are formed, which communicate with the outlet channel (18).

10. Reactor base according to one of claims 1 to 9, characterized in that at least one additional drain channel (23) covered by a sieve (24) opens into the collecting funnel (7).

11. Reactor base according to one of claims 1 to 10, characterized in that the reactor base (2) is formed in one piece with the reactor (1) or the reactor wall (11) or that the reactor (1) or the reactor wall (11) is detachably connected to the reactor base (2) and the reactor wall (11) surrounding the collecting funnel (7) can be fixed on the upper side (5) of the reactor base (2).

12. Reactor base according to one of claims 1 to 11, characterized in that the closure part (16) is adjustable manually or by means of a drive device (20, 21, 22) arranged on the reactor base (2).

13. Reactor base according to one of claims 1 to 12, characterized in that the funnel angle of the collecting funnel (7) is substantially 130 ° to 170 ° and in particular 153 °.

14. A method for separating a phase from a phase mixture in a reactor with a reactor bottom according to one of claims 1 to 13, wherein the phase mixture is introduced into the reactor, the phases are separated and by moving the closure member arranged in its closed position to its removal position is and thereby releases a connection between the harvest opening and the outlet channel, the desired phase is removed from the reactor via the harvest opening and the outlet channel.

15. The method according to claim 14, characterized in that the phase mixture is a mixture of solid and liquid phase and the phase separation is carried out by sedimentation.

16. The method according to claim 14 or 15, characterized in that the phase mixture has a hardening bath and capsules contained in the hardening bath as the phase to be separated.

17. The method according to claim 16, characterized in that in particular before the capsules are removed in a further process step, the hardening bath is drained via the drain channel and fed into the reactor flushing liquid and drained again via the drain channel, this process step being carried out one or more times ,

18. The method according to claim 16 or 17, characterized in that the capsules are sodium cellulose capsules.

19. Seduction according to one of claims 16 to 18, characterized in that the capsules contain biological cells, in particular animal, human or plant cells.