Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
  • C12M27/02—Stirrer or mobile mixing elements
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
  • B01F35/90—Heating or cooling systems
  • B01F35/95—Heating or cooling systems using heated or cooled stirrers
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
  • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
  • C12M41/12—Means for regulation, monitoring, measurement or control, e.g. flow regulation of temperature
  • C12M41/18—Heat exchange systems, e.g. heat jackets or outer envelopes
  • C12M41/24—Heat exchange systems, e.g. heat jackets or outer envelopes inside the vessel

Definitions

• the invention relates to a stirring arrangement according to the preamble of claim 1.
• Such stirring arrangements are used for sensitive suspensions, in particular for bioreactors.
• bio-actuators the metabolic processes in bio-technological processes generally also generate heat as a metabolic product.
• the activity of the biocatalysts, the enzymes decreases with increasing temperature, or these enzymes are even destroyed from a certain temperature, the heat generated must be removed.
• This is not a problem for small reactor volumes, since the reactor surface is large in relation to the content.
• the larger the reactor volume the more unfavorable the ratio of the heat-emitting surface to the volume, since the increase in volume increases with the third power as the size of the reactor vessel container increases, but the size of the container wall available for heat exchange only increases square.
• the size of the container and the heat activity of the microorganisms or cells one therefore reaches a point at which an forced heat exchange becomes unavoidable.
• a double jacket is used for this on the container, through which a heat transfer fluid flows.
• This type of heat exchange on stirred tanks is common in chemical engineering and is available in many embodiments.
• certain boundary conditions must be observed; most microorganisms or cells cannot tolerate large temperature gradients in the culture fluid.
• the inner wall of the reactor has almost the same temperature as the cooling / heating medium due to its good thermal conductivity. The greatest temperature gradient is accordingly in the culture medium.
• the temperature difference between the culture fluid and the heat transfer medium in the double jacket must not be greater than 0.5 to 2.0 Kelvin.
• the exchanged heat flow per volume which is determined by the product of the exchange surface and the temperature difference, becomes smaller and smaller as the volume of the container increases, since the temperature difference must remain constant. Furthermore, the demands on the homogenization performance of the stirrer are becoming ever greater, since the distance from the heat source (the medium in the reactor) to the heat sink (vessel wall) generally also increases with increasing vessel size.
• a stirring arrangement of the type mentioned at the outset is known for example from DE-OS 20 01 739, DE-PS 822 990 and DE-PS 489 146. With these known stirring arrangements, the medium to be stirred again comes into direct contact with the heat exchanger surface, so that these stirring arrangements are less suitable as bioreactors for the reasons already mentioned above.
• the invention is based on the object of providing a stirring arrangement of the type mentioned at the outset which ensures gentle temperature treatment of the stirring medium with effective heat exchange.
• the invention consists in that the heat exchanger surface of the stirrer does not come into direct contact with the stirring medium, but is separated from the stirring medium by partially permeable walls, so that temperature-sensitive biomaterial does not come into contact with the heat exchanger surface Contact comes.
• the design of the stirrer according to the invention also permits higher temperature differences between the medium and the heat exchanger surface, because microorganisms or cells do not come into contact with the exchange surface. Rather, these are kept away from the interior of the stirrer by the porous walls.
• the stirrer in the manner of a Venetian stirrer or to subject it to a tumbling movement, so that a very homogeneous temperature profile can be set.
• the stirrer itself is advantageously in again divided into two chambers.
• the inner chamber serves for gassing the liquid, while the heating / cooling spiral is located in the annular outer chamber.
• this construction is intended to prevent gas bubbles from adhering to the heat exchange surface and recombining there or from deteriorating the heat transfer.
• the medium in the interior of the stirrer is moved violently by the rising gas bubbles or by the forced flow, whereby good heat exchange coefficients are achieved between the heat exchange surface and the liquid.
• the initially strong temperature profile is homogenized before the microorganisms or cells come into contact with the heated or cooled medium.
• a cylindrical stirrer there is an exchange surface similar to an immersion heater, which is formed by a bent tube.
• the heat transfer fluid flows in this tube.
• the feed and discharge lines are guided through a hollow rod formed in the middle of the stirrer.
• a gas supply device is advantageously designed as a porous base plate through which the gas, in particular air or 0, rises vertically. In this way, the medium is swirled inside the stirrer and the swirling movement of the stirrer superimposes a cross flow through the cylinder on this swirling. This will both a good homogenization of the gas enrichment and a good homogenization of the temperature profile in the stirred tank enables.
• the ratio of the stirrer surface to the reactor volume must be kept constant for the ventilation of the cells, and this is also possible with larger reactors, the ratio of the heat exchanger surface to the boiler volume is also kept constant, since the stirrer surface is due to the outer surface of a three-dimensional body is formed, and thus this, in the third power, also enters into an increasing reactor size.
• the heat exchanger tubes are to be arranged in the stirrer in such a way that gas supply through the bottom of the stirrer is not restricted too much. Furthermore, a minimum distance between the heat exchanger tubes and the . porous walls of the stirrer, which are preferably designed as metal grids, are adjusted in order to achieve a temperature compensation in the direction of the flowing medium downstream. Coagulation of the air bubbles on the surface of the heat exchanger tubes should be avoided if possible.
• FIG. 1 shows a cross section I-I from FIG. 2 through a cylindrical stirrer with heat exchangers and gas supply;
• FIG. 2 shows an axial longitudinal section II-II of the stirrer from FIG. 1;
• FIG. 3 shows a detail III from FIG. 1,
• Fig. 4 shows a cross section similar to Fig. 1 by stirrers in other embodiments.
• FIG. 1 and 2 show an elongated, cylindrical stirrer 10 which is designed in the manner of a candle.
• the outer shape of the stirrer 10 is essentially formed by a stirrer shaft 12, at the lower end of which a cover plate 14 for the cylinder jacket 16 of the stirrer body 10 is formed.
• the cylinder jacket 16 is porous, ie permeable to part of the medium to be stirred.
• the cylinder sleeve is - as described in detail later - made of knitted fabric.
• the bottom of the stirrer 10 is closed by a base plate 18.
• the stirrer 10 is thus designed in the manner of a hollow candle or a hollow cylinder.
• the stirring medium consists of a carrier medium and biological cells.
• the stirring medium passes through the porous cylinder jacket 16, as a result of which the space inside the cylinder jacket 16 is flowed through during stirring.
• Heat exchanger tubes 20, through which a cooling liquid flows, are arranged within the cylinder jacket 16.
• a feed channel 22 for the cooling liquid is formed in the stirring axis 12.
• the cooling liquid returns to an external cooling device through a return channel 24 in the base plate and in the stirring axis.
• a porous plate 26 is arranged in the base plate 18 towards the cylinder interior, through which air, oxygen or other gases can be blown into the cylinder interior via a gas supply channel 28.
• the heat exchanger tubes 20 and the porous plate 26 are arranged on a full circle in the stirrer 10.
• the heat exchanger tubes 20 and the porous plate are shown for the sake of simplicity only over a 180 ° sector.
• an alternative embodiment shows heat exchanger tubes 21 with an oval base.
• the heat exchanger tubes can also have an elliptical or similarly designed base area, which provides the heat exchanger tube with the largest possible heat exchanger surface for the heat transfer into the carrier medium.
• the stirrer 10 is used in particular in bioreactors.
• a particular problem with bioreactors is that the biological cells, in particular mammalian cells, cannot tolerate large shear forces and large temperature differences.
• the porous cylinder jacket 16 of the stirrer 10 is therefore designed in such a way that only the carrier medium - but not the biological cells themselves - can get into the interior of the cylinder. As shown in FIG. 3, this is achieved, for example, in that the cylinder jacket 16 consists of a fabric 30, in particular a metal fabric, the mesh size of which is smaller than the diameter of the biological cells.
• the heat exchanger tubes 20 are spaced apart from the metal mesh 30 by the distance d, as a result of which temperature differences of the fluid in the flow path between the heat exchanger tube 20 and metal mesh 30 are reduced by mixing the fluid in this area.
• the temperature difference between the fluid in the bioreactor and the fluid flowing out through the metal mesh 30 is therefore reduced to such an extent that the biological cells in the bioreactor are not damaged.
• the absence of biological cells within the cylinder jacket 16 of the stirrer 10 therefore enables a temperature difference between the heat exchanger tubes 21 and the medium, which would not be possible if the heat exchanger came into direct contact with the biological cells.
• the gas supply in particular the supply of oxygen or air, also causes a strong turbulence, so that the cooler medium flowing past the heat exchanger tubes 21 is swirled vigorously with the not yet cool medium within the cylinder element 16. As a result, the cooling output is delivered relatively uniformly to the entire medium flowing through the stirrer 10.
• the stirrer therefore allows both good temperature control and a good gas supply to the stirring medium.
• the heat exchanger tubes can be connected in series in the manner of a series connection (FIG. 4a), the direction of flow in the circularly arranged heat exchanger tubes 32 then alternating.
• 4b shows a parallel connection of heat exchanger tubes, the cooling liquid, as in FIG. 1, flowing in (+) through heat exchanger tubes 34 and flowing out via a central return 36 (-).
• FIG. 4a A mixture of these two flow principles can be realized in FIG. 4a if the cooling liquid flows in through four heat exchanger tubes labeled "+” and flows out via four heat exchanger tubes labeled "-".
• the heat exchanger tubes can only cover a partial circle in the stirrer 10 within the cylinder jacket 16 if, e.g. a lower cooling or heating output is desired. Furthermore, the heat exchanger tubes can also be arranged in a grid-like manner within the cylinder jacket 16.

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Citations (4)

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• 1991
  • 1991-06-04 DE DE4118337A patent/DE4118337A1/de active Granted
• 1992
  • 1992-06-04 WO PCT/EP1992/001250 patent/WO1992021438A1/de active Application Filing

Patent Citations (4)

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