Liquid purification or separation – Processes – Ion exchange or selective sorption
Reexamination Certificate
2000-03-13
2002-08-06
Barry, Chester T. (Department: 1724)
Liquid purification or separation
Processes
Ion exchange or selective sorption
Reexamination Certificate
active
06428707
ABSTRACT:
TECHNICAL FIELD AND EARLIER KNOWN TECHNIQUES
General About the Technical Field of the Invention
The invention relates to a process for the separation of a substance by adsorption to non-packed beds containing beads which exhibit structures (ligands) with affinity to the substance. Non-packed beds may be generated by expanding/fluidizing sedimented beads by an upward or a downward flow of fluid, the direction of flow being depending on the density of the beads used. A liquid sample containing the substance to be adsorbed is introduced into the flow after expansion. A less effective non-packed bed is generated by agitating suspendible beads with the aid of a turbulent flow or by mechanical stirring.
By selecting a bead population which includes beads varying in sizes and/or densities and using this population in an expanded bed, it is possible to obtain a so-called classified bed in which larger beads and beads with higher densities are located below smaller beads and beads with lower densities. The backmixing in these type of beds becomes low and they have been named stable expanded beds (sometimes stable fluidized beds). An alternative way of stabilizing a fluidized bed is by incorporating magnetic filler particles into the beads and apply a magnetic field during the fluidization. Stabilization by a magnetic field is an example that stable expanded beds can be achieved without using beads covering a certain size/density range. The adsorption in stable fluidized beds will take place during plug flow as in a chromatographic process in a packed bed. The number of theoretical plates will be high. In case the non-packed bed is generated by a turbulent flow or by agitation, backmixing will be high and the adsorption will take place in a batch-wise mode. For a short, recent survey of the field, see the introductory part of Thommes et al., Biotechnol. Bioengin. 48 (1995) 367-374.
Back-mixing in a bed is often measured as axial dispersion (“vessel dispersion number”), see Levenspiel, “Chemical Reaction Engineering” 2nd Edition, John Wiley & Sons (1972). For stable expanded beds, the vessel dispersion number will preferably be <75×10
−3
, more preferably <20×10
−3
, which corresponds >5, more preferably >30 theoretical plates. For total back-mixing, the number of plates will be 1.
Expansion/fluidization of the bed is normally effected in a column having provided at each of its ends a net structure covering the cross-sectional area of the column, or some other perforated device which will not generate turbulence in the flow. See, for instance, WO-A-9218237 (Pharmacia Biotech AB, Uppsala, Sweden) . The similar effect has also been claimed for a system utilizing a stirred inlet flow (WO-A-9200799; Kem-En-Tek/Upfront Chromatography A/S). Also other distributors are likely to be feasible.
Subsequent to adsorption, elution can be effected directly from the expanded bed. Alternatively, the bed may be allowed to settle and adsorbed material eluted from the bed with the aid of a fluid flow often introduced in a direction opposite to that in which the bed was expanded.
The fluid is often aqueous (for instance buffers dissolved in water), but also other liquids may be used.
BACKGROUND PUBLICATIONS
Pharmacia Biotech AB (Uppsala, Sweden) markets Streamline® which in its first version utilized porous beads of agarose with quartz particles as filler material (WO-A-9218237, Pharmacia Biotech AB). In a later version, the quartz particles were replaced with fillers of higher densities than quartz (PCT/SE96/01431, filed with priority from Nov. 7, 1995, Pharmacia Biotech AB). Another main supplier is Bioprocessing Ltd. (Durham, England) whose porous glass beads (Prosep®) can be used for chromatography on expanded beds (Beyzavi et al, Genetic Engineering News, Mar. 1, 1994 17)). Still another supplier is Sepracor.
U.S. Pat. No. 4,976,865 (Sanchez, et al, CNRS) teaches fluidized beds and the use of segmented columns to mimic the multi-step adsorption taking place in packed as well as stabilized expanded beds. The beads used in the experimental part are glass particles (Spherosil) that have been coated.
WO-A-9200799 (Kem-En-Tek; Upfront Chromatography) discloses a large number of fillers and polymeric materials that can be combined to produce beads intended for adsorption in fluidized beds. Each bead contains two or more filler particles.
WO-A-8603136 (Graves and Burns; University Patents Inc) discloses beads containing magnetic filler particles and their use in fluidized beds stabilized by an externally applied magnetic field. See also Burns et al., Biotechnol. Bioengin. 27 (1985) 137-145; and Lochmüller et al., J. Chem. Tech. Biotechnol. 40 (1987) 33-40.
In chromatography on packed beds it has earlier been suggested to use porous beads, the pores of which wholly or partly have been filled with hydrophilic gels carrying affinity ligands, such as ion exchange groups. One example is Macrosob-K which is macroporous kieselguhr which has been filled with agarose which in turn has been derivatized to exhibit DEAE or CM ion exchange groups (Macrosorb-KAX.DEAE and Macrosorb-KAX.CM, respectively (GB-A-1,586,364, Miles). This latter type of materials have also been applied in fluidised bed chromatography (Bite et al., In: Verrall et al., Separations for Biotechnology (1987), Elles Horwood Ltd, Chapter 13, 193-199.
Lochmüller et al., Sep. Sci. Techn. 22(11) (1987) 2111-2125 discloses a comparative study of adsorptions on a packed bed, a fluidized bed in the quiescent state and a magnetically stabilized bed. The beads used are made of Amberlite XAD, which have been coated adsorptively with a synthetic polymer whereafter an affinity ligand for the substance to be adsorbed has been linked to one terminal end of the polymer. Magnetic particles are present in the coat.
Problems Related to Earlier Fluidized Bed System
In the case of adsorption processes on expanded and/or fluidized beds, there is an expressed desire to have the highest possible productivity. Important variables that should be taken into acoount to achieve this is to use beads with the highest possible breakthrough capacity for the substance to be adsorbed and also to increase the flow rate. However, increasing the flow rate leads to decreased breakthrough capacity and also an increased risk for elutriation of beads. One way of solving the elutriation problem is to increase the density of the beads by including filler materials in them. However, filler material as a rule will have a detrimental effect on breakthrough capacity, the size of this effect being dependent on various factors such as the flow rate, the pore size of the beads, the structure that binds the substance to be adsorbed, the substance to be adsorbed etc.
One way of increasing the breakthrough capacity for filler matrices in bead form has recently been presented in International Patent Application PCT/SE96/01431 (Pharmacia Biotech AB), the content of which is hereby incorporated by reference. See below.
OBJECTIVES OF THE INVENTION
A first objective is to improve total yields in adsorption processes on fluidized beds.
A second objective is to improve productivity for adsorption processes on fluidized beds.
A third objective is to provide filler matrices that have improved breakthrough capacity in fluidized beds.
THE INVENTION
We have now realized that the above-mentioned problems can be solved by utilizing beads in which the affinity structure/ligand is linked to the base matrix of the beads via an extender.
The positive effect caused by an extender is believed to reside in the fact that it will provide the inner surfaces (pore surfaces) and/or outer surfaces of the beads with a flexible polymer layer that is permeable to macromolecules and other molecules allowed to pass the bed. This will cause an increase in the effective interacting volume as well as in the steric availability of the affinity structures/ligands for the substance to be adsorbed. This in turn will increase the mass transfer rate as well as the total capacity available.
Accordingly the fir
Berg Hans
Hansson Hasse
Kagedal Lennart
Amersham Pharmacia Biotech AB
Barry Chester T.
Chisholm Robert F.
Ronning, Jr. Royal N.
Ryan Stephen G.
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