Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
  • B01D15/08—Selective adsorption, e.g. chromatography
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
  • B01J20/26—Synthetic macromolecular compounds
  • B01J20/264—Synthetic macromolecular compounds derived from different types of monomers, e.g. linear or branched copolymers, block copolymers, graft copolymers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
  • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
  • B01J20/28004—Sorbent size or size distribution, e.g. particle size
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
  • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
  • B01J20/28016—Particle form
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
  • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
  • B01J20/28033—Membrane, sheet, cloth, pad, lamellar or mat
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
  • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
  • B01J20/28078—Pore diameter
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
  • B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
  • B01J20/3204—Inorganic carriers, supports or substrates
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
  • B01J20/3206—Organic carriers, supports or substrates
  • B01J20/3208—Polymeric carriers, supports or substrates
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
  • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
  • B01J20/3244—Non-macromolecular compounds
  • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
  • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
  • B01J20/3255—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising a cyclic structure containing at least one of the heteroatoms nitrogen, oxygen or sulfur, e.g. heterocyclic or heteroaromatic structures
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
  • B01D15/08—Selective adsorption, e.g. chromatography
  • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
  • B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 and B01D15/30 - B01D15/36, e.g. affinity, ligand exchange or chiral chromatography
  • B01D15/3804—Affinity chromatography
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2220/00—Aspects relating to sorbent materials
  • B01J2220/50—Aspects relating to the use of sorbent or filter aid materials
  • B01J2220/54—Sorbents specially adapted for analytical or investigative chromatography

Definitions

• the invention relates to biocompatible, porous materials, the pore surfaces of which are chemically modified, and to the production thereof
• the outer surface of the porous materials is electroneutral and hydrophilic, while the surface of the pores can be modified with different, functional ligands.
• Porous materials such as chromatographic sorbents, hollow fibers and membranes, are used on a large scale and in many different ways for the analysis, purification and separation of components from complex biological liquids - such as blood, plasma, fermenter broth, supernatants from cell culture or tissue homogenates. This also includes the extracorporeal purification of blood, whereby, for example, toxic or pathogenic blood components are removed.
• porous materials are also widely used, the surface of which is additionally modified with functional ligands (eg separation effectors which form a distribution phase). Examples of this are chromatographic support materials and membranes with ion exchange or reverse phase properties. If catalysts or biocatalysts (for example enzymes or ribozymes) are immobilized as functional ligands, catalytically active porous materials are provided which, for example, make it possible to degrade or detoxify toxic components.
• porous materials When porous materials come into contact, the surface of which is modified with functional ligands such as separation effectors such as ion exchange or hydrophobic alkyl groups, there is also an unspecific adsorption and / or denaturation of cellular components, proteins and / or nucleic acids on the macromolecular ones Components freely accessible outer surface (contact surface) of porous materials.
• functional ligands such as separation effectors such as ion exchange or hydrophobic alkyl groups
• the examples given show that there is a lack of porous materials which are modified on the one hand with functional ligands (eg distribution phases) in order to thereby achieve selective absorption or binding of target components, but which on the other hand have a biocompatible outer surface which has an undesired adsorption and / or excludes denaturation or activation of or by components of biological fluids.
• the invention was therefore based on the object of providing porous materials whose pore surfaces are occupied by functional ligands and whose outer surfaces have electroneutral hydrophilic properties, and to provide processes for producing these materials.
• a biocompatible outer surface should be (bio) chemically inert, electro-neutral and wettable (hydrophilic) with aqueous media.
• the inner surfaces of the pores should be modified with various functional ligands.
• Diol-modified carriers have proven to be hydrophilic materials that are (bio) chemically inert. Reactive groups were therefore chosen as the chemical modification of the outer surface of porous materials, which can be converted to vicinal diol groups or to other hydrophilic groups with the aid of a particulate catalyst.
• Alkyl residues located on the outer surface are hydrolyzed to generate the originally present silanol groups.
• the latter are then reacted with a 3-glycidoxypropyl silane and the epoxy groups are hydrolyzed to diol groups. This creates a diol-substituted outer surface.
• this purely chemical multi-stage process has the disadvantage that the hydrolysis is limited to silanized silica gels, is difficult to control and reproducible and, moreover, the pore structure is changed.
• WO 94/09 063 discloses a method in which, as in the result, as in DE 41 30 475, the inner surfaces of larger pores are modified hydrophilically, while the inner surfaces of smaller pores are modified hydrophobically by the reaction of epoxy groups.
• the disclosed method consequently produces a porous material in which pores with different pore sizes are modified in different ways.
• Differentiation between the pore sizes is made by using a polymeric high molecular weight sulfonic acid derivative as a catalyst. Since both the pore size of the particles and the molecular size of the polymeric catalyst have a clear spread due to the production process, undesired conversions occur when the distribution curves overlap. For example, according to the method disclosed in WO 94/09 063, it is not readily possible to derivatize only the outer surfaces of the particles in a hydrophilic manner.
• the invention was therefore based in particular on the object of providing a method which makes it possible to generate the desired biocompatible outer surface of porous materials in a simple and reproducible manner, regardless of the chemical nature of the base material, and which also allows uniform modification To provide pore inner surfaces, only the outer surfaces of the porous materials being hydrophilically modified. It would be advantageous if, depending on the intended use of the porous materials, different functional ligands could be incorporated into the inner surface of the pores.
• the polymeric catalysts used in WO 94/09 063 are solvated in solution. Surprisingly, it was found that the outer surfaces of porous materials can be converted in a targeted manner by using particulate catalysts. The particle diameter of the catalysts must be significantly larger than the pore size of the porous material.
• the invention relates to porous materials which have hydrophilic outer surfaces and pore surfaces which are filled with functional ligands and which can be obtained by the following reaction steps: a) introduction of epoxy groups into a porous base support, the pore surfaces and the Outer surfaces of the base support are modified, provided that the base support has no epoxy groups; b) catalytic ring opening of the epoxy groups by reaction with a nucleophile using a particulate catalyst, the particle size of the catalyst being larger than the mean pore diameter of the porous base support; c) Implementation of the epoxy groups of the pore surfaces remaining in step b) and introduction of functional ligands.
• the invention further relates to processes for the production of these porous materials and their use.
• Non-particulate base supports are, for example, membranes, such as flat membranes or hollow fiber membranes, or fabrics.
• Suitable porous base supports can consist both of inorganic materials, for example oxidic materials such as porous glass (CPC) or SiO 2 , or of organic materials, for example crosslinked polymers such as copolymers of glycidyl methacrylate and ethylene dimethacrylate or of dihydroxy propyl methacrylate and ethylene dimethacrylate.
• Such base supports can already contain epoxy groups, as is the case with the copolymers of glycidyl methacrylate and ethylene dimethacrylate mentioned.
• epoxy groups into a porous base support by reactions known to those skilled in the art; for example, by silanizing a porous base support with a 3-glycidoxypropyl silane, or by reacting a copolymer of dihydroxypropyl methacrylate and ethylene dimethacrylate with epichlorohydrin.
• Nucleophilic agents which are suitable for reacting with the epoxy groups and thereby introducing hydrophilic groups are known to the person skilled in the art. These include water, monohydric or polyhydric alcohols, where a hydroxyl group can be replaced by an amino or thiol group, such as, for example, ethylene glycol, glycerol, pentaerythritol, 2-aminoethanol, 2-amino-1,3-propanediol, tris ( hydroxymethyl) methylamine (TRIS) or 4-amino-4- (3-hydroxypropyl) -1, 7-heptanediol.
• TMS hydroxymethyl) methylamine
• nucleophilic agents are hydrophilic heterocyclic derivatives, such as 3-amino-1-hydroxy-2-pyrrolidone.
• the particulate catalysts used according to the invention are characterized in that they consist of a (water-insoluble) porous or non-porous support, the surface of which is modified with ion exchange ligands. Silicate-containing can be used as catalyst supports
• Materials such as silica gels or glasses are used.
• Crosslinked natural or synthetic polymers or copolymers such as, for example, crosslinked styrene-divinylbenzene copolymers or particles of polysaccharides such as crosslinked cellulose or agarose are also suitable.
• Composite catalyst supports which contain magnetizable additives are also particularly suitable. Suitable materials are commercially available in large numbers. If the ion exchange groups are not already present in the starting material, the catalyst supports can be converted into suitable ion exchangers by known methods.
• Ion exchange groups which can be used are those with weakly or strongly acidic properties, such as, for example, carboxylic acid or sulfonic acid groups, or those with weakly or strongly basic properties, such as, for example, diethylaminoethyl (DEAE) or diethyl (2-hydroxypropyl) aminoethyl (QAE) groups are used, the cation exchangers must be in the H form and the anion exchangers in the OH ' form.
• weakly or strongly acidic properties such as, for example, carboxylic acid or sulfonic acid groups
• weakly or strongly basic properties such as, for example, diethylaminoethyl (DEAE) or diethyl (2-hydroxypropyl) aminoethyl (QAE) groups
• the cation exchangers must be in the H form and the anion exchangers in the OH ' form.
• Magnetic catalyst particles can be separated from the reaction mixture in a simple manner by using a magnetic field.
• the average pore diameter of the porous base support and its pore size distribution determine the particle size of the particulate catalyst used according to the invention. So that the catalyst particles cannot penetrate into the pores of the base support, their particle diameter must be sufficiently large: the (smallest)
• Diameter of the particulate catalyst used to be larger than the (average) pore diameter of the porous base support The means that the distribution curves of the pore diameter of the porous base support and the particle size of the particulate catalyst must not overlap or only slightly. For practical applications, this condition is met if the overlap area of both distribution curves is less than 10 percent, especially less than 5
• porous materials are obtained when using the method according to the invention, the outer surface of which is modified hydrophilically and the inner surface of the pores are uniformly modified with a functional ligand.
• reaction of the epoxy groups on the outer surface of the porous base support by means of a particulate catalyst according to the invention is carried out in salt-free (bidistilled) water or, if appropriate, in a water-miscible organic solvent - preferably isopropanol (10%, v / v).
• Functional ligands are understood to mean, for example, separation effectors or else catalysts or enzymes.
• Separation effectors create specific interactions that can be used for chromatographic separations or other distribution methods such as liquid-liquid distribution.
• the epoxy groups in the pores can be reacted further and separation effectors introduced, whereby ion exchangers, thiophilic sorbents or sorbents for the metal chelate or the hydro- phobe chromatography and affinity chromatography, as well as for chiral separations.
• ion exchangers thiophilic sorbents or sorbents for the metal chelate or the hydro- phobe chromatography and affinity chromatography, as well as for chiral separations.
• phosphoric acid, ammonia, diethylamine, trimethylamine, sulfurous acid or complexing agents such as iminodiacetic acid, or chiral compounds such as proteins, peptides or polysaccharide derivatives are added to the oxirane ring; Examples of such implementations are:
• room temperature means 15-25 ° C.
• Reaction products are isolated by filtration on a glass filter (GF 2) and washed.
• 1 part by weight (dry weight) of the porous, organic copolymer carrier TSK HW 40 C (Merck KGaA: particle diameter: approx. 30-60 ⁇ m; pore diameter approx. 6 nm) is suspended in 4 parts by weight of double-distilled water and with 1.1 parts by weight 1-chloro-2,3-epoxypropane added.
• the epoxidation takes place with stirring at 45 ° C. for 4 hours at a constant pH (9.0).
• the epoxidized gel is filtered off with suction and washed in succession with 4 parts by weight of double-distilled water, 4 parts by weight of methanol and 4 parts by weight of double-distilled water and dried at 40-50 ° C. in vacuo.
• 1 part by weight (dry weight) of the epoxidized copolymer carrier from Example 1 is bidistilled in 15 parts by weight. Slurried water and with 1 part by weight of a 2.5 weight percent aqueous suspension of the particulate catalyst according to the invention (sulfonated, non-porous latex microspheres; particle diameter: 1 ⁇ m; Polybead® Sulfate, Polysciences, Inc., Warrington, PA, USA) were added and the mixture was stirred at RT for 20 hours.
• a 2.5 weight percent aqueous suspension of the particulate catalyst according to the invention sulfonated, non-porous latex microspheres; particle diameter: 1 ⁇ m; Polybead® Sulfate, Polysciences, Inc., Warrington, PA, USA
• the particulate catalyst Before use, the particulate catalyst is converted into the corresponding H® form with 0.1 N hydrochloric acid. Then the reagent is bidistilled. Washed water free of salt. The particulate catalyst is recovered after conditioning or before and after the washing steps by centrifugation or filtration.
• the particulate catalyst used is separated from the modified support material by filtration, a filter having an appropriate porosity being used.
• a filter having an appropriate porosity In the present example, this is a sintered glass frit of porosity 2.
• the particulate catalyst recovered in this way can, after conditioning and subsequent washing with bidistilled water. Water can be used again.
• the epoxide groups hydrolyzed by the solid phase reagent were quantified using the titration with Na thiosulfate known to the person skilled in the art and gave 20 ⁇ mol / g dry weight or 5% of the epoxy groups of the starting material.
• Example 3 Reaction of the remaining reactive oxirane groups in the interior of the pores with taurine (aminoethanesulfonic acid)
• a porous material is obtained, the outer surfaces of which are covered with hydrophilic diol groups and which has strongly acidic ion exchange groups in the pores; the porous material thus obtained can be used as a cation exchanger.
• Example 4 Reaction of the remaining reactive oxirane groups in the interior of the pores with m-aminophenylboronic acid
• a porous material is obtained, the outer surfaces of which are hydrophilically coated with diol groups and which has affinity ligands in the pores; the porous material obtained in this way can be used as an affinity carrier, for example for the separation of carbohydrate-containing compounds.

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• Chemical & Material Sciences (AREA)
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• Chemical Kinetics & Catalysis (AREA)
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• Inorganic Chemistry (AREA)
• Solid-Sorbent Or Filter-Aiding Compositions (AREA)
• Catalysts (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1998
  • 1998-09-17 DE DE59812924T patent/DE59812924D1/de not_active Expired - Lifetime
  • 1998-09-17 EP EP98951428A patent/EP1019188B1/de not_active Expired - Lifetime
  • 1998-09-17 WO PCT/EP1998/005925 patent/WO1999016545A1/de not_active Ceased
  • 1998-09-17 JP JP2000513670A patent/JP4372994B2/ja not_active Expired - Lifetime
  • 1998-09-18 DE DE19842785A patent/DE19842785A1/de not_active Withdrawn
• 2009
  • 2009-07-03 JP JP2009158948A patent/JP2010014716A/ja active Pending

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