WO1996002577A1 - Perles de gel polymere sensibles - Google Patents

Perles de gel polymere sensibles Download PDF

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Publication number
WO1996002577A1
WO1996002577A1 PCT/US1995/009037 US9509037W WO9602577A1 WO 1996002577 A1 WO1996002577 A1 WO 1996002577A1 US 9509037 W US9509037 W US 9509037W WO 9602577 A1 WO9602577 A1 WO 9602577A1
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WIPO (PCT)
Prior art keywords
gel
cellulose
gel bead
responsive
polymer
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PCT/US1995/009037
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English (en)
Inventor
M. J. Timm
E. C. Lupton
Matthew E. Schiller
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Gel Sciences, Inc.
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Publication date
Application filed by Gel Sciences, Inc. filed Critical Gel Sciences, Inc.
Priority to AU31009/95A priority Critical patent/AU3100995A/en
Publication of WO1996002577A1 publication Critical patent/WO1996002577A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/005—Crosslinking of cellulose derivatives
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C08J3/16—Powdering or granulating by coagulating dispersions
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
    • C08J2301/08—Cellulose derivatives
    • C08J2301/26—Cellulose ethers
    • C08J2301/28—Alkyl ethers

Definitions

  • volumetric change phenomena have been observed in crosslinked polymer gel networks.
  • an external environmental condition e.g. , temperature; solvent composition; pH; electric field; light intensity and wavelength; pressure; ionic strength, etc.
  • the polymer network contracts and/or expands in volume (i.e. , the gel is a "responsive" gel).
  • the volume of such a gel may, under certain circumstances, change reversibly by a factor as large as several hundred when the gel is presented with a change in external conditions. See, Tanaka Phys. Rev. Lett. 40(12), 820- 823 (1978); Tanaka et al, Phys. Rev. Lett. 38(14), 771-774 (1977); Phys. Rev. Lett.
  • responsive gels are formed using a variety of polymer networks, including certain acrylamides, acrylates, polysaccharides and synthetic polymers, such as polyvinylalcohol (PVA) and polyethyleneoxide (PEO).
  • PVA polyvinylalcohol
  • PEO polyethyleneoxide
  • Preparation of responsive gels as a bulk slab or flakes has been reported; however, it is desirable to make responsive gels in the form of beads.
  • the spherical shape of the beads permits more uniform control of swelling and contraction.
  • the beads readily lend themselves to separation processes and/or can be synthesized into a particular size to best suit a particular application and to control properties which are particle size related. Additionally, beads allow close packing and uniform free volume allowing easy measurement of swelling and compression.
  • the responsive gel bead is desirably of relatively small diameter, thereby reducing the amount of time required to swell the gel bead.
  • the responsive gel bead also is capable of rapid swelling by absorbing solvents and collapsing by the subsequent expulsion of entrained solvent.
  • solvents include water, pure solvents, mixed solvents and/or solutions. Such solutions may also be saline, acidic or base, contain ions and/or contain paniculate matter).
  • a desirable responsive gel bead may be capable of absorbing significant amounts of solvent.
  • it is desirable that the gel bead have a lower critical transition temperature (LCST) not significantly above room temperature in order to permit energy efficient cycling of the gel between the swollen and collapsed states.
  • LCST critical transition temperature
  • those monomers known to provide responsive gels such as acrylamide and aery late are highly toxic, mutagenic and carcinogenic.
  • the corresponding polymers i.e., poly aery lamides and polyacrylates
  • poly aery lamides and polyacrylates are significantly less toxic.
  • many natural polymers such as polysaccharides, actually are biocompatible.
  • beads of N- isopropyl acrylamide may be mechanically weak and do not have the mechanical integrity to survive in demanding environments.
  • preparation of a polymer network starting from a polymer permits greater reaction control, since one can select polymers of known composition and molecular weight. Polymer formation is no longer a variable in the formation of the polymer gel network.
  • U.S. Patent No. 3,208,994 to Flodin et.al. (which is incorporated herein by reference) generally discloses a method of preparing gel beads of a wide range of polysaccharides using a technique known as suspension crosslinking.
  • Flodin et al. report the introduction of a water hydrated polysaccharide and crosslinker into a suspension medium under agitation so as to obtain suspended drops of the polysaccharide suspension.
  • Flodin et al. disclose the use of epichlorohydrin as the crosslinker and an aromatic hydrocarbon or a halogenated hydrocarbon as the suspension medium. While Flodin et al.
  • the present invention provides a responsive gel bead possessing desirable performance characteristics under specific operating conditions wherein the selection of the desired polymer is based in part on factors unrelated to gel bead form and size.
  • An object of the present invention is to provide a responsive gel bead of small diameter possessing desirable performance characteristics.
  • a further object of the present invention is to provide a responsive gel bead capable of rapid swelling and collapse in response to environmental stimuli. It is yet a further object of the present invention to provide a responsive gel bead capable of absorbing a large volume of solvent per milliliter of collapsed gel. It is a further object of the invention, to provide a responsive gel bead having an LCST at not significantly above room temperature.
  • the present invention is a responsive gel bead obtainable from a specific method of inverse suspension crosslinking of a polymer.
  • the present invention may be a responsive cellulosic gel bead obtainable under particular process conditions from the inverse suspension crosslinking of a cellulose ether.
  • a responsive gel bead includes a polymer which is chemically crosslinked with a bi-functional or multi ⁇ functional organic compound, the gel bead having an LCST of less than 55 * C.
  • the polymer may be an individual polymer, a polymer blend or an interpenetrating polymer network.
  • the responsive gel bead may have a diameter in a collapsed state of less than 600 ⁇ m, the collapsed state at a temperature of no greater than 75 * C.
  • the ratio of a mean diameter of the gel bead to a median diameter of the gel bead is preferably no more than 1.2 in a collapsed state.
  • the responsive gel bead may also be capable of absorbing at least 5 grams solvent per milliliter of collapsed gel, wherein the collapsed gel is at a temperature of no greater than 75 * C.
  • the responsive gel bead may also be capable of responsively absorbing at least 5 gram solvent per milliliter of collapsed gel in one hour or less, or absorbing and releasing at least 5 gram solvent per milliliter of collapsed gel in two hour or less, wherein the collapsed gel is at a temperature no greater than 75 * C.
  • a responsive cellulosic gel bead in another aspect of the invention, includes a cellulose ether polymer which is chemically crosslinked with a bi- functional or multi-functional organic compound, the gel bead having an LCST of less than 55 * C.
  • the cellulose ether polymer may be an individual polymer, a polymer blend or an interpenetrating polymer network.
  • the responsive cellulosic gel bead may have a diameter in a collapsed state of less than 600 ⁇ m, the collapsed state at a temperature of no greater than 75 * C.
  • the ratio of a mean diameter of the gel bead to a median diameter of the cellulosic gel bead is preferably no more than 1.2 in a collapsed state.
  • the responsive cellulosic gel bead may also be capable of absorbing at least 5 grams solvent per milliliter of collapsed gel, wherein the collapsed gel is at a temperature of no greater than 75 'C.
  • the responsive cellulosic gel bead may also be capable of responsively absorbing at least 5 gram solvent per milliliter of collapsed gel in one hour or less, or absorbing and releasing at least 5 gram solvent per milliliter of collapsed gel in two hour or less, wherein the collapsed gel is at a temperature no greater than 75 'C.
  • a responsive gel bead in another aspect of the present invention, includes a preformed polymer which is then chemically crosslinked with a bi-functional or multi-functional organic compound, the gel bead having a diameter of less than or equal to 400 ⁇ m as prepared and measured at a temperature of less than 30' C.
  • the responsive gel bead may also includes a preformed polymer which is then chemically crosslinked with a bi-functional or multi-functional organic compound, the gel bead having a diameter of less than or equal to 50 ⁇ m as prepared and measured at a temperature of less than 30 * C.
  • the responsive cellulosic gel bead includes hydroxypropyl cellulose (HPC) and methyl cellulose (MC), and mixtures thereof, optionally blended with hydroxy ethyl cellulose (HEC), carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC), ethylhydroxy ethyl cellulose (EHEC), hydroxymethyl cellulose (HMC), and methylhydroxyethyl cellulose (MHEC) and mixtures thereof.
  • the responsive cellulosic gel is preferably a responsive HPC gel, having an LCST of between 42 ' and 46 ' C .
  • a method for the manufacture of particular desirable responsive gel beads under specific reaction conditions by inverse suspension crosslinking is provided. Accordingly, an aqueous polymer suspension, an organic solvent and a crosslinker are provided and admixed to form a two-phase system, where the aqueous suspension is irrimiscible in the organic solvent so as to make up two phases.
  • the two- phase system is agitated sufficient to form droplets of aqueous polymer suspension in the organic solvent.
  • the agitation of the two-phase system is maintained for a time sufficient to form crosslinked polymer gel beads and the crosslinked polymer gel beads are thereafter recovered from the organic solvent.
  • the organic solvent is a hydrocarbon selected from the group consisting of paraffinic hydrocarbons, petroleum- based hydrocarbons, high purity mineral oils and mixtures thereof.
  • the fine mineral oil preferably has a viscosity less than 2 cSt.
  • the organic solvent is selected from the group consisting of decane, octane, nonane, undecane, dodecane, straight chain paraffinic and petroleum-based hydrocarbons and mixtures and blends thereof.
  • the organic solvent may include a cycloalkane, such as cyclohexane and decalin.
  • a compatibilizing agent may be admixed into the organic solvent.
  • a “compatibilizing agent”, as that term is used herein, means a polymer, oligomer or compound that is substantially non-reactive to the components of the crosslinking polymerization system and which includes both hydrophilic and hydrophobic regions.
  • the compatibilizing agent may include an intermixture of hydrophobic and a hydrophilic regions.
  • the compatibilizing agent may include a copolymer of a hydrophilic monomer and a hydrophobic monomer.
  • “intermixture” as that term is used herein, it is meant a compatibilizing agent which includes a mixture of both hydrophilic and hydrophobic regions.
  • the mixture may be that of individual compounds, i.e., mixtures of molecules having either hydrophobic or hydrophilic character, or of subcomponents which together make up a oligomer or polymer, i.e., block co-polymer of hydrophobic and hydrophilic monomers.
  • the beads of the present invention can be used in any application by modifying the bead properties to those required by its intended use.
  • the responsive gel beads of the present invention may be of small diameter, rapidly responsive, highly absorbent and/or responsive at temperatures near room temperature. Further, the method of the present invention, provides a reliable and efficient route for making the responsive gel beads with desirable properties.
  • the Figure is a responsive surface plot illustrating the effect of crosslinker level and polymer concentration on bead formation.
  • cellulosic gel beads having a relatively low LCST and one or more of the desirable properties of small size, rapid response and high absorptivity may be prepared by suspension crosslinking under controlled reaction conditions of an aqueous cellulose suspension dispersed in a continuous organic phase.
  • cellulosic gel beads advantageously may be made by introducing the water hydrated cellulose ether into a high purity fine mineral oil.
  • a responsive gel bead includes a polymer which is chemically crosslinked with a bi-functional or multi- functional organic compound, the gel bead having a lower critical solution temperature (LCST) of less than 55 * C.
  • the polymer may be an individual polymer, polymer blend or an interpenetrating polymer network.
  • lower critical solution temperature as that term is used herein, it is meant the temperature below which a polymer is substantially soluble in a liquid and above which the polymer is substantially insoluble and therefore forms a two phase system.
  • phase transition The transition from solubility to insolubility is termed a "phase transition”.
  • the LCST of responsive cellulosic gels is well known and can be easily determined and verified.
  • Exemplary LCST's are 42 '-46' (hydroxypropyl cellulose; HPC), 59' (hydroxypropylmethyl cellulose; HPMC), 49 'C (methyl cellulose; MC), 60' (methylhydroxyethyl cellulose; MHEC), and 55 '-70° (ethylhydroxyethyl cellulose; EHEC). It is anticipated that the LCST of the gel bead is normally comparable to that of the bulk gel.
  • the LCST of a bulk gel may be lowered or raised by the addition of a hydrophilic, hydrophobic, or ionic element.
  • "LCST” as used herein encompasses bulk LCST, modified LCST and LCST affected by ionization.
  • LCST is a function of the polymer, solvent and crosslink composition, additives, and concentration of the responsive gel. It is desirable to effect such a transition at as low a temperature as possible because of the high amount of energy required in the heating step.
  • HPC with an LCST of 42'C, is a particularly desirable responsive gel.
  • a “bead” is used herein to mean a small, substantially spherical object.
  • the beads of the present invention may have a diameter in the collapsed state of no more than 600 ⁇ m, and preferably having a mean diameter to median diameter ratio of less than 1.2.
  • a “gel”, as used herein, is a material between the solid and liquid state, in which a pure or mixed solvent or solution is entrained within a crosslinked polymer network.
  • pure or mixed solvent and/or solution as stated herein, it is recognized that a mixture of solvents may be absorbed by the polymer network. Additionally, the solvent may include salts or other additives so as to form a solution, which may also be absorbed or entrained within the polymer network.
  • a “responsive gel”, as used herein, is a gel which will undergo reversible swelling (entraining solvent) and collapsing (releasing solvent) upon exposure to an external environmental condition, such as, for example, temperature, pH, solvent concentration, electric field, photon irradiation, solution ionic strength and pressure. Additionally, the gel may be responsive to any of the above environmental stimuli which is triggered by application of an independent environmental condition. For example, chromophores may be activated to change the pH or photon irradiation may generate heat. In order to be classified as a "responsive" gel, the gel must respond to a very small change in environmental conditions.
  • a volumetric change of at least 20 percent in response to the small change in environmental stimulus is typical, in which the gel expands from a less liquid-filled state (collapsed state) or a dry state to a more liquid-filled stated (expanded state).
  • that solvent is water, or substantially water
  • the gel is known as a "responsive hydrogel".
  • Another aspect of the invention is a responsive cellulose gel bead having a diameter in a collapsed state of less than 600 ⁇ m, the collapsed state at a temperature of no greater than 75 'C.
  • the responsive gel bead may be capable of responsively absorbing at least 5 gram solvent per milliliter of collapsed gel, as determined from a collapsed state at a temperature of no more than 75 "C. This ratio is known as the "swelling ratio".
  • the responsive gel bead may additionally be capable of responsively absorbing at least 5 gram solvent per milliliter of collapsed gel in less than one hour or of absorbing and releasing at least 5 gram solvent per milliliter of collapsed gel in less than two hours, as determined from a collapsed state at a temperature of no more than 75 'C.
  • the "collapsed state" is that condition of the responsive gel in which substantially all unbound solvent is released from the gel with the concomitant volume reduction. Some amount of bound solvent remains within the gel, which may be as high as 60% wt/wt of the collapsed gel.
  • the collapsed state is deteirnined under operating conditions which are optimal condition for a particular application.
  • a temperature is selected to be as high above the LCST as is practical for the intended application of the gel.
  • a typical collapsed state is no more than 20 * C above the LCST of the responsive gel (eg, 75 'C for a gel with an LCST of 55 * C).
  • the collapsed state occurs at no more than 75 * C.
  • a "collapsed state” is distinguished from “dry state” in which considerable time and energy is expended to remove substantially all solvent, including bound solvent, from the gel.
  • an aqueous polymer suspension is introduced into a continuous organic phase.
  • the polymer suspension must be immiscible in the continuous organic phase.
  • the process is known as "inverse suspension crosslinking".
  • the aqueous phase containing the polymer is agitated or stirred in the continuous organic phase, thereby dispersing the aqueous phase as droplets in the continuous organic phase.
  • a crosslinker is included in the suspension which crosslinks the polymer.
  • the crosslinker is preferably a bi-functional or multi-functional chemical compound which is capable of reaction with the polymer in the droplet across two or more sites on the polymer chains, thus forming a polymer network which retains the droplet size and shape.
  • the crosslinker is typically added to the aqueous suspension prior to dispersion into the organic phase, although it may be added during or after dispersion of the aqueous phase into the continuous organic phase.
  • Flodin et al. teach a method of making EHEC gel beads by dispersing an aqueous colloidal suspension of the cellulose ether polymer and a high amount of epichlorohydrin crosslinker into an aromatic hydrocarbon or halogenated hydrocarbon solvent. EHEC has been determined to be a responsive polymer and the beads manufactured by Flodin et al. should be expected to be responsive although not usefully so within the objects of this invention. Attempts to prepare responsive HPC gel beads according to the method of Flodin et al.
  • Responsive gels may be made from any polymer which forms a responsive polymer network upon crosslinking.
  • the polymer may be used individually or may be blended with other polymers.
  • the polymer may be an interpenetrating polymer network, in which at least one polymer interpenetrates the polymer network of another polymer.
  • the polymer may be a polysaccharide (including cellulose, starch, sugars, chitin and hyaluronic acid), polypeptides, and synthetic polymers, such as PVA and PEO.
  • the responsive gel beads are prepared from a crosslinkable cellulose ether polymer that has an LCST of no more than 55 "C. Preferred polymers exhibit a low LCST in aqueous solutions.
  • the responsive cellulosic gel bead includes hydroxy propyl cellulose (HPC) and methyl cellulose (MC), and mixtures thereof, optionally blended with hydroxy ethyl cellulose (HEC), carboxy methyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC), ethylhydroxy ethyl cellulose (EHEC), hydroxymethyl cellulose (HMC), and methylhydroxyethyl cellulose (MHEC) and mixtures thereof.
  • a most preferred cellulose ether is HPC because of its low LCST of 42-46 * C. Blends of cellulose ethers result in responsive gels with properties imparted by all cellulose ethers used. IPNs of a cellulose ether with another, non-cellulose ether polymer can result in a responsive gel with properties typical of the cellulose ether component.
  • the gel be crosslinkable, preferably chemically crosslinkable. Any reagent which can react with two or more groups on the polymer can function as a crosslinker and convert that polymer to a gel. Polymers with reactive side groups such as a hydroxyl will be among the easiest to crosslink (note that these groups are also water soluble groups). It is thus most convenient if the crosslinker is water soluble.
  • Crosslinkers suitable for polymers include acetaldehyde, formaldehyde, glutaraldehyde, diglycidyl ether, vinyl sulfone (also known as divinyl sulfone; DVS), diisocyanates, epichlorohydrin, dimethylol urea, phosphoryl chloride, trimetaphosphate, trimethylomelamine, polyacrolein, and eerie ion redox systems.
  • Crosslinkers suitable, in particular, for cellulose ethers include glutaraldehyde, vinyl sulfone and dimethylol urea. Vinyl sulfone is a preferred crosslinker for cellulose ethers.
  • the crosslinker level is generally about 3 to about 100 microliter per gram dry polymer and preferably about 8.5 to about 40 microliter per gram dry polymer.
  • the crosslinking agent effects partial crosslinking of the polymer by changing the crosslinking density, and provides a means of controlling the gel's mechanical strength, swelling degree, and intensity of the volume change trigger.
  • a solvent which does not cause a precipitate is preferred for a number of reasons, including ability to view the ingredients during reaction and increased ease of workup of the synthesized beads.
  • it is preferred to use a solvent in which the crosslinker is not soluble since the crosslinker is quite expensive and is not easily disposed of.
  • any of the crosslinker which dissolves in the solvent may be lost to the reaction and may deleteriously affect the properties of the gel beads. It is preferred to minimize the quantity of crosslink used to insure there is no excess.
  • Solvents which are most preferred include high molecular weight aliphatic hydrocarbons, such as octane, nonane, decane, undecane, dodecane and, in particular, straight chain paraffinic or petroleum-based hydrocarbons, and mixtures and blends thereof.
  • the class of solvents identified as "fine mineral oils” are preferred. Fine mineral oils typically are high purity hydrocarbon mixtures having a high boiling point (above 150'C) and relatively low viscosity (ca. 2 cSt at room temperature).
  • Witsol 45-7 IB petroleum-based hydrocarbon; Hercules
  • Norpar-12 paraffinic hydrocarbon of various chain length; Exxon
  • Isopar-L iso-paraffinic hydrocarbon of various chain length; Exxon
  • the crosslinker is less soluble in such non-polar saturated hydrocarbons than in aromatic hydrocarbons or even shorter chained aliphatic hydrocarbons.
  • the reduced solubility of the crosslinker in the continuous organic phase results in reduced loss of the crosslinker into the secondary phase and better control of the crosslinking process.
  • Successful suspension crosslinking reactions have been carried out in Witsol 45-71B, Norpar-12, Isopar-L and high purity paraffins.
  • Solvents which are acceptable, but not preferred, include hexane, heptane, cycloalkanes such as cyclohexane and decalin, benzene, toluene, xylenes, ethylbenzenes and mesitylenes. Successful suspension crosslinking reactions have been carried out in toluene and decalin.
  • Additives may be included in both the aqueous polymer phase and the continuous organic phase to promote and stabilize the formation of the suspended polymer droplets.
  • surfactant and/or compatibilizing agents may be added to the continuous organic phase.
  • Surfactants include, by way of example and in no way limited to, Span's, including Span-80 (Lonza), Tween's, including Tween-80, -81, -65, -60, and -85 (Lonza),
  • Glycosperse 0-5 (Lonza, CAS No. 9005-65-6), Glycosperse TS-20 (Lonza), Arlacel-83 (Lonza, CAS No. 8007-43-0), Arlacel-186 (Lonza), G946 (ICI), Glycomul S (Lonza), Glycomul L (Lonza), Igepal's, including Igepal 520, 530 (Rhone-Poulenc), Atsurf 594 (ICI), Hypermer 2296 (ICI), Hypermer (B246), Surfynol CT-111 (Air Products) and Surfynol 420 (Air Products).
  • defoamers may be added to the aqueous polymer phase to suppress foaming of the suspension and encourage formation of the suspended polymer droplets.
  • Defoamers include, by way of example and in no way limited to, Surfynol CT-111 (Air Products), Surfynol 420 (Air Products), Surfynol TG (Air Products), L371 (Drew), L474 (Drew), L475 (Drew), Y250 (Drew), L418 (Drew), and L139 (Drew).
  • a compatibilizing agent may be added to the two-phase system, either into the organic solvent or into the aqueous polymer suspension.
  • a compatibilizing agent means a polymer, oligomer or compound that is substantially non- reactive to the components of the crosslinking system and which includes both hydrophilic and hydrophobic regions.
  • a compatibilizing agent may be a copolymer of hydrophobic and hydrophilic components.
  • the compatibilizing agent may be a copolymer of vinylpyrrolidinone and long chain ⁇ -olefins or it may be an alkylated poly (vinylpyrrolidinone).
  • Suitable compatibilizing agents include, by way of example and in no way limited to, poly(vinyl-pyrrolidinone/l-hexadecene) copolymer and poly(vinylpyrrolidinone/l-eicosene) copolymer.
  • the compatibilizing agent acts in a manner similar to a surfactant, in that it contains hydrophilic regions which interact favorably with the aqueous soluble solution and hydrophobic regions which interact favorably with the organic solvent. It is not expected to have the traditional hydrophobic head and hydrophilic tail arrangement of a surfactant.
  • antimicrobial agents may be added to the responsive gel to improve the shelf-life of the gel.
  • Adhesive modifiers which reduce or increase the stickiness of the gel beads, may also be included in the gel bead or on the surface. Further, other surface modifiers or coatings may be applied to the bead to improve surface hardness, control surface adsorption, control pore size, or modify other characteristics of the surface of the bead.
  • antimicrobial agents include, by way of example only, Dowicil ® , butylated hydroxytoluene, methionine, cysteine, ascorbic acid, catalase, superdioxide dismutase, glutathione, parabens, methyl p- hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, polyethyleneglycol and polyethyleneoxide.
  • Dowicil ® butylated hydroxytoluene, methionine, cysteine, ascorbic acid, catalase, superdioxide dismutase, glutathione, parabens, methyl p- hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, polyethyleneglycol and polyethyleneoxide.
  • a random sample of beads is removed from the reaction vessel prior to neutralizing and wash cycling and placed into a petri dish.
  • a subset of at least twenty beads (and in some cases fifty or more) are separated indiscriminately and measured with a Hand Wetzler microscope (Seiler W0042) equipped with a Hitachi color camera (KP-C550, CCD) and Optech (Imagen HR 1024), Video Measuring System. After several repetitions of measuring 100 beads and randomly selecting subsets of twenty beads, it was determined that twenty beads provided a reasonable representation of the batch. For experiments in which exceptionally small beads were produced the average calculation of the subset of twenty was comprised of only those beads which measured larger than 30 ⁇ m in diameter, those less than 30 ⁇ m were omitted from the calculation.
  • reaction variables affect the final gel bead diameter for a given polymer and crosslinking density, for example, aqueous suspension viscosity (which is a function of the polymer molecular weight and concentration), organic solvent viscosity, degree of agitation of the two- phase system, and use and type of surfactant and/or compatibilizing agents and defoamers (preferential surface tension).
  • aqueous suspension viscosity which is a function of the polymer molecular weight and concentration
  • organic solvent viscosity degree of agitation of the two- phase system
  • surfactant and/or compatibilizing agents and defoamers preferential surface tension
  • the amount of solvent absorbed from the collapsed state over a given temperature range is determined as follows. A quantity of gel beads is placed in a graduated cylinder at room temperature and solvent is added. The graduated cylinder is held in a water bath at the stated elevated temperature (above the LCST) for the time indicated. The height of the collapsed gel is determined from the volume indications of the graduated cylinder. The graduated cylinder containing the gel beads is then held in a water bath at a temperature below the LCST (typically, room temperature) for the time indicated and the volume of the expanded gel beads is then measured from the graduated cylinder. The amount of solvent absorption is the difference in heights (assuming void volume remains constant) and the swelling ratio is the ratio of the volume of solvent absorbed to the volume of the collapsed gel beads.
  • the amount of solvent absorbed from the collapsed state over a given temperature range and in a given period of time is determined as follows.
  • a quantity of gel beads is placed in a graduated cylinder at room temperature and solvent is added.
  • the graduated cylinder is held in a water bath at the stated elevated temperature (above the LCST) and agitated for the time indicated.
  • the height of the collapsed gel is determined from the volume indications of the graduated cylinder.
  • the graduated cylinder containing the gel beads is then held in a water bath at a temperature below the LCST (typically, room temperature) and agitated for the time indicated and the volume of the expanded gel beads is then measured from the graduated cylinder.
  • the rate of solvent absorption is the swelling rate and is determined as the ratio of the volume of solvent absorbed to the volume of the collapsed gel beads per unit time.
  • a polymer colloidal suspension (100 mL) containing 10-32% wt/wt cellulose ether polymer and deionized water (Millipore, Alpha-Q) is hydrated over night.
  • To this suspension is added 2.0 mL of 5 N NaOH (Baker, Catalogue No. JT37722-11) such that the pH of the solution is ca. 12.5 and the solution is allowed to stand for approximately 45 minutes.
  • NaOH may optionally be added when the polymer suspension originally is prepared.
  • a 500 mL baffled flask with a three neck top (Chemglass CG-1951 and CG-1960) is used for the reaction vessel.
  • the impeller used is a six flat-bladed turbine (Lightnin RlOO 2.0") with a 5/16" stainless steel shaft which is placed in the center neck of the reaction vessel.
  • An organic solvent is used for the continuous organic phase.
  • the organic solvent (ca. 350-450 mL) is introduced into the 500 mL baffled flask equipped with the impeller blade.
  • the organic solvent is stirred at a constant rate in the range of 300- 1000 rpm (Lab Assistants RZR-2000).
  • a crosslinker in the range of 3.0-100 microliters per gram dry polymer
  • the polymer/crosslinker suspension is added to the stirred organic solvent.
  • the aqueous component is approximately 13-20% vol/vol of a total volume of 500 mL reaction mixture. Beads are observed almost immediately and the reaction vessel is allowed to stir overnight at room temperature to complete the crosslink reaction.
  • the typical method for neutralizing and washing the beads is to decant the continuous phase solvent from the beads and place the beads into a clean beaker.
  • An acidic solution (pH 3.0-4.0) is made by dissolving approximately one gram of ammonium chloride (Fisher, Catalog No. A661- 500) in 100 mL of deionized water (Millipore, Alpha-Q) and adding two drops of concentrated hydrochloric acid (Aldrich, Catalog No. 25,814-8) to the solution.
  • the acidic solution is added to the beads while simultaneously monitoring the pH of the bead/acid solution with a pH meter (Orion, 420A, with Orion triode electrode) to a pH of 7.0-7.5.
  • the beads in solution are then heated in this neutralizing solution at 50-60 °C to collapse the beads.
  • the water is filtered off, 100-150 mL of fresh deionized water (Millipore, Alpha-Q) is added and the beads are allowed to swell to complete the thermal cycle. This thermal cycling is done for a total of three times.
  • Example 1 Effect of crosslinker concentration and polvmer concentration on bead manufacture. A range of polymer and crosslinker levels were evaluated for their effect on bead formation and swelling capacity. HPC polymer suspensions containing various amounts of crosslinker and HPC polymer were dispersed into Norpar-12 (Exxon). The aqueous to organic volume ratio was held constant at 17% aqueous (85 mL aqueous suspension and 415 mL Norpar-12). In those cases where beads were formed, the swelling ratio was determined by measuring the equilibrium volume change over a temperature range of 25 " C (selected between the temperature range of 30'C to 65 * C). Experimental results indicated that there is a strong synergistic effect of polymer concentration and crosslinker concentration, as illustrated in Table 1. Table 1. Formation of HPC Beads. 2
  • Norpar-12 organic solvent; D microliter crosslinker (x 10 " ') per gram dry cellulose polymer; c wt% in a total 100 g suspension.
  • Beads can not be made from an inverse polymer crosslinking process if the crosslinker level is too low or if the polymer concentration in water is too low. At high polymer concentration, use of a lower crosslinker level is possible. For example, no beads were formed with a crosslinker level of 5.0 microliter per gram dry polymer when the polymer concentration was 7.5% wt/wt; or at a crosslinker level of 26 microliter per gram dry polymer when the polymer concentration was 10% wt/wt. However, satisfactory beads were formed from an inverse suspension crosslinking process with a crosslinker level of 8.5 microliter per gram dry polymer and a polymer concentration of 20% wt/wt.
  • crosslinker is the most expensive component of the gel and because lower crosslinker levels result in gel beads of higher swelling ratios.
  • a responsive surface plot illustrating bead formation under a range of crosslinker and polymer levels is shown in the Figure. A value of "1 " is assigned to conditions producing beads and a value of "0" is assigned to conditions which did not produce beads. The regression analysis used resulted in a continuous function, which can be viewed as the likelihood of bead formation under the stated conditions.
  • the data suggests that a useful region for responsive gel bead synthesis can be defined.
  • the line ranging through the point at a crosslinker level of 21-28 microliter per gram dry polymer and a polymer concentration of 10% wt/wt to the point defined by a crosslinker level of 5.0 to 8.0 microliter per gram dry polymer and a polymer concentration of 20% wt/wt defines an area where responsive gel beads will be formed.
  • the range of acceptable reaction conditions is limited by an upper boundary, where the polymer solution becomes so viscous that it is unmanageable and unpourable. Under the present conditions, this occurs at a polymer concentration for HPC (M w 95k) of about 22-25% wt/wt.
  • the responsive surface of the Figure indicates that, where the reactions conditions satisfy the following equation, [polymer] + 5 x [crosslinker x 10 " '] > 24, satisfactory responsive gel beads may be prepared. More desirably, the responsive surface of the Figure indicates that, where the reactions conditions satisfy the following equation
  • Example 2 Inverse Suspension Crosslinking of Hydroxypropyl Cellulose (M. paste 95k) with Vinyl Sulfone using Glycosperse 0-5 Surfactant. Twenty grams of HPC (Aqualon, Klucel LF NF, M w 95k) was added to 80 mL of deionized water and allowed to hydrate overnight. To this suspension was added 20 drops of a 5N NaOH solution to form a solution of approximately pH 12.5. The suspension was stirred thoroughly to disperse the basic solution, and was then allowed to stand for 45 minutes.
  • the average diameter of the beads was 478 ⁇ m with a median diameter of 439 ⁇ m (a mean to median ratio of 1.09). In the as synthesized state, the average diameter was 635 ⁇ m with a standard deviation of 148 ⁇ m. These beads have a swelling ratio of 6.8 after a cycle of swelling at 30'C and subsequent collapse at 55'C in two hours (1 hr at 30'C and 1 hr at 55 'C). At near equilibrium ( > 24 hours at constant temperature before measurement), the total swell ratio from room temperature to 65 °C was 11.6.
  • Example 3 Inverse Suspension Crosslinking of Hvdroxypropyl Cellulose (M...95k) with Vinyl Sulfone using Arlacel-83 Surfactant. Twenty grams of HPC (Aqualon, Klucel LF NF, M w 95k) was added to 80 mL of deionized water and allowed to hydrate overnight.
  • the continuous phase solvent Witsol 45-7 IB (415 mL, petroleum hydrocarbon, Hercules) was added to a 500 mL baffled reaction vessel equipped with an impeller blade, and stirring was initiated at 450 rpm.
  • To the hydrated polymer suspension was added 170 ⁇ l of vinyl sulfone (Sigma, Catalog No. V9501), which was then stirred with a glass rod for 30 seconds. This polymer suspension was then poured into the agitating reaction vessel. The mixture was allowed to react at room temperature overnight.
  • the beads were worked up in the typical manner as described in the Protocol.
  • the average diameter of the collapsed bead was 1.75 mm with a standard deviation of 0.243 mm.
  • the median diameter of the beads was 1.69 mm (a mean to median ratio of 1.04).
  • the significantly larger bead size reflects the absence of surfactant in the process.
  • Example 5 Inverse Suspension Crosslinking of Hydroxypropyl Cellulose (M... 95k) with Vinyl Sulfone in Isopar-L. Twelve and one-half (12 1/2) grams of HPC (Aqualon, Klucel LF NF, M w 95k) was added to 80 mL of deionized water and allowed to hydrate overnight. To this suspension was added 20 drops of a 5N NaOH solution to form a solution of approximately pH 12.5. The suspension was stirred thoroughly to disperse the basic solution, and was then allowed to stand for 45 minutes.
  • HPC Hydropropyl Cellulose
  • the continuous phase solvent Isopar-L (415 mL, iso-paraffinic hydrocarbon, Exxon) was added to a 500 mL baffled reaction vessel equipped with an impeller blade, and stirring was initiated at 450 ⁇ m.
  • To the hydrated polymer suspension was added 375 ⁇ l of vinyl sulfone (Sigma, Catalog No. V9501), which was then stirred with a glass rod for 30 seconds. This polymer suspension was then poured into the agitating reaction vessel. The mixture was allowed to react at room temperature overnight. The beads were worked up in the typical manner as described in the Protocol. The equilibrium swell ratio from 30'C to 55" C was 5.0.
  • Example 6 Inverse Suspension Crosslinking of Hydroxypropyl Cellulose (M ⁇ r 95k) with Vinyl Sulfone in Toluene.
  • HPC Hydrophilpropyl Cellulose
  • Toluene Ten grams of HPC (Aqualon, Klucel LF NF, M w 95k) was added to 90 mL of deionized water and allowed to hydrate overnight.
  • To this suspension was added 20 drops of a 5N NaOH solution to form a solution of approximately pH 12.5. The suspension was stirred thoroughly to disperse the basic solution, and was then allowed to stand for 45 minutes.
  • Example 7 Inverse Suspension Crosslinking of Methyl Cellulose with Vinyl Sulfone in No ⁇ ar-12. Twelve grams of MC (Dow, Methocel A15LV) was added to 88 mL of deionized water and allowed to hydrate overnight. To this suspension was added 20 drops of a 5N NaOH solution to form a solution of approximately pH 12.5. The suspension was stirred thoroughly to disperse the basic solution, and was then allowed to stand for 45 minutes.
  • the continuous phase solvent No ⁇ ar-12 (415 mL, paraffinic hydrocarbon, Exxon), was added to a baffled reaction vessel equipped with an impeller blade, and stirring was initiated at 450 ⁇ m.
  • To the hydrated polymer suspension was added 600 ⁇ l of vinyl sulfone (Sigma, Catalog No. V9501) and then stirred with a glass rod for 30 seconds. This polymer suspension was then poured into the agitating reaction vessel. The mixture was allowed to react at room temperature overnight.
  • the beads were worked up in the typical manner as described in the Protocol.
  • the near equilibrium swell ratio measured from room temperature to 65 * C was 0.5.
  • Example 8 Inverse Suspension Crosslinking of Hydroxypropyl Cellulose with Vinyl Sulfone using Surfynol CT-111 Defoamer. Twenty grams of HPC (Aqualon, Klucel LF NF, M w 95k) and 500 ⁇ l of Surfynol CT-111 (Air Products) was added to 80 mL of deionized water and allowed to hydrate overnight. To this suspension was added 20 drops of a 5N NaOH solution to form a solution of approximately pH 12.5. The suspension was stirred thoroughly to disperse the basic solution, and was then allowed to stand for 45 minutes.
  • HPC Hydrophilic acid
  • Surfynol CT-111 Air Products
  • the continuous phase solvent No ⁇ ar-12 (415 mL, paraffinic hydrocarbon, Exxon), was added to a baffled reaction vessel equipped with an impeller blade, and stirring was initiated at 450 ⁇ m.
  • To the hydrated polymer suspension was added 170 ⁇ l of vinyl sulfone (Sigma, Catalog No. V9501) and then stirred with a glass rod for 30 seconds. This polymer suspension was then poured into the agitating reaction vessel. The mixture was allowed to react at room temperature overnight.
  • the beads were worked up in the typical manner as described in the Protocol. In the collapsed state (20 * C above the LCST), the average diameter of the beads was 841 ⁇ m and the median diameter was 819 ⁇ m (a mean to median ratio of 1.03). The equilibrium swell ratio measured from 30'C to 55 'C was 7.4. The larger bead size was due to the absence of surfactant in the process.
  • Example 9 Inverse Suspension Crosslinking of Hydroxypropyl Cellulose (M, 140k) with Vinyl Sulfone in No ⁇ ar-12. Seventeen and one- half (17 1/2) grams of HPC (Aqualon, Klucel JF, M w 140k) was added to 82.5 mL of deionized water and allowed to hydrate overnight. To this suspension was added 20 drops of a 5N NaOH solution to form a solution of approximately pH 12.5. The suspension was stirred thoroughly to disperse the basic solution, and was then allowed to stand for 45 minutes.
  • HPC Hydropropyl Cellulose
  • the continuous phase solvent N ⁇ ar-12 (415 mL, paraffinic hydrocarbon, Exxon), was added to a baffled reaction vessel equipped with an impeller blade, and stirring was initiated at 450 ⁇ m.
  • N ⁇ ar-12 415 mL, paraffinic hydrocarbon, Exxon
  • To the hydrated polymer suspension was added 223 ⁇ l of vinyl sulfone (Sigma, Catalog No. V9501) and then stirred with a glass rod for 30 seconds. This polymer suspension was then poured into the agitating reaction vessel. The mixture was allowed to react at room temperature overnight.
  • the beads were worked up in the typical manner as described in the Protocol.
  • the near equilibrium swelling ratio was 6.0 from room temperature to 65'C.
  • Example 10 Inverse Suspension Crosslinking of Hydroxypropyl Cellulose (M 1v 95k) with Vinyl Sulfone in the Continuous Phase. Twenty grams of HPC (Aqualon, Klucel LF NF, M w 95k) was added to 80 mL of deionized water and allowed to hydrate overnight. To this suspension was added 20 drops of a 5N NaOH solution to form a solution of approximately pH 12.5. The suspension was stirred thoroughly to disperse the basic solution, and was then allowed to stand for 45 minutes.
  • HPC Hydropropyl Cellulose
  • the continuous phase solvent No ⁇ ar-12 (415 mL, paraffinic hydrocarbon, Exxon) was added to a 500 mL baffled reaction vessel equipped with an impeller blade, and stirring was initiated at 450 ⁇ m.
  • the polymer suspension was poured into the agitating reaction vessel and allowed to mix for several minutes.
  • To the organic solvent was added 340 ⁇ l of vinyl sulfone (Sigma, Catalog No. V9501). The mixture was allowed to react at room temperature overnight.
  • Example 11 Inverse Suspension Crosslinking of Hydroxypropyl Cellulose (M... 95k) with Vinyl Sulfone at 1000 mm.
  • HPC Hydrophilic Cellulose
  • the continuous phase solvent, No ⁇ ar-12 (415 mL, paraffinic hydrocarbon, Exxon) was added to a baffled reaction vessel equipped with an impeller blade, and stirring was initiated at 1000 ⁇ m (Caframo RZRI stirrer, ⁇ m confirmed with Onosoki Tachometer HT-3100).
  • To the hydrated polymer suspension was added 400 ⁇ l of vinyl sulfone (Sigma, Catalog No. V9501) and then stirred with a glass rod for 30 seconds. This polymer suspension was then poured into the reaction vessel which was being agitated. The mixture was allowed to react at room temperature overnight.
  • the beads were worked up in the typical manner as described in the Protocol.
  • the near equilibrium swelling ratio from 30'C to 55'C was 7.0.
  • Example 12 Inverse Suspension Crosslinking of Hvdroxypropyl Cellulose (M w 95k) with Vinyl Sulfone using Ganex V216 Compatibilizing Agent. Twenty grams of HPC (Aqualon, Klucel LF NF, M w 95k) was added to 80 mL of deionized water and allowed to hydrate overnight. To this suspension was added 20 drops of a 5N NaOH solution to form a solution of approximately pH 12.5. The suspension was stirred thoroughly to disperse the basic solution, and was then allowed to stand for 45 minutes.
  • HPC Hydrophilic acid
  • No ⁇ ar-12 352.5 mL, paraffinic hydrocarbon, Exxon
  • No ⁇ ar-12 352.5 mL, paraffinic hydrocarbon, Exxon
  • a 500 mL baffled reaction vessel equipped with an impeller blade stirring was initiated at 450 ⁇ m.
  • To the agitated solvent was added 62.5 mL of a 2.5% vol/vol solution of Ganex V216 (poly(vinylpyrrolidinone/l-hexadecene), ISP Technologies, Inc.) in No ⁇ ar-12 and the solution was dispersed for 30 minutes.
  • Ganex V216 poly(vinylpyrrolidinone/l-hexadecene), ISP Technologies, Inc.
  • Example 13 Inverse Suspension Crosslinking of Hydroxypropyl Cellulose (M, 95k) with Vinyl Sulfone using Ganex V216 Compatibilizing Agent on a Five Liter Scale. Two hundred grams of HPC (Aqualon, Klucel LF NF, M w 95k) was added to 800 mL of deionized water and allowed to hydrate overnight. To this suspension was added 20 mL of a 5N NaOH solution to form a solution of approximately pH 12.5.
  • Example 14 Inverse Suspension Crosslinking of Hydroxypropylmethyl Cellulose with Vinyl Sulfone using Ganex V216 Compatibilizing Agent. Twenty seven grams of HPMC (Dow, Methocel 5LV) was added to 72.5 mL of deionized water and allowed to hydrate overnight.
  • the average diameter is 377 ⁇ m with a standard deviation of 130 ⁇ m.
  • Medical, pharmaceutical and diagnostic applications including electrophoresis, iontophoresis, free drug assay, spinal fluid diagnostics, assay, blood ultracentrifugation, cell culturing, wound dressing, exudate abso ⁇ tion and bacterial indicators; and 5) Toys.

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Abstract

L'invention concerne une perle de gel polymère sensible qui comprend un polymère dont la forme est choisie dans le groupe comprenant des polymères individuels, des mélanges de polymères et des réseaux polymères intercalés, qui est réticulé chimiquement avec un composé organique bifonctionnel ou multifonctionnel, la perle de gel présentant une température de transition critique minimum de moins de 55 °C. De plus, ladite perle de gel sensible présente un diamètre à l'état affaissé de moins de 600 νm, s'affaisse à une température ne dépassant pas 75 °C, et peut absorber au moins 5 grammes de solvant par millimètre de gel affaissé. L'invention porte également sur un procédé de fabrication de perles de gel cellulosique sensibles par réticulation par suspension inversée qui consiste à produire une suspension aqueuse d'un polymère d'éther de cellulose, un solvant organique et un agent de réticulation, le solvant organique étant immiscible dans la suspension aqueuse, et à mélanger la suspension aqueuse d'éther de cellulose, le solvant organique et l'agent de réticulation pour former un système à deux phase, la suspension aqueuse et le solvant organique renfermant les deux phases du système. Des agents tensioactifs, des agents de compatibilité et d'autres additifs peuvent être nécessaires. Le système à deux phases peut être agité suffisamment de sorte que des gouttelettes de la suspension aqueuse d'éther de cellulose soient formées dans le solvant organique, et ce pendant suffisamment longtemps pour que des perles de gel d'éther de cellulose réticulées soient formées. Les perles de gel d'éther de cellulose réticulées sont extraites du solvant organique.
PCT/US1995/009037 1994-07-18 1995-07-18 Perles de gel polymere sensibles WO1996002577A1 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
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WO1999012975A1 (fr) * 1997-09-08 1999-03-18 Fleximer, Llc Entites bioactive couplees a des polymeres intelligents et utilisations de ces entites
WO2000017257A1 (fr) * 1998-09-23 2000-03-30 Amersham Pharmacia Biotech Ab Production de billes de polysaccharide
US6312667B1 (en) 1998-11-12 2001-11-06 3M Innovative Properties Company Methods of etching hard tissue in the oral environment
US6312666B1 (en) 1998-11-12 2001-11-06 3M Innovative Properties Company Methods of whitening teeth
WO2002053598A2 (fr) * 2000-12-29 2002-07-11 Amersham Biosciences Ab Procede de fabrication d'un materiau poreux
US6465227B1 (en) * 1997-09-09 2002-10-15 Biochemie Gesellschaft M.B.H. Spherical particles containing microorganism cells having enzyme activity
US6620405B2 (en) 2001-11-01 2003-09-16 3M Innovative Properties Company Delivery of hydrogel compositions as a fine mist
US6669927B2 (en) 1998-11-12 2003-12-30 3M Innovative Properties Company Dental compositions
US8158002B1 (en) 1999-03-17 2012-04-17 Foster-Miller, Inc. Responsive gels and methods of use thereof
US8163886B2 (en) 2006-12-21 2012-04-24 Emd Millipore Corporation Purification of proteins
US8362217B2 (en) 2006-12-21 2013-01-29 Emd Millipore Corporation Purification of proteins
US8569464B2 (en) 2006-12-21 2013-10-29 Emd Millipore Corporation Purification of proteins
US8691918B2 (en) 2010-05-17 2014-04-08 Emd Millipore Corporation Stimulus responsive polymers for the purification of biomolecules
US8999702B2 (en) 2008-06-11 2015-04-07 Emd Millipore Corporation Stirred tank bioreactor
US9090930B2 (en) 2006-06-27 2015-07-28 Emd Millipore Corporation Method and unit for preparing a sample for the microbiological analysis of a liquid
US9803165B2 (en) 2008-12-16 2017-10-31 Emd Millipore Corporation Stirred tank reactor and method

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999012975A1 (fr) * 1997-09-08 1999-03-18 Fleximer, Llc Entites bioactive couplees a des polymeres intelligents et utilisations de ces entites
US6465227B1 (en) * 1997-09-09 2002-10-15 Biochemie Gesellschaft M.B.H. Spherical particles containing microorganism cells having enzyme activity
WO2000017257A1 (fr) * 1998-09-23 2000-03-30 Amersham Pharmacia Biotech Ab Production de billes de polysaccharide
US6590096B1 (en) 1998-09-23 2003-07-08 Amersham Biosciences Ab Process for the production of polysaccharide beads
US6669927B2 (en) 1998-11-12 2003-12-30 3M Innovative Properties Company Dental compositions
US6312667B1 (en) 1998-11-12 2001-11-06 3M Innovative Properties Company Methods of etching hard tissue in the oral environment
US6312666B1 (en) 1998-11-12 2001-11-06 3M Innovative Properties Company Methods of whitening teeth
USRE42024E1 (en) 1998-11-12 2011-01-11 3M Innovative Properties Company Dental compositions
US8158002B1 (en) 1999-03-17 2012-04-17 Foster-Miller, Inc. Responsive gels and methods of use thereof
WO2002053598A3 (fr) * 2000-12-29 2002-10-17 Amersham Biosciences Ab Procede de fabrication d'un materiau poreux
WO2002053598A2 (fr) * 2000-12-29 2002-07-11 Amersham Biosciences Ab Procede de fabrication d'un materiau poreux
US6984733B2 (en) 2000-12-29 2006-01-10 Amersham Biosciences Ab Manufacturing process for porous material
US6620405B2 (en) 2001-11-01 2003-09-16 3M Innovative Properties Company Delivery of hydrogel compositions as a fine mist
US9090930B2 (en) 2006-06-27 2015-07-28 Emd Millipore Corporation Method and unit for preparing a sample for the microbiological analysis of a liquid
US9410181B2 (en) 2006-06-27 2016-08-09 Emd Millipore Corporation Method and unit for preparing a sample for the microbiological analysis of a liquid
US8362217B2 (en) 2006-12-21 2013-01-29 Emd Millipore Corporation Purification of proteins
US8569464B2 (en) 2006-12-21 2013-10-29 Emd Millipore Corporation Purification of proteins
US9376464B2 (en) 2006-12-21 2016-06-28 Emd Millipore Corporation Purification of proteins
US8163886B2 (en) 2006-12-21 2012-04-24 Emd Millipore Corporation Purification of proteins
US10233211B2 (en) 2006-12-21 2019-03-19 Emd Millipore Corporation Purification of proteins
US10793593B2 (en) 2006-12-21 2020-10-06 Emd Millipore Corporation Purification of proteins
US8999702B2 (en) 2008-06-11 2015-04-07 Emd Millipore Corporation Stirred tank bioreactor
US9803165B2 (en) 2008-12-16 2017-10-31 Emd Millipore Corporation Stirred tank reactor and method
US8691918B2 (en) 2010-05-17 2014-04-08 Emd Millipore Corporation Stimulus responsive polymers for the purification of biomolecules
US9217048B2 (en) 2010-05-17 2015-12-22 Emd Millipore Corporation Stimulus responsive polymers for the purification of biomolecules
US9731288B2 (en) 2010-05-17 2017-08-15 Emd Millipore Corporation Stimulus responsive polymers for the purification of biomolecules

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