EP0000507B1 - Procédé de préparation d'hydrogels sous forme de perles sphériques de plus grand diamètre - Google Patents

Procédé de préparation d'hydrogels sous forme de perles sphériques de plus grand diamètre Download PDF

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Publication number
EP0000507B1
EP0000507B1 EP78100375A EP78100375A EP0000507B1 EP 0000507 B1 EP0000507 B1 EP 0000507B1 EP 78100375 A EP78100375 A EP 78100375A EP 78100375 A EP78100375 A EP 78100375A EP 0000507 B1 EP0000507 B1 EP 0000507B1
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Prior art keywords
water
hydrogel
weight
vinyl
insoluble
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EP0000507A1 (fr
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Karl Friedrich Müller
Sonia Jaworiw Heiber
Walter Lawrence Plankl
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Novartis AG
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Ciba Geigy AG
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
    • C08F290/02—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated end groups
    • C08F290/06—Polymers provided for in subclass C08G
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/20—Esters of polyhydric alcohols or phenols, e.g. 2-hydroxyethyl (meth)acrylate or glycerol mono-(meth)acrylate
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F291/00—Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00

Definitions

  • the present invention relates to a process for the production of uniform, spherical beads with a diameter of up to 5 mm, which consist of a cross-linked, water-insoluble hydrogel.
  • Hydrogels have been described since 1956 (US-A-2 976 576) and since that time a large number of patents have been published which focus on the production and use of hydrogels which are based primarily on 2-hydroxyethyl methacrylates and to a lesser extent on N. -Vinylpyrrolidonen based.
  • these hydrogels are cross-linked, water-swelling polymers which are prepared by copolymerizing 2-hydroxyethyl methacrylates with a small amount of ethylene or butylene dimethacrylates. These compounds mentioned are used as polymeric, inert carriers for active substances which are released slowly and controllably by these carriers.
  • Such substances can be pharmaceuticals (US-A-: 3,574,826, 3,577,512, 3,551,556, 3,520,949, 3,576,760, 3,641,237, 3,660,563), agricultural chemicals (US-A-3,576,760) or flavorings (U.S.-A-3,567,118 and 3,697,643).
  • US-A- 3,574,826, 3,577,512, 3,551,556, 3,520,949, 3,576,760, 3,641,237, 3,660,563
  • agricultural chemicals US-A-3,576,760
  • flavorings U.S.-A-3,567,118 and 3,697,643
  • Hydrogen granules are preferably produced by polymerization in suspension. This is carried out by suspending a liquid monomer phase in a non-solvent with vigorous stirring and with the aid of a protective colloid as a stabilizer and polymerizing the stirred suspension obtained in a conventional manner. The polymerization is induced catalytically by heat or with the help of free radicals. This method produces uniformly shaped spherical beads in a one-step process and is mainly used in the production of polystyrenes, polyvinyl chlorides, polyacrylates and polyvinyl acetates (cf. E. Farber: Encyclopedie der Polymerjudicialen und -technologie, Vol. 13, pages 552-571 (1970 ), Interscience, New York).
  • HEMA 2-hydroxyethyl methacrylate
  • a suspending agent is not necessarily specified as a necessary part of the recipe. However, it can be shown that without such a suspending agent, no usable particles or beads are obtained, but only large agglomerations of the polymer.
  • water-soluble polymers such as. B. polyvinylpyrrolidones and hydroxyethyl celluloses are excellent suspending agents for polymerization in suspension.
  • certain poorly soluble, inorganic compounds such as. As calcium sulfate, barium sulfate, calcium phosphate, magnesium phosphate, calcium carbonate and magnesium hydroxide can also be used.
  • magnesium hydroxide as suspension stabilizers for the polymerization of vinyl monomers is described in US Pat. No. 2,801,992, but with the express reference that an excess of alkali metal or hydroxyl ions must be present. Magnesium hydroxide in the absence of excess hydroxyl ions (alkali) is ineffective as a suspension stabilizer.
  • FR-A-2 276 063 relates to the preparation of water-insoluble crosslinked hydrophilic gels by polymerizing either a hydrophilic polymer from water-soluble monomeric monoolefins or a hydrophobic copolymer water-soluble monoolefins with 1-70% water-insoluble monomeric monoolefins with a hydrophobic polymer which has two olefinic end groups and a molecular weight of 400-8000, 30-90% of the former component and 10-70% of the latter.
  • the polymerization temperatures are preferably between 40 and 150 ° C.
  • water-soluble monomers preference is given to using acrylic or methacrylic acid or its esters, amides, imides or monoolefin salts, and as hydrophobic polymers to those having polytetramethylene oxide chains and two terminal olefinic groups.
  • catalysts By adding catalysts, beads can also be obtained at 90 ° C. with rapid stirring of the mixture, but they are very small and therefore technically uninteresting.
  • the gels can be used as carriers for pharmaceutically active substances.
  • hydrogel granules were of a very irregular shape and a very porous surface.
  • the beads shaped in this way are also of such a small size (for example 0.3 mm in diameter) that they have no practical value for the slow release of active agents.
  • the preferred pearl sizes for controllable delivery of oral medication are between 0.6mm and 1.5mm.
  • the present invention therefore relates to a process for producing substantially uniform, spherical beads up to the size of 5 mm in diameter from a crosslinked, water-insoluble hydrogel by polymerization in suspension of (A) 95-30% by weight, based on the hydrogel, at least a water-soluble monoolefinic monomer which can be replaced by up to 70% by weight, based on the total amount of monomers, of at least one water-insoluble monoolefinic monomeric compound, the hydrogel containing at most 60% by weight of the water-insoluble monomeric compound and at least 5 %
  • the total monomer consists of a hydroxy-substituted hydrophilic vinyl monomer, with (B) 5 to 70% by weight, based on the hydrogel, of a terminally diolefinic, crosslinking compound having a molecular weight of 400-8000 in the presence of a polymerization initiator in a concentrated, aqueous inorganic salt solution and a suspending agent els and by treating the hydrogel with an acid
  • the process is characterized in that the suspension medium used is 0.01-5% by weight, based on the hydrogel, of at least one water-insoluble, gelatinous, water-binding, inorganic metal hydroxide or metal hydroxy salt in the absence of excess alkali and free hydroxyl ions.
  • water-soluble monomers substituted by hydroxy water-soluble derivatives of acrylic and / or methacrylic acid, such as, for. B. hydroxyalkyl esters in which the alkyl radical contains 2-4 carbon atoms, for example 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl or 2,3-dihydroxypropyl ester, furthermore ethoxylated and polyethoxylated hydroxyalkyl esters of acrylic or methacrylic acid such as esters of alcohols of the formula wherein m is 2 to 5 and n is 1 to 20, or esters of analog alcohols in which part of the ethylene oxide unit has been replaced by propylene oxide units.
  • Suitable esters are furthermore, for example, the 3- (dimethylamino) -2-hydroxypropyl esters.
  • Another class of suitable derivatives of such acids are their water-soluble amides or imides which are substituted by lower hydroxyalkyl groups in which a lower alkyl group contains 2-4 carbon atoms, e.g. N- (hydroxymethyl) acrylamide and methacrylamide, N- (3-hydroxypropyl) acrylamide, N- (2-hydroxyethyl) methacrylamide and N- [1,1-dimethyl-2- (hydroxymethyl) -3-oxabutyl) -acrylamide; water-soluble hydrazine derivatives, such as. B. trialkylaminomethacrylimides, e.g. B. trimethylaminomethacrylimide and dimethyl (2-hydroxypropyl) aminomethacrylamide and the corresponding derivatives of acrylic acid.
  • B. trialkylaminomethacrylimides e.g. B. trimethylaminomethacrylimide and dimethyl (2-hydroxypropyl) aminomethacrylamide and the corresponding derivatives of acrylic acid.
  • Water-soluble monomers which require a comonomer for the polymerization are also suitable, e.g. Hydroxyalkyl esters of maleic and fumaric acid, in which the alkyl radical has 2-4 carbon atoms, such as. B. di- (2-hydroxyethyl) maleate and alkoxylated hydroxyalkyl maleates, hydroxyalkyl monomaleates, such as. B. 2-hydroxyethyl monomaleate and alkoxylated hydroxyalkyl monomaleate with vinyl ethers, vinyl esters, styrene or generally monomers which easily copolymerize with maleates or fumarates; Hydroxyalkyl vinyl ether, such as. B. 2-hydroxyethyl vinyl ether, 4-hydroxybutyl vinyl ether with maleates, fumarates or generally all monomers that easily copolymerize with vinyl ethers.
  • Hydroxyalkyl esters of maleic and fumaric acid in which the alkyl radical has 2-4 carbon atoms
  • hydroxyalkyl acrylates and methacrylates such as. B. _2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 2,3-dihydroxypropyl methacrylate. Most preferably as a monomer can be called 2-hydroxyethyl methacrylate.
  • Water-soluble comonomers which contain no hydroxyl groups are acrylic and methacrylic acids and alkyl ethers of polyethoxylated hydroxyalkyl testers, such as esters of alcohols of the formula wherein m is 2 to 5 and n is 4 to 20.
  • Dialkylaminoalkyl esters and amides such as e.g. 2- (dimethylamino) ethyl acrylate and methacrylates, as well as the corresponding amides.
  • the amides substituted by lower oxaalkyl or lower dialkylaminoalkyl groups such as e.g. the N- (1,1-dimethyl-3-oxabutyl) acrylamide; water-soluble hydrazine derivatives, e.g. Trialkylaminomethacrylimides, e.g.
  • Trimethylamino methacrylimides and the corresponding derivatives of acrylic acid monoolefinic sulfonic acids and their salts, such as sodium ethylene sulfonate, sodium styrene sulfonate and 2-acrylamido-2-methylpropane sulfonic acid; N- [2-dimethylamino) ethyl acrylamine and methacrylamide in question.
  • Another class of water-soluble monomers are mono-olefinic derivatives of monocyclic, heterocyclic, nitrogen-containing monomers, such as e.g. N-vinylpyrrole, N-vinyl succinimide, N-vinyl-2-pyrrolidone, 1-vinyl-imidazole, 1-vinyl-indole, 2-vinyl-imidazole, 4 (5) -vinylimidazole, 2-vinyl-1-methylimidazole , 5-vinyl-pyrazoline, 3-methyl-5-isopropenyl-pyrazole, 5-methylene hydantoin, 3-vinyl-2-oxazolidone, 2- and 4-vinyl pyridine, 5-vinyl-2-methyl pyridine, 2-vinyl pyridine 1-oxide, 3-isopropenylpyridine, 2- and 4-vinyl-piperidine, 2- and 4-vinyl-quinoline, 2,4-dimethyl-6-vinyl-s-triazine
  • Preferred among these monomers mentioned, which can be used in an amount of 0-15% by weight of the total monomers, are: acrylic acid, methacrylic acid, 2-vinyl-pyridine, 4-vinyl-pyridine, 2- (dimethylamino) ethyl methacrylate, N- [2-dimethylamino) ethyl] methacrylate, N- [2- (dimethylamino) ethyl] methacrylamide and sodium styrene sulfonate.
  • water-soluble monomers are 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate, 2,3-dihydroxypropyl acrylate, 2,3-dihydroxypropyl methacrylate, N-vinyl-2- pyrrolidone and N-methylolacrylamide.
  • Suitable hydrophobic comonomers which can be incorporated into the reaction mixture are e.g. B. water-insoluble olefinic monomers, such as alkyl acrylates or methacrylates, in which alkyl has 1 to 18 carbon atoms, for. B. methyl and ethyl methacrylate or acrylate; Vinyl esters derived from alkane carboxylic acids with 1-5 C atoms, e.g. B. vinyl acetate, vinyl propionate or vinyl benzoate; Acrylonitrile, styrene and vinyl alkyl ether, in which the alkyl group of the ether chain has 1-5 C atoms, e.g. B. (methyl, ethyl, propyl, butyl or amyl) vinyl ether.
  • B. water-insoluble olefinic monomers such as alkyl acrylates or methacrylates, in which alkyl has 1 to 18 carbon atoms, for. B. methyl and
  • Preferred compounds are alkyl acrylates or methacrylates in which the alkyl radical has 1 to 18 carbon atoms.
  • Other preferred compounds are the vinyl alkyl ethers in which the alkyl radical has 1 to 5 carbon atoms.
  • the olefinic part is preferably an acyl radical of a lower a, ⁇ -mono-unsaturated aliphatic monocarboxylic or dicarboxylic acid or vinyloxy radicals.
  • These vinyl parts can be crosslinked by a macromolecular chain with repeated ester, amide or urethane groups, but in particular ether groups.
  • the molecular weight of the chain can preferably vary between 600 and 5000, and very particularly between 1500 and 3000.
  • component (B) corresponds to the formulas or wherein a is 1 or 2 and R is a polycondensate chain containing hydrocarbon residues bound by ether, ester, amide, urethane or urea residues
  • R 2 is hydrogen, methyl or -CH 2 COOR 4 , wherein R 4 is hydrogen or an alkyl group having 1 to 10 carbon atoms
  • R 3 is hydrogen or -COOR 4 with the condition that at least one of the radicals R 2 or R 3 is hydrogen
  • X is oxo, -COO- or -CONR 5 -, in which R 5 is hydrogen or alkyl having up to 5 carbon atoms and Y is a direct bond or the radical -R 6 -Z 1 -CO-NH-R 7 -NH-CO-Z 2 -, in which R 6 is bound to X and represents a branched or straight-chain alkylene radical having up to 7 carbon atoms
  • Z is oxo or -NR S
  • R I in particular denotes a polypropylene oxide or a polytetramethylene oxide chain, or a chain which consists of a polyethylene oxide-polypropylene oxide copolymer block, but it can also mean a chain derived from dicarboxylic acids, diols, diamines or diisocyanates, which are obtained by known polycondensation processes.
  • R1 can also mean a chain containing a polysiloxane.
  • the terminal residues of the compound of formula B correspond to the definitions of R 2 and R 3 , and, if X means -COO- or -CONR s -, the acyl residue is derived from acrylic or methacrylic acid or the monoalkyl esters from malein -, Fumaric or itaconic acid, or of monoalkyl esters of these acids with straight or branched chain alkanols with 1 to 10 carbon atoms, such as methanol, ethanol, propanol, butanol, diisobutyl alcohol or decanol, or, if X is oxygen, with the vinyloxy radical of vinyl ethers.
  • diesters of macromolecular diols in which two hydroxyl groups on the polycondensate R, in opposite terminated or almost terminated positions are bonded, with a, ⁇ -unsaturated acids.
  • diesters can be prepared from the macromolecular diols mentioned by known acylation processes, using reactive functional derivatives of suitable acids, for example acrylic or methacrylic acid chloride, or of monoalkyl esters of maleic, fumaric or itaconic acid.
  • Compounds of formula B with the amide group X are diamides which are obtained from macromolecular diamines by known acylation processes, for example by using the abovementioned acid chlorides or anhydrides.
  • the macromolecular diamines are e.g. B. prepared from the corresponding macromolecular diols with twice the molar amount of alkyleneimine, such as propyleneimine.
  • the macromolecular bis-maleic acid acids are obtained in accordance with the described reaction by using maleic anhydride as an acylating agent for macromolecular diamines with heating or reaction with dewatering agents to produce macromolecular bis-maleimido compounds of the formula B 2 .
  • R e.g. B. be one of the macromolecular polycondensate chains, which are mentioned as components of the compounds according to formula B.
  • Y can also mean a divalent radical -R 6 -Z 1 -CONH-R 7 -NH-CO-Z 1 .
  • R 6 z. methylene, propylene, trimethylene, tetramethylene, pentamethylene, neopentylene (2,2-dimethyltrimethylene), 2-hydroxytrimethylene, 1,1-dimethyl-2- (1-oxoethyl) trimethylene or 1- (dimethyleneaminomethyl) ethylene and in particular Ethylene.
  • the divalent radical R 7 is derived from an organic diisocyanate and is an aliphatic radical such as alkylene, for example ethylene, tetramethylene, hexamethylene, 2,2,4-trimethylhexamethylene, 2,4,4-trimethylhexamethylene, fumaroyldiethylene or 1-carboxypentamethylene; a cycloaliphatic radical, for example 1,4-cyclohexylene or 2-methyl-1,4-cyclohexylene; an aromatic radical, such as m-phenylene, p-phenylene, Z-methyl-m-pnenylene, T, z-, T, 3-, 1, b-, T, 6-, T; / -, 1,8- , 2,3- and 2,7-naphthylene, 4-chloro-1,2- and 4-chloro-1,8-naphthylene, 1-methyl-2,4-, 1-methyl-2,7-, 4th -Methyl-1,2-, 6-methyl-1
  • R is derived in particular from diols and diamines with a molecular weight of approximately 200-8000.
  • Suitable such diols are polyethylene oxide diols with a molecular weight of 500-3000, polypropylene oxide diols with a molecular weight of 500-3000, poly-n-butylene oxide diols with a molecular weight of 500-3000, poly.
  • polyester diols with a molecular weight of 500-3000 which are obtained by known methods of polycondensation from diols and Dicarboxylic acid such as B. can be obtained from propylene glycol, ethylene glycol, butanediol or 3-thia-pentanediol and adipic acid, terephthalic acid, phthalic acid or maleic acid, which may also contain diols of the above-mentioned types of polyethers.
  • diamines with a molecular weight of 500-4000 in particular the bis-aminopropyl ethers of the above-mentioned diols, such as e.g. the bis-3-aminopropyl ether of polyethylene oxide and polypropylene oxide diol.
  • a preferred embodiment of the present process consists in compound (B), in which R, a polyethylene oxide, polypropylene oxide or polytetramethylene oxide chain with a molecular weight of 600-4000 or a chain, which is obtained by condensation of an aliphatic, alicyclic or aromatic dicarboxylic acid or a corresponding diisocyanate with an aliphatic diol or diamine.
  • the preferred compounds (B) consist of polyalkylene ether glycols, in particular polytetramethylene oxide glycols with a molecular weight of about 600 to about 4000, in particular 1500-3000, first saturated with 2,4-toluene diisocyanate or isophorone diisocyanate and with 2 moles of a hydroxyalkyl acrylate or methacrylate end saturated, in which "alkyl” means a radical with 2-4 carbon atoms.
  • R 1 is derived from a polysiloxane containing diols, triols or dithiols.
  • These polysiloxanes with di or poly functions can have 2 different structures: or wherein R 8 is a straight or branched alkylene chain with 1-7 C atoms or a - (CH 2 CHO) n group, R 9 wherein n is 1 to 20, R 9 is hydrogen or methyl, and X is a number of 3 to 120 and Y is 2 or 3.
  • polysiloxane compounds are preferably end-saturated with isophorone diisocyanate or 2,4-toluenediisocyanate and reacted with an excess of 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate or 2-hydroxypropyl acrylate.
  • (C) means a vinyl ether containing an active hydrogen atom, such as. B. a hydroxyalkyl vinyl ether or an aminoalkyl vinyl ether. If X represents the -COO or -CONR s group, then (C) is an acrylate, methacrylate, maleate, fumarate, itaconate or a corresponding amide which contains an active hydrogen atom in the alkyl group.
  • the mixture of monomers (A) and macromolecular compounds (B) contains 20-100% of a hydroxy-substituted vinyl monomer and 0-40% of a water-insoluble vinyl monomer, in particular 40-100% of a hydroxy-substituted vinyl monomer and no water-insoluble monomer.
  • the free radical polymerization is initiated by means of a catalyst which can generate free peroxy or alkyl radicals in a sufficiently high concentration in order to bring about the polymerization of the vinyl monomer used at the synthesis temperature.
  • catalysts are preferably peroxide or azo catalysts which have a half-life of at least 20 minutes at the polymerization temperature.
  • Suitable catalysts are diisopropyl peroxidicarbonates, tert-butyl perctoate, benzoyl peroxide, decanoyl peroxide, lauroyl peroxide, succinic acid peroxide, methyl ethylene ketone peroxide, tert-butyl peroxyacetate, propionyl peroxide, 2,4-dichlorobenzyl peroxide, tert.-butyl peroxyl, peroxyl butoxide, peroxypyl peroxide, 5-dimethyl-2,5-bis (2-ethylhexanoyl-peroxy) hexane, p-chlorobenzoyl peroxide, tert-butyl peroxy butyrate, tert-butyl peroxymaleic acid, tert-butyl peroxy isopropyl carbonate, bis- (1-hydroxy -cyclohexyl) -peroxide; the azo compounds are: 2,2'-azo
  • the amount of the catalyst can be between 0.01-1% by weight of the monomer (A) and the macromolecular compound (B). It is preferably between 0.03-0.3% by weight.
  • the suspension medium used is dissolved at the end of the suspension polymerization by adding an acid, for example hydrochloric acid.
  • the hydrogel beads are isolated by filtration.
  • the process according to the invention is normally carried out in a reaction vessel which is provided with a reflux condenser, nitrogen flow, heat regulator and, most importantly, with a stirrer of special design which allows good mixing at low speed.
  • the anchor-like glass stirrers which are connected to a stirrer motor, the speed of which can be easily regulated, are preferably used in the laboratory.
  • the aqueous solution of the salt is first placed in the reaction vessel with a soluble magnesium or aluminum salt. The solution is then heated to the polymerization temperature and the gelatinous metal hydroxide is then precipitated by adding a calculated amount of an aqueous base. After this step, the stirring speed is reduced if necessary to obtain beads of a given size.
  • the mixture (A) and (B), which already contains the catalyst in solution, is now added and the reaction hold under nitrogen at constant temperature and stirring speeds for at least 3 hours.
  • the mixture is then heated under reflux at 100 ° C for 1 hour.
  • the reaction mixture is then cooled to room temperature and enough organic acid such as acetic acid or mineral acid is added to dissolve the metal hydroxide.
  • the pearls are now filtered off, washed off the surface salt water, then soaked in water or alcohols to extract unreacted monomers, and dried.
  • any water-soluble inorganic salt of a concentration of 5-25% by weight can be used as the aqueous salt solution; in practice, however, an inexpensive, commercially available chloride or sulfate of an alkali or alkaline earth metal is used, for example sodium chloride, potassium sulfate, magnesium chloride and magnesium sulfate. These can be used individually or as a mixture in a concentration that approaches the solubility limit in water. As a general rule, the higher the salt concentration, the lower the amount of water-soluble monomers that are dissolved in the aqueous phase and, at the same time, the more uniform the spherical hydrogel bead.
  • Sodium chloride is very particularly preferably used in a concentration of 20% by weight in water.
  • the metal hydroxides used as suspending agents of the present process can be prepared by adding, preferably in situ, to an aqueous solution of a water-soluble metal salt (chloride, nitrate, sulfate, etc.) alkali, usually 1N sodium hydroxide solution, in the amount, however does not exceed the stoichiometric amount necessary for the formation of the metal hydroxide or a metal hydroxide salt where not all valences of the metal ion are saturated with hydroxyl groups.
  • a water-soluble metal salt chloride, nitrate, sulfate, etc.
  • the metal hydroxides of magnesium, aluminum, zirconium, iron, nickel, chromium, zinc, lead, calcium, cobalt, copper, tin, gallium, manganese, strontium, barium, uranium, titanium, lanthanum, thorium and cerium are suitable for use as Suspension agent to be used for the present process.
  • hydroxides of certain transition metals such as -. B. manganese, iron and chromium are excellent suspending agents, but are not necessarily the hydroxides of choice since they could conflict with free radical polymerization through electron transfer reactions. The inherent color also hinders the use, since this is undesirable in the hydrogel beads.
  • the degree of swelling (DS) in water is determined by swelling a certain weight of pearls until equilibrium is reached; the swollen and dried pearls are weighed.
  • the average particle size (M.P.S.) is expressed as the number in millimeters at which the particle size distribution curve obtained by sieving the total amount of beads through a series of sieves with mesh sizes of 8-50 mesh intersects the 50% line.
  • the temperature degrees Celsius degrees and the percentages mean percentages by weight.
  • a smooth-walled 1000m1 plastic flask is equipped with a reflux condenser, nitrogen inlet tube, thermometer, which is connected to a heat controller, a separating grille and an anchor-like stirrer, which is driven by an adjustable motor. A slow stream of nitrogen is passed through the entire reaction.
  • the stirring speed is reduced to 150 revolutions / min and a mixture of monomer (A) and the macromolecular compound (B), in which 0.2 g of tert-butyl peroctoate as the initial catalyst for the preparation free radicals is added.
  • the mixture of (A) and (B) is prepared by terminally providing 60 g (about 0.024 mol) of a polytetramethylene oxide glycol (average molecular weight 2000) with isophorone diisocyanate, dissolving it in 140 g (1.08 mol) of 2-hydroxyethyl methacrylate (HEMA) and 72 React for hours at room temperature.
  • HEMA 2-hydroxyethyl methacrylate
  • the reaction mixture which has a pH of 7.8, is stirred under nitrogen at 150 revolutions / min for 3 hours at 80 °. The temperature is then raised to 100 ° for 1 hour and cooled to room temperature. Then 10ml conc. Hydrochloric acid was added to dissolve the magnesium hydroxide as a suspending agent.
  • the reaction mixture is filtered through a very fine-walled cloth and the then isolated beads are washed with 2000 ml of water and immersed in 500 ml of ethanol overnight to remove remaining monomers.
  • the beads obtained are filtered through a bag made of polyester cloth. The sewn-in sack and the contents are dried in a tumble dryer. Uniform spherical beads are obtained in a yield of 193 g (96.5% of theory) with an average diameter of 1.02 ⁇ 0.3 mm, which have a degree of swelling in water of 37% (DS H2O ).
  • Example 2 The procedure is the same as described in Example 1, but using (A) 47.5 g of HEMA and 5 g of N-vinylpyrrolidone (NVP) and (B) 47.5 g of the polytetramethylene oxide glycol used in Example 1. Hydrogel beads with an average size of 1.1 mm and a degree of swelling DS in H 2 0 of 21% are obtained.
  • An increase in the amount of NVP in the hydrogel causes an increase in the degree of swelling.
  • the mixture of monomers (A) and macromolecular compound (B) is prepared by dissolving and neutralizing 96 g of polytetramethylene oxide glycol (average molecular weight approx. 2000), which is saturated at the end with isophorone diisocyanate, in 64 g of 2-hydroxyethyl methacrylate and 40 g of acrylic acid before the polymerization begins .
  • Uniform spherical beads are obtained which have an average diameter of 1.02 mm ⁇ 0.2 mm in a yield of 180 g (90% of theory).
  • the degree of swelling depends on the pH, a degree of swelling of 65.4% being obtained at pH 3 and a degree of swelling of 75.8% at pH 8.
  • the mixture of (A) and (B) used is prepared by dissolving 84 g of polytetramethylene oxide glycol (average molecular weight 2000), finally saturated with isophorone diisocyanate, in 56 g of 2-hydroxyethyl methacrylate and 60 g of N- (2-dimethylamino) ethyl methacrylate.
  • Hydrogel beads are prepared in an analogous manner to that described in Example 1 by adding 24 g of polytetramethylene oxide glycol (MW 2000), which is saturated with isophorone diisocyanate, in 42 g of 2-hydroxyethyl methacrylate, 54 g of N as a mono mixture of (A) and (B) -Vinyl-2-pyrrolidone and 80g methoxypolyethylene glycol methacrylate, which contains an average of 9 ethoxy units. Uniform round beads are obtained with an average diameter of 0.72 mm and a degree of swelling (DS HZ o) of 27.2%.
  • DS HZ o degree of swelling
  • hydrogel beads are prepared by adding 33.3 g of a 60% aqueous solution of N-methylolacrylamide with 171 of a mixture of 40% polytetramethylene C. oxide glycol (MW 2000), finally saturated with 2 moles of isophorone diisocyanate , and 60% 2-hydroxyethyl methacrylate and receives 180g (85% of theory) of uniform round beads with a diameter of 1.10mm and a degree of swelling (DS H2O ) of 32%.
  • a gelatinous precipitate of magnesium hydroxide forms with the addition of 123 ml of 1N sodium hydroxide solution with vigorous stirring.
  • the mixture (A) + (B) used in this example is prepared by using 107.5 g of polydimethylsiloxane diol of the formula available from Dow Corning as Q 4-3667, saturated at the end with isophorone diisocyanate, dissolved in 107.5 g of 2-hydroxyethyl methacrylate.
  • Uniform, spherical beads (200 g, 93% of theory) are obtained which have an average diameter of 1.66 ⁇ 0.5 mm and a degree of swelling DS H2O of 28.1%.
  • a smooth-winded 1000m1 plastic flask is equipped with a reflux condenser, nitrogen inlet tube, thermometer, which is equipped with a temperature controller, a separating grille and an anchor-like stirrer, which is driven by an adjustable motor.
  • the contents of the flask are filtered through a fine mesh cheese cloth, as described above, washed with 21 water and soaked in 500 ml of ethanol overnight to extract the remaining monomers. As described in Example 1, the beads are filtered and dried. 180 g of uniform, round beads with an average diameter of 0.85 mm are obtained. The degree of swelling is pH-dependent and is 30.7% at pH 1 (DSp H 1 ) and 51.1% at pH 8.

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  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Macromonomer-Based Addition Polymer (AREA)
  • Medicinal Preparation (AREA)
  • Polymerisation Methods In General (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Claims (3)

1. Procédé de fabrication de perles sphériques, pratiquement uniformes, dont le diamètre peut aller jusqu'à 5mm, à partir d'un hydrogel réticulé insoluble dans l'eau, par polymérisation en suspension de (A) 95 à 30% en poids, par rapport à l'hydrogel, d'au moins un monomère mono-oléfi- nique soluble dans l'eau, lequel peut être remplacé, en une proportion pouvant aller jusqu'à 70% en poids par rapport à la quantité totale des monomères, par au moins un composé monomère insoluble dans l'eau, l'hydrogel contenant au maximum 60% en poids du composé monomère ïnsoluble dans l'eau, et au moins 5% en poids de l'ensemble des monomères étant constitués d'un monomère vinylique hydrophile porteur d'un groupe hydroxy, avec (B) de 5 à 70% en poids, par rapport à l'hydrogel, d'un composé réticulant porteur de deux groupes terminaux olé- finiques et ayant un poids moléculaire de 400 à 8000, en présence d'un catalyseur de polymérisation, dans une solution aqueuse concentrée d'un sel minéral et en présence d'un agent de suspension, ainsi que par traitement de l'hydrogel par un acide, procédé caractérisé en ce qu'on utilise, comme agent de suspension, de 0,01 à 5% en poids, par rapport à l'hydrogel, d'au moins un hydroxyde métallique ou d'un hydroxy-sel métallique minéral, insoluble dans l'eau, ayant la consistance d'une gelée et capable de fixer l'eau, en l'absence d'un excès d'alcali ou d'ions hydroxyles libres.
2. Procédé selon la revendication 1 caractérisé en ce qu'on utilise, comme agent de suspension, un hydroxyde métallique ou hydroxy-sel métallique, insoluble dans l'eau et de consistance gélatineuse, du magnésium, de l'aluminium, du zirconium, du fer, du nickel, du chrome, du zinc, du plomb, du calcium, du cobalt, du cuivre, du zinc, du gallium, du manganèse, du strontium, du baryum, du l'uranium, du titane, du lanthane, du thorium ou du cérium.
3. Procédé selon la revendication 1 caractérisé en ce qu'on utilise, comme agent de suspension, l'hydroxyde de magnésium, l'hydroxyde d'aluminium, un hydroxy-sel de magnésium ou un hydroxy-sel d'aluminium.
EP78100375A 1977-07-20 1978-07-12 Procédé de préparation d'hydrogels sous forme de perles sphériques de plus grand diamètre Expired EP0000507B1 (fr)

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US81740477A 1977-07-20 1977-07-20
US817404 1977-07-20

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EP0000507B1 true EP0000507B1 (fr) 1982-09-29

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EP (1) EP0000507B1 (fr)
JP (1) JPS5440891A (fr)
AT (1) AT366066B (fr)
CA (1) CA1136317A (fr)
DE (1) DE2862045D1 (fr)
DK (1) DK149002C (fr)
ES (1) ES471862A1 (fr)

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US4914170A (en) * 1987-11-17 1990-04-03 Rohm And Haas Company Superabsorbent polymeric compositions and process for producing the same
ES2102352T3 (es) * 1988-02-26 1997-08-01 Ciba Geigy Ag Una lente de contacto humectable, flexible, permeable al oxigeno, hinchable y que contiene unidades de espina dorsal de polioxialquileno y uso de la misma.
JP2783679B2 (ja) * 1989-03-23 1998-08-06 株式会社日本触媒 塗料組成物
FR2759702B1 (fr) * 1997-02-14 1999-04-02 Essilor Int Compositions polymerisables comprenant un oligomere urethane comme agent de reticulation, polymeres et polymeres hydrates obtenus a partir de ces compositions, et articles finis et semi-finis formes a partir de ces polymeres
US20060015083A1 (en) * 2002-03-11 2006-01-19 Munro Hugh S Absorbent hydrogels
EP1664168B1 (fr) * 2003-08-29 2008-12-03 Mayo Foundation for Medical Education and Research Agents porogenes a base d'hydrogel permettant de fabriquer des ossatures biodegradables
AU2005304567B2 (en) 2004-11-12 2011-10-27 Mayo Foundation For Medical Education And Research Photocrosslinkable poly(caprolactone fumarate)
AU2006242487B2 (en) 2005-04-29 2011-12-01 Mayo Foundation For Medical Education And Research Hydrophilic/hydrophobic polymer networks based on poly(caprolactone fumarate), poly(ethylene glycol fumarate), and copolymers thereof

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US2801992A (en) * 1953-08-19 1957-08-06 Distillers Co Yeast Ltd Suspension stabilizer of magnesium hydroxide and excess alkali
CH616694A5 (en) * 1974-06-27 1980-04-15 Ciba Geigy Ag Process for the preparation of crosslinked, water-insoluble, hydrophilic copolymers

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DK322778A (da) 1979-01-21
AT366066B (de) 1982-03-10
DK149002C (da) 1986-08-25
CA1136317A (fr) 1982-11-23
DE2862045D1 (en) 1982-11-11
JPS614401B2 (fr) 1986-02-10
ES471862A1 (es) 1979-02-01
DK149002B (da) 1985-12-16
JPS5440891A (en) 1979-03-31
ATA523278A (de) 1981-07-15
EP0000507A1 (fr) 1979-02-07

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