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EP0000507A1 - 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
EP0000507A1
EP0000507A1 EP78100375A EP78100375A EP0000507A1 EP 0000507 A1 EP0000507 A1 EP 0000507A1 EP 78100375 A EP78100375 A EP 78100375A EP 78100375 A EP78100375 A EP 78100375A EP 0000507 A1 EP0000507 A1 EP 0000507A1
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European Patent Office
Prior art keywords
water
weight
hydrogel
monomer
insoluble
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EP78100375A
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German (de)
English (en)
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EP0000507B1 (fr
Inventor
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 an improved 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 of this type are obtained by means of suspended polymerization in a concentrated aqueous solution of a salt in which 95-30% by weight of a monoolefinic monomer (A) which consists of at least 5% of a hydroxyl-substituted hydrophilic vinyl monomer and 5-70% by weight of a terminal di-olefinic macromers (B) are present as crosslinking agents, in the presence of a water-insoluble gelatinous, strongly water-binding inorganic metal hydroxide as a suspending agent in the absence of excess alkali. Hydrogels of this type can be used in a variety of ways for pharmaceutical and industrial purposes.
  • the spherical beads have a degree of swelling in water of 5-200%.
  • Hydrogels have been described since 1956 (U.S. Patent 2,976,576), and a large number of patents have been published since that time the preparation and use of hydrogels which pre w i e e s d to 2-Hydroxyäthylmethacrylaten and to a lesser extent on N-vinyl pyrrolidones are based.
  • this H y dro g ele crosslinked, water-swelling polymers which are prepared by copolymerization of 2-Hydroxyäthylmethacrylaten with a small amount of ethylene or Butylendimethacrylaten.
  • Drug-containing hydrogel preparations have been described in the form of wound dressings, subcutaneous implants and devices in the oral mucosa, in the uterus and in eye inserts and are obtained using complicated manufacturing methods. Normally, the menomeric solution is poured into a suitable mold and in the presence of a catalyst which Free radicals generated, pelymerized.
  • 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.
  • magnesium hydroxide as suspension stabilizers for the polymerization of vinyl monomers is disclosed in the U.S. Patent No. 2,801,912, but with the express reference; that there must be an excess of alkali or hydroxyl ions. Magnesium hydroxide in the absence of excess hydroxyl ions (alkali) is ineffective as a suspension stabilizer.
  • hydrogel granules were of a very irregular shape and a very porous surface.
  • the uniformly shaped beads in this way are of such a small size (for example ⁇ 0.3 mm diameter) that they have no practical value for the slow release of active agents.
  • the inorganic compounds only the insoluble gelatinous metal hydroxides gave uniform beads. If poly (2-hydroxyethyl methacrylate) or hydron is used, beads of unusable size and inconsistent spherical shape are obtained.
  • regular, uniform spherical beads with a soft surface up to a size of 5 mm in diameter are obtained.
  • the subject of the present application is the development of an improved method for the production of uniform, spherical hydrogel beads up to a size of 5 mm in diameter, which have a myriad of pharmaceutical and industrial uses.
  • Another object of the invention is the production of uniform, spherical hydrogel beads, which consist of crosslinked polymers, which by polymerization in suspensions in an aqueous salt solution, the 95-30% by weight of a hydrophilic monomer (A), which consists of 5-100% by Hydroxy substituted vinyl monomers, and 5-70% by weight of a terminally substituted diolefinic cross-linking macromers (B) and in the presence of a suspending agent, such as the water-insoluble, gelatinous, strongly water-binding, inorganic metal hydroxides and metal hydroxy salts in the absence of excess alkali.
  • a suspending agent such as the water-insoluble, gelatinous, strongly water-binding, inorganic metal hydroxides and metal hydroxy salts in the absence of excess alkali.
  • the present process comprises the combined use of special gelatinous inorganic hydroxides, of monomeric cross-linking compounds and hydroxy substituted homonomers in order to produce uniform, spherical beads up to 5 mm in diameter.
  • special gelatinous inorganic hydroxides of monomeric cross-linking compounds and hydroxy substituted homonomers in order to produce uniform, spherical beads up to 5 mm in diameter.
  • the present invention relates in particular to an improved process for the production of essentially.
  • a suspending agent for example a water-insoluble, gelatinous, strongly water-binding, inorganic metal hydroxide and metal hydroxy salt in the absence of excess alkali and free hydroxyl ions is used.
  • the hydrophilic part of the hydrogel compound is prepared by polymerizing a water-soluble monoolefinic monomer or a mixture of such monomers which contains at least 5% by weight of a hydroxy-substituted vinyl monomer and which contains 0-70% by weight, and preferably at most 50% by weight, of the Total amount of the monomers of one or a mixture of this water-insoluble monomer contains.
  • water-soluble derivatives of acrylic and / or methacrylic acid such as e.g. 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.
  • esters of acrylic or methacrylic acid are the ethoxylated and polyethoxylated hydroxyalkyl esters, 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, e.g. Trialkylaminomethacrylimides, e.g. Trimethylaminomethacrylimid and Dimethyl- (2-hydroxypropyl) -aminomethacrylimid and the corresponding derivatives of acrylic acid.
  • Trialkylaminomethacrylimides e.g. Trimethylaminomethacrylimid and Dimethyl- (2-hydroxypropyl) -aminomethacrylimid 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, e.g. Di- (2-hydroxyethyl) maleate and alkoxylated hydroxyalkyl maleates, hydroxyalkyl monomaleates such as e.g. 2-hydroxyethyl monomaleate and alkoxylated hydroxyalkyl monomaleate with vinyl ethers, vinyl esters, styrene or in general monomers which readily copolymerize with maleates or fumarates; Hydroxyalkyl vinyl ethers such as e.g. 2-hydroxyethyl vinyl ether, 4-hydroxybutyl vinyl ether with maleates, fumarates or generally all monomers that easily copolymerize with vinyl ethers.
  • Hydroxyalkyl vinyl ethers such as e.g. 2-hydroxyethyl vinyl ether, 4-
  • Hydroxyalkyl acrylates and methacrylates such as e.g. 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 2,3-dihydroxypropyl methacrylate.
  • the most preferred monomer is 2-hydroxyethyl methacrylate.
  • Water-soluble comonomers which contain no hydroxyl groups are acrylic and methacrylic acids and alkyl ethers of polyethoxylated hydroxyalkyl esters, 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 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] acrylamide and methacrylamide, N- [3- (dimethylamino) -2-hydroxypropyl] 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-exazolidone, 3-methacrylyl-2-oxazolidone, 3-methacrylyl-5-methyi-2-oxazolidone, 2- and 4-vinylpyridine, 5-vinyl-2-methylpyridine, 2-vinylpyridine-l-oxide, 3-isopropenylpyridine, 2- and 4-
  • 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- (dimethylaminol-ethyl methacrylamide and sodium styrene sulfonate.
  • 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 are particularly valuable as water-soluble monomers N-methylol acrylamide.
  • Suitable hydrophobic comonomers which can be incorporated into the reaction mixture are e.g. water-insoluble olefinic monomers such as alkyl acrylates or methacrylates in which alkyl has 1 to 18 carbon atoms, e.g. Methyl and ethyl methacrylate or acrylate; vinyl esters derived from alkane carboxylic acids with 1-5 C atoms, e.g. Vinyl acetate, vinyl propionate or vinyl benzoate; Acrylonitrile, styrene and vinyl alkyl ethers in which the alkyl group of the ether chain has 1-5 C atoms, e.g. (Methyl, ethyl, propyl, butyl or amyl) vinyl ether.
  • water-insoluble olefinic monomers such as alkyl acrylates or methacrylates in which alkyl has 1 to 18 carbon atoms, e.g. Methyl and eth
  • 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 ⁇ , ⁇ -mono-unsaturated aliphati see monocarboxylic or dicarboxylic acid or vinyloxy residues.
  • These vinyl parts are cross-linked by a macromolecular chain with repeated ester, amide or urethane groups, but especially ether groups.
  • the molecular weight of the chain can vary from 400 to about 8000, preferably between 600 and 5000, and most particularly between 1500 and 3000.
  • G effless the component (B) corresponds to the formulas or wherein a represents 1 or 2 and R 1 represents a polycondensate chain with a molecular weight of approximately 200 to 8000, which contains hydrocarbon radicals which are bonded by ether, ester, amide, urethane or urea radicals,
  • R 2 is hydrogen, methyl or -CH 2 COOR 4 , in which R 4 is hydrogen or an alkyl group having 1 to 10 C 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 -, wherein 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 - means in which R 6 is bound to X and is a branched or straight chain term alkylene
  • R 1 means in particular 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. R 1 can also mean a chain containing a polysiloxane.
  • the terminal radicals of the compound of the formula B 1 correspond to the definitions of R 2 and R 31 and, if X is -COO- or -CONr 5 -, the acyl radical is derived from acrylic or methacrylic acid or the monoacyl radicals from maleic acid. , 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, for example, 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 1 in opposite terminated or almost terminated positions are bonded, with ⁇ , ⁇ -unsaturated acids can be prepared from the macromnecular diols mentioned by known acylation processes, by reactive functional derivatives of suitable acids, for example acrylic or methacrylic acid chloride, or of monoalkyl esters of Maleic, fumaric or itaconic acid can be used.
  • Compounds of the formula B 1 with the amide group X are diamides, which are obtained from macromolecular diamines by known acylation by using the above acid chlorides or anhydrides, for example.
  • the macromolecular diamines are produced, for example, from the corresponding macromolecular diols with twice the molar amount of alkyleneimine, such as, for example, 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 dehydrating agents to produce macromolecular bis-maleimido compounds of the formula B 2 .
  • R 1 can be, for example, one of the macromolecular polycondensate chains which are mentioned as constituents of the compounds of the formula B 1 .
  • Y can furthermore mean a divalent radical -R 6 -Z 1 -CONH-R 7 -NH-CO-Z 1 .
  • R 6 is, for example, methylene, propylene, trimethylene, tetramethylene, pentamethylene, neopentylene (2,2-dimethyltrimethylene), 2-hydroxytrimethylene, 1,1-dimethyl-2- (1-oxo-ethy1) -trimethylene or 1- (dimzthyleneaminomethyl ) ethylene and especially 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, fumaroyl diethylene or 1-carboxy - pentamethylene; a cycloaliphatic radical, for example 1,4-cyclohexylene or 2-methyl-1,4-cyclohexylene; an aromatic radical, such as m-phenylene, p-phenylene, 2-methyl-m-phenylene, 1,2-, 1,3-, 1,5-, 1,6-, 1,7-, 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-, 4-methyl-1,2-, 6-methyl-1,3- and 7-methyl-1,3-naphth
  • R 1 is derived in particular from macromeric diols and diamines with a molecular weight of 200-8000.
  • Suitable macromeric 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 5C0-3000, poly (block ethylene oxide-co-propylene oxide) diols with one.
  • Molecular weight of 500-3000 in which the percentage of ethylene oxide units can vary between 10 and 90% ', or polyester diols with a molecular weight of 500-3000, which according to known methods of polymer condensation from diols and dicarboxylic acid, such as from propylene glycol, ethylene glycol, butanediol or 3-thia-pentanediol and adipic acid, terephthalic acid, phthalic acid or maleic acid can be obtained, which are also macromeric diols of the above-mentioned types of polyethers.
  • any 500-3000 molecular weight diol that can be obtained by polycondensing diols, diamines, diisocyanates or dicarboxylic acids and containing ester, urea, urethane or amide groups as linkers is suitable for this purpose.
  • 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 ethers of polyethylene oxide and polypropylene oxide diol.
  • a preferred embodiment of the present method consists in the use of a macromer (B) in which R 1 denotes a polyethylene oxide, polypropylene oxide or polytetramethylene oxide chain with a molecular weight of 600-4000.
  • Another preferred embodiment of the present process consists in the use of a macromer (B) in which R 1 denotes 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 macromers (B) consist of polyalkylene ether glycols, in particular polytetramethylene oxide glycols having a molecular weight of about 600 to about 4000, first saturated with 2,4-toluene diisocyanate or isophorone diisocyanate and finally saturated with 2 moles of a hydroxyalkyl acrylate or methacrylate, wherein "alkyl '' means a residue with 2-4 C atoms.
  • Maeromer (B) made of polytetramethylene oxide glycol with a molecular weight of approximately 1500 to 3000 is particularly valuable, the hydroxyalkyl methacrylate being the 2-hydroxyethyl methacrylate means.
  • R 1 is derived from a polysiloxane containing diols, triols or dithiols and has a molecular weight of 400-8000.
  • These di- or polyfunctional polysiloxanes can have 2 different structures: or wherein R 8 is a straight or branched alkylene chain with 1-7 C atoms or one A group in which n is 1 to 20, R 9 is hydrogen or methyl, and X is a number from 3 to 120 and Y is 2 or 3.
  • polysiloxane macromers 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) is a vinyl ether containing an active hydrogen atom, such as a hydroxyalkyl vinyl ether or an aminoalkyl vinyl ether. If X represents the -C00- or -CONR 5 group, then (C) is an acrylate, methacrylate, maleate, fumarate, itaconate or a corresponding amide which contain an active hydrogen atom in the alkyl group.
  • the macromolecular diols or diamines are preferably used in a small excess.
  • the ratio of the isocyano groups to the hydroxyl or amino groups in the first stage of macromer synthesis is at least 1: 1, but preferably at least 1: 1.05. If the compound of formula (C) used in the second stage of macromer synthesis is identical to the hydrophilic monomer of formula (A), a large excess of this compound can be used so that the resulting solution of macromer B 1 dissolved or dispersed in compound C can be used directly for the preparation of the final hydrogel.
  • the synthesis of macromere B is carried out in a suitable manner in a temperature range between approximately 20 and 100 ° C.
  • the temperature is preferably maintained in the range between 30-60 ° C.
  • the conversion of the isocyanate group is followed by infrared spectroscopy or titration.
  • Preferred diisocyanates for the production of macromers are 2,4-toluenediisocyanate or isophorone diisocyanate.
  • a polytetramethylene oxide glycol chain which is end-capped with 2,4-toluene diisocyanate is commercially available from DuPont under the name "Adiprene".
  • 2,4-toluene diisocyanate and isophorone diisocyanate are also commercially available.
  • Another process for the preparation of macromers consists in reacting with a terminal hydroxyl-provided prepolymer, such as polybutylene or polypropylene oxide, with acryloyl chloride, methacryloyl chloride or halic acid anhydride, a macromer being formed without crosslinking urethane bonds, such as a macromer of the formula B 2 or B 1 , wherein Y is a direct bond.
  • a terminal hydroxyl-provided prepolymer such as polybutylene or polypropylene oxide
  • acryloyl chloride, methacryloyl chloride or halic acid anhydride a macromer being formed without crosslinking urethane bonds, such as a macromer of the formula B 2 or B 1 , wherein Y is a direct bond.
  • the macromere is dissolved in monomers or diluted with monomers to produce the final polymerizable mixture.
  • This mixture of monomers and macromers can consist of 95-30% by weight of monoolefinic vinyl monomers, which must contain at least 5% of a water-soluble vinyl monomer substituted by a hydroxyl group and can also contain 0-2C% of a water-insoluble vinyl monomer. Preferably, however, cnt it holds 20-100% of a hydroxy-substituted vinyl monomer and 0-40% of a water-insoluble vinyl monomer, but especially 40-100% of a hydroxy-substituted vinyl monomer and not a water-insoluble monomer.
  • B is a terminal polyolefin macromer containing 5-70% by weight as a crosslinking agent. The amount of the macromer is preferably 15-100%, with the amount of 25-45% being most preferred.
  • the improved process of the present invention relates to a process for the production of uniform, spherical hydrogel beads with a diameter of up to 5 mm by means of the polymerization in suspension of a monomer (A) -macromere (B) mixture as described above.
  • the suspension polymerization is carried out in a medium consisting of an aqueous solution of a water-soluble inorganic salt in which a water-insoluble, gelatinous, highly water-binding inorganic metal hydroxide or metal hydroxide salt is suspended as a suspending agent, in the absence of excess alkali or free hydroxyl ions.
  • 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.
  • the amount of the catalyst varies between 0.01-1% by weight of the monomer (A) and the macromer (B), but preferably the amount of the catalyst is between 0.03 - 0.3% by weight.
  • the polymerization takes place in the form of monomer-macromer droplets, which are insoluble in aqueous salt solution.
  • the droplets are stabilized by the presence of suspending agents which prevent coagulation.
  • the size of the droplets and finally the size of the hydrogel beads is determined by the stirring speed. Rapid stirring generally leads to smaller pearls, while slow stirring leads to larger pearls which, however, are inconsistent and irregular in the absence of a gelatinous metal hydroxide as a suspending agent.
  • the gelatinous metal hydroxide or metal hydroxide salt 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 is usually done in a reak tion vessel, which is equipped with a reflux condenser, nitrogen flow, heat regulator and, most importantly, a stirrer with a special design that 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 monomer-macromere mixture which already contains the catalyst in solution, is now added and the reaction is held at constant temperature and stirring speeds for at least 3 hours. The mixture is then heated under reflux at 100 ° C for 1 hour. A nitrogen blanket (nitrogen atmosphere) is maintained throughout the reaction time. The reaction mixture is then cooled to room temperature and enough organic acid, for example acetic acid or mineral acid, is added to dissolve the metal hydroxide. The beads are now filtered off, washed off the surface salt water and then soaked in water or alcohols to extract non-reacted monomers. After drying, the beads are weighed, the particle size and the distribution of the individual particle sizes are determined by screening.
  • organic acid for example acetic acid or mineral acid
  • the degree of swelling (DS) is then determined in various solvents. Lots Steps in this very general process can be modified to suit the specific requirements of the products.
  • the suspension medium can be precipitated after adding the monomer-macromere mixture and, for example, monomers can be added continuously during the polymerization.
  • the monomers used can be the same throughout the process, or they can be exchanged, with the result that beads of heterogeneous composition are obtained.
  • the non-solvent aqueous phase for the process according to the invention is an aqueous salt solution.
  • it can be any water-soluble inorganic salt at a concentration of 5-25% by weight; 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.
  • the preferred salt used is sodium chloride or sodium sulfate in concentrations which are between 5% by weight, but preferably between 10% by weight and 15% by weight.
  • Sodium chloride is very particularly preferably used in a concentration of 20% by weight in water.
  • the ratio of the aqueous phase to the monomer-macromere phase varies in volume terms 2: 1 and 15: 1.
  • the ratio should be large and with a less pronounced degree of swelling small, preferably between 2.5: 1 to 3: 1.
  • the essence of the process according to the invention lies in an extremely effective suspension system which consists of a water-insoluble, gelatinous, strongly water-binding inorganic metal hydroxide or a metal hydroxide salt in the absence of an excess of alkali or free hydroxyl ions, a macromere (B) and a small amount (at least 5%) of a hydroxy substituted vinyl monomer.
  • the preferred metal atom is one having stable valences, so that no oxidation / reduction reactions take place. Magnesium, aluminum and zirconium are mainly used for this.
  • the metal hydroxides of the present process used as suspending agents are prepared by adding alkali to an aqueous solution of a water-soluble metal salt (chloride, nitrate, sulfate, etc.) in an amount which, however, does not exceed the stoichiometric amount required 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, is necessary.
  • a metal hydroxide salt is, for example, aluminum hydroxychloride or magnesium hydroxychloride.
  • metal hydroxide be highly water-binding in character, as is appropriate when forming a voluminous gel.
  • Crystalline, highly insoluble salts or oxides, which are generally used as suspending agents, for example in the production of polystyrene or polyvinyl chloride beads, are completely unsuitable for the production of uniform and large beads from polymers which are made from 2-hydroxyethyl methacrylate (HEMA) or N-vinyl-2-pyrrolidone can be produced.
  • HEMA 2-hydroxyethyl methacrylate
  • N-vinyl-2-pyrrolidone N-vinyl-2-pyrrolidone
  • the choice of the metal hydroxide is only decided according to whether a voluminous, gelatinous precipitate can precipitate in the aqueous medium or not.
  • the metal hydroxides are 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 suspending agents in the present process.
  • hydroxides of certain transition metals e.g. Manganese, iron and chromium are excellent suspending agents, but are not necessarily the hydroxides of choice, as 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.
  • Magnesium or aluminum hydroxide in the absence of excess alkali metal or free hydroxyl ions is regarded as the preferred suspending agent.
  • the amount of suspension medium varies between 0.01-5% by weight (based on the hydrogel) of water-insoluble, gelatinous metal hydroxides.
  • the suspending agent is preferably prepared in situ by adding a prescribed amount of aqueous base (usually 1N sodium hydroxide solution) to the aqueous solution of the metal salt (such as magnesium, aluminum, nickel, etc.).
  • aqueous base usually 1N sodium hydroxide solution
  • the metal salt such as magnesium, aluminum, nickel, etc.
  • aqueous base usually 1N sodium hydroxide solution
  • the metal salt such as magnesium, aluminum, nickel, etc.
  • the metal salt such as magnesium, aluminum, nickel, etc.
  • the monomers in this process are normal commercial products, as in the case of the inorganic salts for the preparation of the metal hydroxides as suspending agents.
  • the degree of swelling (DS) in water is determined by allowing a certain amount by weight of pearls to swell 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.
  • a smooth-walled plastic 1000 ml flask provided with a reflux condenser, Stickscherinleitrschreibchen, thermometer, which is connected to a thermoregulator, a t race-lattice and a ankerähnlchen agitator 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 rpm and a mixture of the monomer (A) and macromer (B), in which 0.2 g of tert-butyl peroctate is dissolved as an initial catalyst for the preparation of free radicals
  • the mixture of the monomer and macromere is prepared by terminally providing 60 g (approx. 0.024 mol) of a polytetramethylene oxide glycol (average molecular weight 200 ° C.) with isophorone diisocyanate, in 140 g (1.08 mol) of 2-hydroxyethyl methacrylate (HEMA ) can be solved and reacted for 72 hours at room temperature
  • the reaction mixture is under nitrogen at 150 revolutions / min. Stirred at 80 ° for 3 hours. The temperature is then raised to 100 ° for 1 hour, cooled to room temperature and then 10 ml of 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 (cheese preparation cloth) and the then isolated beads are washed with 2000 ml of water and immersed in 500 ml of ethanol overnight in order 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 H 2nd 0 ).
  • hydrogel beads are obtained as described below:
  • hydrogel beads are obtained as follows Properties:
  • the mixture of monomers (A) and macromers (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, and each free hydroxyl ion beforehand 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 18Cg (90% of theory).
  • the degree of swelling depends on the pH, with a degree of swelling of 65.4 at pH 3 and a degree of 75.8% at pH 8.
  • the monomer (A) and macromers (B) mixture used is prepared by adding 84 g of polytetra methylene oxide glycol (average molecular weight 2000), saturated at the end with isophorone diisocyanate, dissolves in 56 g of 2-hydroxyethyl methacrylate and 60 g of N- (2-dimethylamino) ethyl methacrylate.
  • Example 2 If the procedure described in Example 1 is used, but instead of the 140 g of 2-hydroxyethyl methacrylate, a mixture of 40 g of 2-hydroxyethyl methacrylate and 100 g of 3-hydroxypropyl methacrylate is used, uniform spherical beads are obtained in a yield of 193 g (96.5% i.e. an average diameter of 1.02 ⁇ 0.3 mm and a degree of swelling in water of DS H2 O of 37.9 water of DS H2 O of 37.9%
  • Hydrogel beads are prepared in a manner analogous to that described in Example 1, by adding 24 g of polynetramethylene oxide glycol (MW 2000), which is terminally reduced to mse e lsephorone diisocyanate, in 42 g of 2-hydroxyethyl methaerylate, 54 g N- as a monomer-macromeene mixture. Vinyl-2-pyrrolidone and 80 g of yethoxypolyethylene glycol methacrylate, which on average Contains ethoxy units, solves. Uniform round beads with an average diameter of 0.72 mm and a degree of swelling (DS H 2nd O ) of 272% .
  • hydrogel beads are prepared by adding 33.3 g of a 60% aqueous solution of N-methylolacrylamide with 171 g of a mixture of 40% polytetramethylene oxide glycol (MW 2000), finally saturated with 2 moles of isophorone diisocyanate , and 60% .
  • the monomer (A) -macromere (B) mixture used here is prepared by adding 80 g of a polysiloxane polyol of the formula available from Dow Corning as Q 4-3557, saturated at the end with isophorone diisocyanate in 89.2 g of 2-hydroxyethyl methacrylate and 30.8 g of N-vinylpyrrolidone.
  • magnesium hydroxychloride approximately half of the stoichiometric amount of the sodium hydroxide solution required is used to obtain a precipitate of magnesium hydroxide, which can also be formally referred to as magnesium hydroxychloride.
  • the pH when carrying out the suspension polymerization was 7.8.
  • Aluminum ions can also be used to instantly produce hydrogel beads.
  • the stoichiometric amount was used to make aluminum hydroxide as a suspending agent.
  • Example 30 is repeated, but only 90% of the stoichiometric (equivalent) amount of alkali hydroxide solution (sodium hydroxide solution, 0.112 equivalent) is used to produce the aluminum hydroxysulfate as a suspending agent with the aluminum sulfate hexadecahydrate (0.123 equivalent).
  • the pH is 7. Round beads with an average diameter of 1 mm are obtained in good yield.
  • Example 1 and Examples 27-31 are replaced by various, finely divided inorganic products, such as e.g. Calcium phosphate, calcium carbonate, magnesium carbonate, magnesium phosphate or calcium oxalate, so the polymerization takes place, but the product obtained clumps in large lumps. No uniform, spherical hydrogel beads are obtained.
  • the following examples show that, when using generally customary polymeric suspending agents, no hydrogel beads are normally obtained.
  • Example 1 The procedure as described in Example 1 is repeated with little change. Instead of the magnesium hydroxide, polyvinylpyrrolidone (PVP-K 90 from GAF Corporation) is used and this is dissolved in a concentration of 0.08%, based on the weight of the monomer-macromer mixture in the aqueous phase.
  • PVP-K 90 polyvinylpyrrolidone
  • the polymerization takes place 100%, but non-uniform granules form instead of round, uniformly shaped beads, a considerable amount Amount of coagulated material accumulates on the stirrer shaft and on the wall of the reaction vessel.
  • Example 2 The procedure is repeated as described in Example 1, but instead of magnesium hydroxide, use is made of hydroxyethyl cellulose (HEC QP 32000, Union Carbide), which is present in a concentration of 0.01%, based on the weight of the monomer-macromer mixture, in the aqueous phase is solved.
  • HEC QP 32000 hydroxyethyl cellulose
  • the polymerization takes place, the reaction taking place essentially. 68% of pearls with a diameter of ⁇ 0.4 mm are obtained. Lowering the stirring speed or lowering the amount of dispersion does not lead to larger, round pearls. Large clusters of grapes and granules form.
  • Example 2 The procedure is repeated as in Example 1. A solution of 24 g of polytetramethylene oxide glycol having a molecular weight of 2000 and finally saturated with isophorone diisocyanate in 42 g of 2-hydroxyethyl methacrylate and 54 g of N-vinyl-2 is used to prepare hydrogel beads from a monomer (A) -macr.omer (B) mixture -pyrrolidcn and 80 g of one of the water-insoluble comonomers listed below.
  • Example 2 The process is carried out as described in Example 1, but using different concentrations of sodium chloride in the aqueous polymerization medium. The effect on the yield, average average size of the beads and the degree of swelling are given below. Examples in which low molecular weight compounds are used as crosslinking agents.
  • Examples 50 and 51 describe the preparation of hydrogels, generally using the method described in Example 1 with the current monomer (A) -macromers (B) mixture, which is obtained by a conventional hydrogel compound, namely by a monomer such as, for example Substituted 2-hydroxyethyl methacrylate, which is cross-linked by a monomeric cross-linking agent such as divinylbenzene or ethylene-bis-methacrylate. No macromer (B) is present in Examples 50 and 51 below. Hydrogel products are obtained, however their size can be described as non-uniform and small in any case.
  • Example 1 The procedure described in Example 1 is generally maintained.
  • the monomer mixture used here consists of 199.4 g of 2-hydroxyethyl methacrylate, 2 g of divinylbenzene and 0.2 g of tert-butyl peroxypivate as an initial catalyst.
  • the polymerization is carried out at 70 ° for 35 hours, at a stirring speed of 100 revolutions / min. executed. The temperature is raised to 100 for 1 hour.
  • the process is carried out as described in Example 1.
  • the monomer mixture used here consists of 199.7 g of 2-hydroxyethyl methacrylate, 2 g of ethylene bis-methacrylate and 0.2 g of tert-butyl peroxypivalate and C, 1 g of tert-butyl peroctoate as the initial catalyst.
  • the polymerization is carried out at 65 ° for one hour, at, 85 ° for 2 hours and finally at 100 ° l hour and a stirring speed of 100 revolutions / min. executed.
  • Small, inconsistent pearls are created in one out Loot of 195.3 g (97% of theory) with an average diameter of 0.62 ⁇ 0.2 mm and a degree of swelling of 79% in water.
  • a hydroxy substituted monomer e.g. 2-hydroxyethyl methacrylate (HEMA)
  • HEMA 2-hydroxyethyl methacrylate
  • a gelatinous hydroxide e.g. Magnesium hydroxide
  • a macromeric crosslinking agent is required to make round beads.
  • a smooth-walled 1000 ml plastic flask is equipped with a return flow cooler, nitrogen inlet tube, thermometer, which is connected to a temperature controller, a separating grille and an anchor-like stirrer, which is driven by an adjustable motor.
  • a fully reacted mixture consisting of 20% by weight of a poly-n-butylene oxide glycol (MW 2000), which has been reacted with 2 moles of isophorone diisocyanate, and then finally saturated with 2 moles of 4-hydroxybutyl vinyl ether and 80% -% of a monomeric mixture, such as given in the table, in which 0.065 g of tert-butyl peroctoate has been dissolved as the initial catalyst.
  • the temperature is kept at 85 ° for three hours, with constant at 150 revolutions / min. stirred under a nitrogen atmosphere. After 3 hours, the temperature is raised to 100 ° for 1 hour, after which time the flask is cooled to room temperature. 5 ml of conc.
  • Example b) leads to an aggregation.
  • NVP N-vinyl-2-pyrrolidone
  • a terminal vinyl ether macromere is used as the macromer.
  • a smooth-walled 1000 ml 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 cheese cloth (fine mesh) as described above, washed with 2 l of water and soaked in 500 ml of ethanol overnight to add the remaining monomers. ex t ra - here.
  • the beads are filtered and dried as described in the previous examples. 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 (DS pH 1) and 51.1% at pH 8.

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  • Chemical & Material Sciences (AREA)
  • 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)
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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AT (1) AT366066B (fr)
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0317138A3 (fr) * 1987-11-17 1990-09-12 Rohm And Haas Company Compositions polymères superabsorbantes et procédé de leur préparation
WO1998036006A1 (fr) * 1997-02-14 1998-08-20 Essilor International Compagnie Generale D'optique 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
WO2003077964A1 (fr) * 2002-03-11 2003-09-25 First Water Limited Hydrogels absorbants
EP1664168A4 (fr) * 2003-08-29 2006-09-13 Mayo Foundation Agents porogenes a base d'hydrogel permettant de fabriquer des ossatures biodegradables
US8912247B2 (en) 2005-04-29 2014-12-16 Mayo Foundation For Medical Education And Research Hydrophilic/hydrophobic polymer networks based on poly(caprolactone fumarate), poly(ethylene glycol fumarate), and copolymers thereof
US9255178B2 (en) 2004-11-12 2016-02-09 Mayo Foundation For Medical Education And Research Photocrosslinkable poly (caprolactone fumarate)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330614B1 (fr) * 1988-02-26 1997-06-04 Novartis AG Polymère avec gonflabilité, perméable à l'oxygène, flexible, mouillable, avec tronc à unités polyoxyalkylène, et lentille de contact
DE69031894T2 (de) * 1989-03-23 1998-09-03 Nippon Catalytic Chem Ind Beschichtungszusammensetzung enthaltend vernetzte kugel- förmige Teilchen

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2801992A (en) * 1953-08-19 1957-08-06 Distillers Co Yeast Ltd Suspension stabilizer of magnesium hydroxide and excess alkali
FR2276063A1 (fr) * 1974-06-27 1976-01-23 Ciba Geigy Ag Nouveaux copolymeres hydrophiles insolubles dans l'eau

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2801992A (en) * 1953-08-19 1957-08-06 Distillers Co Yeast Ltd Suspension stabilizer of magnesium hydroxide and excess alkali
FR2276063A1 (fr) * 1974-06-27 1976-01-23 Ciba Geigy Ag Nouveaux copolymeres hydrophiles insolubles dans l'eau

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0317138A3 (fr) * 1987-11-17 1990-09-12 Rohm And Haas Company Compositions polymères superabsorbantes et procédé de leur préparation
WO1998036006A1 (fr) * 1997-02-14 1998-08-20 Essilor International Compagnie Generale D'optique 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
FR2759702A1 (fr) * 1997-02-14 1998-08-21 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
US6177507B1 (en) 1997-02-14 2001-01-23 Essilor International Compagnie Generale D'optique Polymerizable compositions comprising a urethane oligomer as crosslinking agent, polymers and hydrated polymers obtained from these compositions, and finished and semi-finished articles formed using these polymers
WO2003077964A1 (fr) * 2002-03-11 2003-09-25 First Water Limited Hydrogels absorbants
EP1664168A4 (fr) * 2003-08-29 2006-09-13 Mayo Foundation Agents porogenes a base d'hydrogel permettant de fabriquer des ossatures biodegradables
AU2004268013B2 (en) * 2003-08-29 2011-05-12 Mayo Foundation For Medical Education And Research Hydrogel porogens for fabricating biodegradable scaffolds
US9255178B2 (en) 2004-11-12 2016-02-09 Mayo Foundation For Medical Education And Research Photocrosslinkable poly (caprolactone fumarate)
US10717813B2 (en) 2004-11-12 2020-07-21 Mayo Foundation For Medical Education And Research Photocrosslinkable poly(caprolactone fumarate)
US8912247B2 (en) 2005-04-29 2014-12-16 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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AT366066B (de) 1982-03-10
DE2862045D1 (en) 1982-11-11
ATA523278A (de) 1981-07-15
JPS614401B2 (fr) 1986-02-10
JPS5440891A (en) 1979-03-31
DK149002B (da) 1985-12-16
DK322778A (da) 1979-01-21
DK149002C (da) 1986-08-25
EP0000507B1 (fr) 1982-09-29
CA1136317A (fr) 1982-11-23

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