EP0000507B1 - Process for the production of hydrogels in the form of spherically shaped beads with larger diameters - Google Patents

Description

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. Significantly, 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). The use of these hydrogels for the preparation of anti-fog layers in a moist environment, body implants and wound dressings have been described in US-A-3,577,516, 3,695,921, 3512183 and 3,674,901. The widely used soft contact lenses are also made from this material in accordance with US Pat. Nos. 3,488,111 and 3,660,545.

The use of drug-containing hydrogel granules in oral application form has already been proposed in US-A-3,551,556.

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 Polymerwissenschaften und -technologie, Vol. 13, pages 552-571 (1970 ), Interscience, New York).

US Pat. No. 3,390,050 describes the polymerization in suspension of water-soluble monomers in the presence of large amounts of active ingredients. However, this method is unsuitable for the production of hydrogel beads for drugs to be administered orally, since it is impossible to purify the polymer obtained without leaching out the drug.

Most references to a polymerization in suspension of a 2-hydroxyethyl methacrylate point to silicone oil or an organic medium such as e.g. B. mineral oil or xylene as the insoluble phase (US-A-: 3,567,118, 3,674,826, 3,575,123, 3,577,518, 3,678,822, 3,583,957). These methods generally result in particles with very irregular, unfinished porous surfaces that are unsuitable for use in which diffusion plays a role as a working mechanism rather than adsorption and desorption. In addition to these factors, processing the polymer on an industrial scale would also pose a problem.

The polymerization of 2-hydroxyethyl methacrylate (HEMA) in suspension in the presence of 0.5-2% of short chain crosslinking agents (a compound commonly called "hydron") using an aqueous salt solution as the medium is described in US-A - 3,689,634, but 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.

However, it is known that certain water-soluble polymers, such as. B. polyvinylpyrrolidones and hydroxyethyl celluloses are excellent suspending agents for polymerization in suspension. It is also known that 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.

The use of 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.

While the excess of alkali and free hydroxyl ions does not cause harmful side reactions in some suspension polymerization systems, there are still many vinyl monomers, such as. As acrylic acid esters, vinyl acetates and the like, which are subject to undesirable base-catalyzed hydrolysis in such a high pH system.

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. As 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. 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.

When using inorganic substances or water-soluble polymers as suspending agents, it was found that the 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.

It has now been found that surprisingly useful beads are obtained with the aid of a production process which largely corresponds to that of FR-A 2 276 063, but with the use of very specific suspending agents. Uniform, spherical hydrogel beads up to a size of 5 mm in diameter are obtained by the process according to the invention. These are suitable for a number of pharmaceutical and industrial uses.

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 % By weight of 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.

As already indicated, the starting materials are known from FR-A-2 276 063.

worin m 2 bis 5 und n 1 bis 20 bedeuten, oder Ester von analogen Alkoholen, in denen ein Teil der Äthylenoxid-Einheit durch Propylenoxid-Einheiten ersetzt ist. Ferner sind geeignete Ester beispielsweise die 3-(Dimethylamino)-2-hydroxypro- pylester.The following are suitable as 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.

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.

Particularly valuable as water-soluble monomers are 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.

worin m 2 bis 5 und n 4 bis 20 bedeutet.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.

Furthermore, 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, 4-acrylic morpholine. Particularly noteworthy is the N-vinyl-2-pyrrolidone.

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.

Particularly valuable as 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.

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.

oder

worin a 1 oder 2 bedeutet und R, eine Polykondensatkette bedeutet, die Kohlenwasserstoffreste enthält, die durch Äther-, Ester-, Amid-, Urethan- oder Harnstoffreste gebunden sind, R₂ ist Wasserstoff, Methyl oder -CH₂COOR₄, worin R₄ Wasserstoff oder eine Alkylgruppe mit 1 bis zu 10 C-Atomen bedeutet, R₃ ist Wasserstoff oder -COOR₄ mit der Bedingung, dass mindestens einer der Reste R₂ oder R₃ Wasserstoff ist, X ist Oxo, -COO- oder -CONR₅-, worin R₅ Wasserstoff oder Alkyl mit bis zu 5 C-Atomen ist und Y eine direkte Bindung oder den Rest -R₆-Z₁-CO-NH-R₇-NH-CO-Z₂- bedeutet, worin R₆ an X gebunden ist und einen verzweigten oder geradkettigen Alkylenrest mit bis zu 7 C-Atomen bedeutet, Z, ist Oxo oder -NR_S, Z₂ ist Z_I oder ein Schwefelatom und R₇ ist der zweiwertige Rest eines aliphatischen, alicyclischen oder aromatischen Diisocyanats mit der Bedingung, dass wenn X Oxo bedeutet, Y keine direkte Bindung ist und R₂ und R₃ Wasserstoff bedeuten. Das Symbol a bedeutet vorzugsweise 1.In the terminally diolefinic, crosslinking macromolecular compounds (B), the olefinic part is preferably an acyl radical of a lower a, β-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. Accordingly, 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 , Z ₂ is Z _I or a sulfur atom and R ₇ is the divalent radical of an aliphatic, alicyclic or aromatic Diisocyanate with the condition that when X is oxo, Y is not a direct bond and R ₂ and R _{3 are} hydrogen. The symbol a preferably means 1.

In the compounds of the formulas B and B ₂ , 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. Compounds of the formula B _1, wherein Y is a direct bond, are diesters of macromolecular diols in which two hydroxyl groups on the polycondensate R, in opposite terminated or almost terminated positions are bonded, with a, β-unsaturated acids. Such 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 . In these compounds R, e.g. B. be one of the macromolecular polycondensate chains, which are mentioned as components of the compounds according to formula B.

According to the definition of formula B ₁ , Y can also mean a divalent radical -R ₆ -Z ₁ -CONH-R ₇ -NH-CO-Z ₁ . In it R ₆ z. B. 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-1,3- and 7-methyl-1,3-naphthylene, 1,8-dinitro-2,7-naphthylene, 4,4'-diphenylene, 3,3 '-Dichloro-4,4'-diphenylene,3,3'-dimethoxy-, 4, '- diphenylene, 2,2'-dimethyl- and 3,3'-dimethyl-4,4'-diphenylene, 2, 2'-dichloro-5,5'-dimethoxy-4,4'-diphenylene, methylene-di-p-phenylene, methylene-bis- (3-chlorophenylene), ethylenedi-p-phenylene or hydroxydiphenylene.

If the symbol Y in the formula part B is not a direct bond, R ₆ must always be connected to X.

There are, therefore, compounds of the formula B _1, wherein Y is the divalent radical mentioned Bisvinyläther when X is oxygen, or bis-acrylates, bis-methacrylate, bis-maleate, bis-fumarate and bis-itaconate when X is -COO -or -CONR ₅ .

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. (Block ethylene oxide-co-propylene oxide) diols with a 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 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.

Likewise suitable are 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.

oder

worin R₈ eine gerade oder verzweigte Alkylenkette mit 1-7 C-Atomen oder eine -(CH₂CHO)_n-Gruppe, R₉ worin n 1 bis 20 ist, R₉ Wasserstoff oder Methyl ist, bedeutet, und X eine Zahl von 3 bis 120 und Y 2 oder 3 bedeuten.Other preferred macromolecular compounds (B ₁ ) are those in which 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.

These 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.

worin R₂, R₃, X, R_e und Z₁ die oben angegebenen Bedeutungen für B₁ haben, reagieren lässt.Compounds of formula B _l, wherein Y is a bivalent radical -R ₈ Z ₁ CONHR ₇ -NH-CO-Z ₂ -bedeutet be obtained in a 2-stage reaction in which one first macromolecular diols or diamines, such as compounds which Have 2 hydroxyl or amino groups on the polycondensate chain, R, in the opposite end position or almost in the end position, with at least twice the molar amount of aliphatic, cycloaliphatic or aromatic diisocyanates which contain two isocyanate groups which are bonded to the radical R ₇ , and secondly the macromolecular diisocyanates thus obtained with a compound of the formula

wherein R ₂ , R ₃ , X, R _e and Z _{1 have} the meanings given above for B ₁ .

If X is oxygen, then (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.

Preferably, 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. These catalysts are preferably peroxide or azo catalysts which have a half-life of at least 20 minutes at the polymerization temperature. Examples of 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-bis-isobutyronitrile, 2,2'-azo-bis- (2,4-dimethylvaleronitrile), 1,1'-azo-bis- (cyclohexane carbonitrile), 2,2'- Azo-bis- (2,4-dimethyl-4-methoxyvaleronitrile).

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 above-mentioned monomers or polymeric compounds, catalysts and their quantitative ratios are all described in FR-A 2 276 063.

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. For a typical synthesis, 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. Low speeds lead to larger pearls and higher speeds lead to smaller pearls. 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.

Preferably, 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.

The 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.

Magnesium or aluminum hydroxide or magnesium hydroxy salt or aluminum hydroxy salt, such as the basic chlorides, are regarded as preferred suspending agents.

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.

In the following examples, the temperature degrees Celsius degrees and the percentages mean percentages by weight.

Example 1:

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.

360 g of a 20% aqueous sodium chloride solution and 23.0 g of solid magnesium chloride hexahydrate are placed in the flask. The solution is slowly heated to 80 ° with rapid stirring. 123 ml (0.123 mol) of a 1N sodium hydroxide solution are added dropwise to this solution, a fine, gelatinous precipitate of magnesium hydroxide being obtained in the reaction flask.

After the total amount of sodium hydroxide solution has been added, 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.

After this reaction time, the disappearance of the terminal isocyanate groups is demonstrated by the disappearance of the characteristic infrared spectral bands at 2270 cm '(characteristic of the isocyanate group).

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 ).

If the quantity ratio (B) to (A) is increased, the average size of the beads also increases and the degree of swelling in water decreases.

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.

Examples 3-8:

If one proceeds as described in Example 1, but using differently substituted macromolecular compounds (B) which are derived from polytetramethylene oxide glycols which are terminally saturated with isophorone diisocyanate (IPDI), the result is hydrogels with the following properties:

The procedure is the same as that described in Example 1, but 3.15 g (0.005 mol) of aluminum sulfate hexadecahydrate is used instead of the magnesium chloride hexahydrate and 31 ml (0.031 mol) of 1N sodium hydroxide solution are used as the suspending agent for the production of aluminum hydroxide.

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.

Example 10:

The procedure is the same as that described in Example 1, but 0.2 g of azobisisobutyronitrile is used instead of tert-butyl peroctoate as the initial catalyst for the peroxy-catalysis.

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.

193 g of uniform spherical beads (yield 96.5% of theory) with an average diameter of 1.02 ± 0.4 mm are obtained. The degree of swelling is pH-dependent, with the following values DSp _H3 of 83.2% and DSp _Hs of 71.1%.

Example 11:

If one proceeds as described in Example 1, but instead of using the 140g of 2-hydroxyethyl methacrylate a mixture of 40g of 2-hydroxyethyl methacrylate and 100g of 3-hydroxypropyl methacrylate, uniform spherical beads are obtained in a yield of 193 g (96.5% of theory) .Th.) With an average diameter of 1.02 ± 0.3mm and a degree of swelling in water of DS _H20 of 37.9%.

Example 12:

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%.

Example 13:

In an analogous manner to that described in Example 1, 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%.

Example 14:

The procedure is as described in Example 1, but the mixture (A) and (B) is replaced by 80 g of a polysiloxane polyol (Q 4-3557 from Dow Corning), finally saturated with isophorone diisocyanate, dissolved in 89.2 g of 2-hydroxyethyl methacrylate and 30 , 8g N-vinyl pyrrolidone.

192 g (yield 96% of theory) of uniform, spherical beads with an average diameter of 1.02 ± 0.4 mm and a degree of swelling DS _H2O of 39.8% are obtained.

Example 15:

In an analogous manner to that described in Example 1, 115 g of sodium chloride are dissolved in 310 g of water together with 25 g (0.247 equivalents) of magnesium chloride hexahydrate.

A gelatinous precipitate of magnesium hydroxide forms with the addition of 123 ml of 1N sodium hydroxide solution with vigorous stirring.

erhältlich von Dow Corning als Q 4-3667, endständig abgesättigt mit Isophorondiisocyanat, in 107,5g 2-Hydroxyäthylmethacrylat löst.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%.

Examples 16-20:

In an analogous manner to that described in Example 1, the following hydrogels are prepared using the same reactants with the exception of the metal hydroxides as suspending agents:

Examples 21-27:

The procedure is as described in Example 1 and a solution of 24 g of polytetramethylene oxide glycol of molecular weight 2000, finally saturated with isophorone diisocyanate, in 42 g of 2-hydroxyethyl methacrylate, 54 g of N-vinyl-2 is used to prepare hydrogel beads from a mixture (A) + (B) -pyrrolidone and 80g of one of the water-insoluble comonomers listed below.

The reactions all run smoothly and give beads with a degree of swelling and diameter, which can be described as average values.

Example 28:

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.

360 g of a 20% aqueous sodium chloride solution and 13.2 g of aluminum sulfate hexadecahydrate are placed in the flask. The solution is slowly warmed to 80 ° and 160 ml of 1N sodium hydroxide solution are added dropwise with vigorous stirring. A slow nitrogen flow is maintained in the piston. After adding all of the sodium hydroxide solution, the stirring speed is increased to 150 revolutions / min. reduced and 196g of a completely converted mixture consisting of 29.4% poly-n-butylene oxide (MW 2000), which is saturated with 2 moles of isophorone diisocyanate, 68.6% 2-hydroxyethyl methacrylate, 2% sodium styrene sulfonate, the 2 g water and 0 , 2 g of tert-butyl peroctoate were added as an initial catalyst. The temperature is kept at 80 ° for three hours, with constant at 150 revolutions / min. stirred under a nitrogen blanket. After 3 hours, the temperature is raised to 100 ° for 1 hour and the flask is then cooled to room temperature. 10 ml of conc. Add hydrochloric acid to dissolve the aluminum hydroxide. 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.

Claims (3)

1. A process for producing essentially uniform spherical beads of up to 5mm diameter of a crosslinked, waterinsoluble hydrogel by suspension polymerisation of (A) 95-30% by weight, relative to the hydrogel, of at least one watersoluble, monoolefinic monomer, which can be replaced to the extent of up to 70% by weight, relative to the total amount of the monomer, by at least one water-insoluble monomeric compound, the hydrogel containing at most 60% by weight of the water-insoluble monomeric compound, and at least 5% by weight of the total monomer consisting of a hydroxyl-substituted, hydrophilic vinyl monomer, with (B) 5 to 70% by weight, relative to the hydrogel, of a terminal diolefinic, crosslinking compound having a molecular weight of 400-8000, in the presence of a polymerisation catalyst in a concentrated, aqueous inorganic salt solution, and of a dispersing agent, and also by treatment of the hydrogel with an acid, characterised in that there is used, as dispersing agent, 0.01-5% by weight, based on the hydrogel, of at least one water-insoluble, gelatinous, water- binding, inorganic metal hydroxide or metal hydroxide salt in the absence of excess alkali or free hydroxyl ions.

2. A process according to Claim 1, characterized in that there is used, as dispersing agent, a water-insoluble, gelatinous metal hydroxide or metal hydroxide salt of magnesium, aluminium, zirconium, iron, nickel, chromium, zinc, lead, calcium, cobalt, copper, zinc, gallium, manganese, strontium, barium, uranium, titanium, lanthanum, thorium or cerium.

3. A process according to Claim 1, characterized in that there is used, as dispersing agent, magnesium hydroxide, aluminium hydroxide, magnesium hydroxide salt or aluminium hydroxide salt.