EP0000507A1 - Process for the production of hydrogels in the form of spherically shaped beads with larger diameters - Google Patents

Abstract

1. A process for producing essentially uniform spherical beads of up to 5 mm diameter of a cross-linked, 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.

Description

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. Significantly, 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. These compounds mentioned are used as polymers, inert carriers for active substances, which are released slowly and controllably by these carriers. Such substances can include drugs (U.S. Pat. Nos. 3,574,826; 3,577,512; 3,551,556; 3,520,949; 3,576,760; 3,641,237; 3,660,563); Agrochemicals (US Patent No. 3,576,760) or flavors (US patent _N os Letters Patent No. 3,567,118;. 3,697,643) to be. The use of these hydrogels for the production of anti-fog layers in a moist environment, body implants and dressings have been described in the US patents Nos. 3,577,516; 3,695,921; 3,512,183 and 3,674,901. The widely used soft contact lenses are also made from this material in accordance with US Patents Nos. 3,488,111 and 3,660,545.

The main interest in the pharmaceutical sector is the slow and controllable release of drugs. 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.

pie use of drug-containing hydrogel granules in oral application form is included in the U. _S. patent No. 3,551,556 has been proposed. Indeed, this application is one of the most useful in medicine because it enables the oral drug to be delivered into the blood in an easily reproducible manner over a period of several hours. This application eliminates the wasteful and potentially dangerous concentration peaks in the blood and extends the maintenance of a preferred and effective drug level in the blood.

• 1. Die eine Methode besteht in der Aufteilung in Würfeln und Granulaten einer Hydrogelfolie, die auf konventionelle Weise gegossen worden ist und in der Aussiebung nach brauchbaren Teilchengrössen. Diese Methode weist verschiedene Nachteile auf.
  • a) z.B. verkörpert diese Methode eine zeitversehwendende Massenpolymerisation grcsser Mengen von Ausgangsmaterial in Form relativ dünner Folien und
  • b) die Endprodukte bestehen aus gezackten (oder mit Zacken versehenen), rauhen Teilchen mit grosser Oberfläche und scharfen Kanten, die nicht nur vom ästhetischen Standpunkt aus als anstössig zu bezeichnen sind, sondern auch als ungeeignet für die kontrollierte Freigabe von Arzneimitteln, da diese von einer gleichförmigen Diffusionsrate und hiermit auch von einer gleichförmigen Teilchengestaltung mit einer wohl-definierten Cberfläche und Volumen abhängt.
• 2. Die zweite Methode zur Herstellung von Hydrogcigranulaten, welche Übrigens die weitaus überlecenere Methode ist, erfolgt durch Polymerisation in Suspension. Die Polymerisation in Suspension wird ausgeführt, indem man eine flüssige monomere Phase in einem nicht lösenden Mittel unter starkem Rühren (nicht mischbar) und mit Hilfe eines Schutzkolloides als Stabilisator suspendiert und die erhaltene gerührte Suspension auf konventionelle Weise polymerisiert. Die Polymerisation wird durch Wärme induziert oder mit Hilfe von freien Radikalen katalytisch induziert. Diese Methode ergibt einheitlich geformte kugelförmige Perlen in einem einstufigen Verfahren und wird mehrheitlich bei der Herstellung von Polystyrolen, Polyvinylchloriden, Polyacrylaten und Polyvinylacetaten verwendet. Eine gute Zusammenfassung des gegenwärtigen Standes der Technik wird durch die von E. Farber verfasste Encyclopedie der Polymerwissenschaften und -technologie, Vol. 13, Seiten 552-571 (1970), Interscience, New York, wiedergegeben. Die relevanten Lehren sind an Hand von Referenzen aufgenommen worden. Im Falle von wasserlöslichen Monomeren, die für die Herstellung von Hydrogelen, wie z.B. 2-Hydroxyäthylmethacrylaten und N-Vinylpyrrolidon verwendet werden, benutzt man als nicht-lösliches Medium üblicherweise eine organische Flüssigkeit oder eine wässrige Salzlösung.

There are two methods for the production of hydrogel granules.

• 1. One method consists of dividing into cubes and granules of a hydrogel film that has been cast in a conventional manner and sieving for usable particle sizes. This method has several disadvantages.
  • a) for example, this method embodies a time-consuming mass polymerization of large amounts of starting material in the form of relatively thin films and
  • b) the end products consist of jagged (or jagged), rough particles with a large surface and sharp edges, which are not only to be described as objectionable from an aesthetic point of view, but also as unsuitable for the controlled release of medicinal products, since these are from a uniform diffusion rate and thus also depends on a uniform particle design with a well-defined surface and volume.
• 2. The second method for the production of Hydrogcigranulate, which by the way is the much more exuberant method, is carried out by polymerization in suspension. The Polymerization in suspension is carried out by suspending a liquid monomer phase in a non-solvent with vigorous stirring (immiscible) 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 by heat or catalytically induced 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. A good summary of the current state of the art is given by E. Farber's Encyclopedie of Polymer Science and Technology, Vol. 13, pages 552-571 (1970), Interscience, New York. The relevant teachings have been included on the basis of references. In the case of water-soluble monomers which are used for the preparation of hydrogels, such as, for example, 2-hydroxyethyl methacrylates and N-vinylpyrrolidone, an organic liquid or an aqueous salt solution is usually used as the insoluble medium.

In U.S. Patent 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 manufacture 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 polymerization in suspensions of a 2-hydroxyethyl methacrylate have Silicone oil or an organic medium such as mineral oil or xylene as an insoluble (immiscible) phase (US Pat. Nos. 3,567,118; 3,574,826; 3,575,123; 3,577,518; 3,578,822; 3,583,957). These processes 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 has been described in U.S. Pat. Patent No. 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 well known in the art that certain water soluble polymers such as e.g. Polyvinylpyrrolidones and hydroxyethyl celluloses are excellent suspending agents for polymerization in suspension. It is also known that certain poorly soluble inorganic compounds such as e.g. 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 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.

While the excess of alkali and free hydroxyl ions caused by the excess of alkali ions (high pH) does not cause any harmful side reactions in some suspension polymerization systems, there are still many vinyl monomers, e.g. Acrylic acid esters, vinyl acetates and the like, which are subject to unwanted base catalyzed hydrolysis in such a high pH system. Certainly, it is preferred to polymerize such vinyl monomers under optionally neutral conditions and not under those described in U.S. Pat. Patent No. 2,801,992 specified conditions.

When using water-soluble polymers as suspending agents, it was found that the hydrogel granules were of a very irregular shape and a very porous surface.

However, 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 same applies to the inorganic suspension medium, but there is also an additional accumulation. Of all 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. In contrast to the aforementioned, in the presence of macromeric crosslinking agents, as described in this invention, regular, uniform spherical beads with a soft surface up to a size of 5 mm in diameter are obtained.

In the course of these investigations, it was unexpectedly found that the simultaneous presence of at least 5 percent by weight of 2-hydroxymethacrylate (HEMA) or another hydroxy-substituted vinyl monomer and at least 5 percent by weight of a diolefinic macromeric crosslinking agent in the polymerization mixture and in the presence of insoluble gelatinous Metal hydroxide in the absence of excess alkali or free hydroxyl ions in the aqueous suspension medium, which allows the production of uniform spherical beads up to a diameter of 5 mm. The suspension medium is an aqueous salt that dissolves HEMA up to a maximum of 10%. The particle size can also be easily controlled by stirring. Slower stirring speeds result in large pearls, higher (higher) stirring speeds in small pearls.

Although the present process can be modified by very rapid stirring to obtain small beads (<0.3 mm), no other process is known for uniformly obtaining beads larger than 0.3 mm in diameter than the one according to the invention. The preferred pearl sizes for controllable delivery of oral medications are between 0.6 mm and 1.5 mm. Some hydrogel compositions of this invention are Subject of the still pending US patent application Ser. No. 581.065.

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.

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. Each of the three components mentioned unexpectedly turned out to be necessary for the production of beads up to 5 mm in size.

The present invention relates in particular to an improved process for the production of essentially. Lichen uniform, spherical beads up to the size of 5 mm in diameter, consisting of a cross-linked, water-insoluble hydrogel, which by polymerization in suspension from (A) 95-30% by weight of the hydrogel from a water-soluble monoolefinic monomer or a mixture of these water-soluble monomers, and from 0-70% by weight based on the total amount of the macromers of water-insoluble monoolefinic monomers or a mixture of these water-insoluble monomers, with the proviso that the final hydrogel contains no more than 60% by weight of the water-insoluble monomeric compound, with (B) 5 to 70% by weight of the hydrogel of a polyolefinic crosslinking agent in the presence of a polymerization initiator in a concentrated aqueous inorganic salt solution, the improvement being that the polymerization is carried out in suspension with a monoolefinic monomer which is at least 5% by weight of the total monomer Contains hydroxy-substituted hydrophilic vinyl monomers, using a polyolefinic macromer with a molecular weight of 400-8000 as the crosslinking agent. Furthermore, 0.01-5% by weight, based on the hydrogel, of 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.

In this process, 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.

worin m 2 bis 5 und n 1 bis 20 bedeuten, oder Ester von analogen Alkoholen, in denen ein Teil der Aethylenoxid-Einheit durch Propylenoxid-Einheiten ersetzt ist. Ferner sind geeignete Ester beispielsweise die 3-(Dimethylamino)-2-hydroxypropylester.Another group of water-soluble hydroxy-substituted 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.

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 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.

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 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.

Furthermore, 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-vinylpiperidine, 2- and 4-vinylquinoline, 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- (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.

It is known, when using N-vinyl-2-pyrrolidone or any other water-soluble monomer without a hydroxyl group, that a second monomer with a hydroxyl group must be used in the present process.

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.

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 R₁ eine Polykondensatkette mit einem Molekulargewicht von ungefähr 200 bis 8000 bedeutet, die Kohlenwasserstoffreste enthält, die durch Aether-, 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, Z₁ ist Oxo oder -NR₅, Z₂ ist Z₁ 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 terminal polyolefinic, crosslinking macromers (B), the olefinic part is preferably an acyl radical of a lower α, β-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 emäss 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 radical having up to 7 carbon atoms, Z ₁ is oxo or -NR ₅ , Z ₂ is Z ₁ or a sulfur atom and R ₇ is the divalent radical of an aliphatic, alicyclic or aromatic diisocyanate with the condition that when X Oxo means 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 ₁ and B ₂ , 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. Compounds of the formula B _1, wherein Y is a direct bond, diesters of macromolecular diols in which two hydroxyl groups on the polycondensate R ₁ in opposite terminated or almost terminated positions are bonded, with α, β-unsaturated acids. Such diesters 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 . In these compounds, 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 .

According to the definition of 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-naphthylene, 1,8-dinitro-2,7-naphthylene, 4 , 4'-diphenylene, 3,3'-dichloro-4,4'-diphenylene, 3,3'-dimethoxy-4,4'-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 _{1 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 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.

More generally, 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.

oder

worin R₈ eine gerade oder verzweigte Alkylenkette mit 1-7 C-Atomen oder eine

Gruppe, 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 macromers (B ₁ ) are those in which 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.

These 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.

worin R₂, R₃, X, R₆ und Z₁ die'oben angegebenen Bedeutungen für B₁ haben.Compounds of the formula B ₁ , in which Y is a divalent radical -R ₆ Z ₁ CONHR ₇ -NH-CO-Z ₂ -, are obtained in a 2-stage reaction, first of all macromolecular diols or diamines, for example compounds which 2 hydroxyl or amino groups on the polycondensate chain have, R ₁ 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 ₆ and Z _{1 have the} meanings given above for B ₁ .

When X is oxygen, then (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. For example, 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.

In the following synthesis, 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. 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 peroctoate, benzoyl peroxide, decanoyl peroxide, lauroyl peroxide, succinic acid peroxide, methyl ethyl ketone peroxide, tert-butyl peroxyacetate, propionyl peroxide, 2,4-dichloro- benzoylpero, eroxide, tert-butyl peroxypivalate, pelargonyl peroxide, 2,5-dimethyl-2,5-bis (2-ethylhexanoyl-peroxy) -hexane, p-chlorobenzoyl peroxide, tert-butyl peroxy butyrate, tert-butyl peroxymaleic acid, tert-butyl -peroxyisopropyl carbonate, bis- (1-hydroxycyclohexyl) 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 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. 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 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. 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. For example, 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. In theory, 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. 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 ratio of the aqueous phase to the monomer-macromere phase varies in volume terms 2: 1 and 15: 1. For a polymer with a high degree of swelling, 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. Such a metal hydroxide salt is, for example, aluminum hydroxychloride or magnesium hydroxychloride. The exact structure of a water-insoluble gelatinous precipitate produced in this way cannot be determined exactly, but compounds of this type can be used extremely effectively as suspension stabilizers.

It is important that the 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.

It appears that the strong overlap of the hydrogen bond between the hydroxy group of HEMA, water and the hydroxyl group of the hydroxide is responsible for this stabilizing effect.

The choice of the metal hydroxide is only decided according to whether a voluminous, gelatinous precipitate can precipitate in the aqueous medium or not. For example, 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.

The 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.). Generally applicable are magnesium chloride, magnesium sulfate and aluminum sulfate, or any other source that gives magnesium ⁺⁺ or aluminum ⁺⁺⁺ ions.

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.

The following examples are presented for the purposes of illustration only and are in no way intended to limit the scope of the present invention.

example 1

A smooth-walled plastic 1000 ml flask provided with a reflux condenser, Stickstoffeinleitröhrchen, 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.

360 g of a 20% (weight percent) 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 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

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

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} ).

Examples 2 to 4

The same procedure as described in Example 1 is used, but the ratio of the monomer (A) to the macromer (B) is changed.

It appears that with the same reaction conditions, as the amount of macromers (B) increases, the average size of the beads also increases and the degree of swelling (DS _{H 0} ) decreases.

Examples 5 to 13

Using the same procedure as described in Example 1, but with different stirring speeds and using different mixtures of HEMA and N-vinylpyrrolidone (NVP) as monomer (A) with the macromers (B), hydrogel beads are obtained as described below:

An increase in the amount of NVP in the hydrogel causes an increase in the degree of swelling while maintaining all other polymerization conditions.

Even if you enter the compositions of Examples 1, 6, 8 and 13 in the form of a triangle on graph paper, the individual coordinates being entered as% -NVP,% -HEMA and% Maeromer, you get a straight line, which is a composition of the same degree of swelling. The same group of examples also indicates that an increase in NVP content also results in an increase in the average size of the pearls.

Examples 14 to 19

Using the same procedure as described in Example 1, but using differently substituted macromers (B) derived from polytetramethylene oxide glycols which are terminally saturated with isophorone diisocyanate (IPDI), hydrogel beads are obtained as follows Properties:

Example 20

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

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.

Example 21

Using the same procedure as described in Example 1, 0.2 g of azobisisobutyronitrile is used instead of tert-butyl peroctate as an initial catalyst for the peroxy-catalysis.

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.

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 DS _PH3 of 83.2% and DS _PH8 of 71.1%.

Example 22

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%

Example 23

Aethoxyeinheiten enthält, löst. Man erhält einheitliche runde Perlen mit einem Durchschnittsdurchmesser von 0.72 mm und einem Quellungsgrad (DS_H2O)von 272 %_. 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% _.

Example 24

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 g of a mixture of 40% polytetramethylene oxide glycol (MW 2000), finally saturated with 2 moles of isophorone diisocyanate , and 60% _. 2-hydroxyethyl methacrylate and receives 18C g (85% of theory) of uniform round beads with a diameter of 1.10 mm and a degree of swelling (DS _{H 2nd O} ) of 32%

Example 25

The general procedure is as described in Example 1, but the monomer (A) -macromere (B) mixture has been replaced.

erhältlich von Dow Corning als Q 4-3557, endständig abgesättigt mit Isophorondiisocyanat in 89,2 g 2-Hydroxyäthyl- methacrylat und 30.8 g N-Vinylpyrrolidon, löst.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.

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 _{H are obtained 2nd O} of 39.8%. 2nd

Example 26

In a manner analogous 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.

It forms a fine, gelatinous Precipitation of magnesium hydroxide with the addition of 123 ml of 1N sodium hydroxide solution with vigorous stirring.

y + y' = 26 erhältlich von Dow Corning als Q 4-3667, endständig abgesättigt mit Isophorondiisocyanat, in 107.5 g 2-Hydroxyäthylmethacrylat löst.The monomer (A) -macromere (B) mixture used in this example is prepared by adding 107.5 g of polydimethylsiloxane diol of the formula

y + y '= 26 available from Dow Corning as Q 4-3667, terminally saturated 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 _{H 0} of 28.1%. 2nd

Examples 27-31

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:

In order to reduce the hydrolysis of 2-hydroxyethyl methacrylate and other similar acrylic acid esters as monomers as far as possible, it is desirable to carry out the suspension polymerization in a pH which is as neutral as possible (at least in the vicinity of the neutral range) by using no more alkali lye than for the preparation and precipitation of the metal hydroxide or metal hydroxide salt is necessary.

In example 1 with magnesium chloride, 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.

Example 31 a

Aluminum ions can also be used to instantly produce hydrogel beads. In Example 30, 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.

In another experiment, 5% excess (measured stoichiometrically) of sodium hydroxide solution to aluminum precipitate minium hydroxide as a precipitate, a pH of 10.5 is obtained during the polymerization in suspension, decidedly too alkaline, so that the risk of ester saponification of the monomer occurs as a side reaction.

Example 32

If the water-insoluble, gelatinous, strongly water-binding inorganic hydroxides used in 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 33

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.

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 34

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. 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.

Examples 35 to 41

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.

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

Examples 42 to 46

Einheitliche, kugelförmige Hydrogelperlen werden in jedem Fall erhalten (Ausbeuten: 96 - 97% d.Th.)The process is carried out as described in Example 1, but using a different salt instead of sodium chloride for the polymerization in the aqueous medium. The effect of the salts on the average size of the pearls and the degree of swelling in water can be seen in the table below.

Uniform, spherical hydrogel beads are obtained in each case (yields: 96 - 97% of theory)

Examples 47 to 49

Beispiele, in denen als Vernetzungsmittel niedermolekulare Verbindungen verwendet werden.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 50

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.

Small, non-uniform beads are formed in a yield of 190.8 g (95% of theory) with an average diameter of 0.48 ± 0.2 mm and a degree of swelling of 78% in water.

Example 51

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.

The following example shows that the combination of a hydroxy substituted monomer, e.g. 2-hydroxyethyl methacrylate (HEMA) with a gelatinous hydroxide, e.g. Magnesium hydroxide, and a macromeric crosslinking agent is required to make round beads.

Example 52 (a to c)

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.

180 ml of a 20% aqueous sodium chloride solution and 12.5 g of magnesium chloride hexahydrate are placed in the flask. The solution is slowly warmed to 85 ° and 62 ml of a 1N sodium hydroxide solution are added dropwise with vigorous stirring. A slow stream of nitrogen flows through the flask. After adding the total amount of sodium hydroxide solution, the stirring speed is increased to 150 revolutions / min. reduced and 100 g of 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. Add hydrochloric acid to dissolve the magnesium hydroxide. The contents of the flask are filtered through a fine-mesh cheese cloth, washed with 2 liters of water and immersed in 500 ml of ethanol overnight to remove remaining monomers. The beads are separated by filtration with a sack made of polyester cloth which is sewn in, and the sack is dried in a tumble dryer.

Nur die Beispiele a) und c) ergeben Perlen; Beispiel b) führt zu einer Zusammenballung.

Only examples a) and c) produce pearls; Example b) leads to an aggregation.

HEMA: 2-hydroxyethyl methacrylate

MMA: methyl methacrylate

NVP: N-vinyl-2-pyrrolidone

A terminal vinyl ether macromere is used as the macromer.

Example 53

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.

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 196 g of a fully reacted 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 peroctate were added as an initial catalyst. The temperature is kept at 80 ° for three hours, with constant 15C 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 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.

Claims (18)

1. An improved process for the production of substantially uniform, spherical beads up to a size of 5 mm in diameter, consisting of a crosslinked, water-insoluble hydrogel, which by polymerization in suspension from (A) 95-30% by weight of the hydrogel from a water-soluble monoolefinic monomers or a mixture of these water-soluble monomers and from 0-70% by weight, based on the total amount of monomers, of water-insoluble monomers, with the proviso that the final hydrogel contains no more than 60% by weight of the water-insoluble monomeric compound , with (B) 5 to 70% by weight of the hydrogel of a polyolefinic crosslinking agent, in the presence of a polymerization initiator in a concentrated, aqueous inorganic salt solution, characterized in that the improvement consists in that the polymerization is carried out in suspension with a mono- olefinic monomers, which carries at least 5% by weight of the Contains total monomers of a hydroxy-substituted hydrophilic vinyl monomer, with a polyolefinic macromer with a molecular weight of 400-8000 as the crosslinking agent and 0.01-5% by weight as the suspending agent based on the hydrogel, of water-insoluble, gelatinous, strongly water-binding, inorganic metal hydroxides or Metal hydroxide salts used in the absence of excess alkali or free hydroxyl ions. 2. The method according to claim 1, characterized in that a monoolefinic, monocyclic, azacyclic compound is used as the water-soluble monomer. 3. Process according to Claims 1 and 2, characterized in that a hydroxyalkyl ester of acrylic or methacrylic acid is used as the water-soluble monomer, in which the alkyl radical contains 2-4 carbon atoms. 4. Process according to Claims 1 to 3, characterized in that the water-soluble monomers are acrylic acid or methacrylic acid esters, which are derived from an alcohol of the formula

where R is hydrogen or methyl, m is an integer from 2-5 and n is a number from 1-20. 5. Process according to claims 1 and 2, characterized in that an N-substituted amide or imide of acrylic or methacrylic acid, in which the N-substituent is a hydroxyalkyl group with 2-4 C atoms in the alkyl radical, is used as the water-soluble monomer, used. 6. Process according to Claims 1 and 2, characterized in that the water-soluble monomers are acrylic acid, methacrylic acid, 2-hydroxyethyl or 2- or 3-hydroxypropyl acrylate or methacrylate, 2,3-dihydroxypropyl acrylate, 2,3-dihydroxypropyl methacrylate, N- Vinyl or tert-amino methacrylamide used. 7. The method according to claims 1, 2 and 6, characterized in that 2-hydroxyethyl methacrylate or N-vinyl-2-pyrrolidone is used as the water-soluble monomer. 8. The method according to claim 1, characterized in that a vinyl ester of a carboxylic acid having 2-7 C atoms is used as the water-insoluble monomer. 9. The method according to claim 1, characterized in that a vinyl alkyl ether, wherein the alkyl radical has 1-5 carbon atoms, is used as the water-insoluble monomer. 10. The method according to claim 1, characterized in that acrylonitrate or styrene is used as the water-insoluble monomer. 11. The method according to claim 1, characterized in that the macromeric compounds B ₁ or B _{2 of} the formulas

or

where a is 1 or 2 and R _{1 is} a polycondensate chain with a molecular weight of approximately 200 to 8000, the hydrocarbon radicals contain 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, C00- 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 - means in which R _{6 is} bound to X and denotes a branched or straight-chain alkylene radical having up to 7 C atoms, Z ₁ and Z ₂ is oxo or -NR ₅ ; Z ₂ is Z ₁ 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. 12. The method according to claims 1 and 11, characterized in that a macromer in which R _{1 is} a polyethylene oxide, polypropylene oxide, polytetramethylene oxide chain with a molecular weight of about 600 to about 4000, or wherein R _{1 is} a by condensation of an aliphatic or carbocyclic, aromatic dicarboxylic acid or a diisocyanate with an aliphatic diol or diamine-containing chain. 13. The method according to claims 1 and 11, characterized in that a macromer in which R _{1 is} a polysiloxane chain of the formulas

or

wherein R _{8 is} a straight or branched alkylene chain with 1-7 C atoms or one

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. 14. The method according to claims 1 and 11, characterized in that the macromer is a polytetramethylene oxide glycol with a mol weight of about 600 to about 4000, end saturated with 2,4-toluenediisocyanate or isophorone diisocyanate and with 2 mol of a hydroxyacrylate or methacrylate reacted with 2-4 C atoms in the alkyl radical, used. 15. The method according to claims 1, 11 and 14, characterized in that the macromer is a polytetramethylene oxide glycol with a mol weight of about 1500 to about 3000, end-saturated with 2,4-toluenediisocyanate and reacted with about 2 mol of 2- Hydroxyethyl methacrylate used. 16. The method according to claim 1, characterized in that a water-insoluble, gelatinous metal hydroxide or metal hydroxide salt of magnesium, aluminum, zirconium, iron, nickel, chromium, zinc, lead, calcium, cobalt, copper, is used as the suspending agent. Zinc, gallium, manganese, strontium, barium, uranium, titan, lanthanum, thor or cer. 17. The method according to claims 1 and 16, characterized in that magnesium hydroxide, aluminum hydroxide, magnesium hydroxy salt or aluminum hydroxy salt is used as the suspending agent. 18. The method according to claims 1 to 17, characterized in that peroxy or alkyl radical-releasing catalysts are used as free radical-forming catalysts.