CA1136317A - Process for preparing hydrogels as spherical beads of large size - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The disclosure describes an improved process for the preparation of uniform, spherical beads of up to 5 mm diameter of a crosslinked, water-insoluble hydrogel by suspension polymerization in a concentrated aqueous salt solution of 95-30% by weight of a monoolefinic water-soluble monomer containing at least 5% of a hydroxy sub-stituted hydrophilic vinyl monomer with 5-70% by weight of a terminal diolefinic macromer crosslinking agent in the presence of water-insoluble, gelatinous, strong water-bonding inorganic metal hydroxides as suspending agents in the ab-sence of excess alkali. The hydrogels have a host of pharmaceutical and industrial uses.

Description

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-Background of the In~ention This invention pertains to an improved process for the preparation of uniform, spherical beads of up ~o 5 ~nm diameter of a crosslinked, water-insoluble hydrogel by suspension polymerization in a concentrated aqueous -salt solution of 95-30% by weight o~ a monoolefinic monomer containiny at least 5~ of a hydroxy substituted hydrophilic ~inyl monomer with 5-70% by weight of a terminal polyolefinic -macromer crosslinking agent in the presence of water-insoluble, gelatinous, strong water-bonding inorganic metal hydroxides as suspending agents in the absence of excess alkali. The hydrogels have a host of pharmaceutical and industrial uses. The spherical beads exhibit a degree of.swelling in water of from 5 to 200%.

~ ydrog21s have been described since 1956 (U.S. 2,976j~76) and subsequently a large number of patents have been issued describing the synthesis and use of hydrogels based primarily on 2-hydroxyethyl methacrylate and, to a lesser extent, on N-vinylpyrrolidone. Typically, these hydrogels are crosslinked, water-swellable polymers made by copolymerization of 2-hydroxyethyl methacrylate with a --small amount of ethylene or butylene dimethacrylate.
They are used as polymeric, inert carriers for active substances, which are slowly and controllably released . ' ~
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from these carriers; such active substances may be drugs (U.S. 3,57~,82~; 3,577,512; 3,551,556; 3,520,94gi 3,576,760;

3,641,237i 3,660,563)i agricultural chemicals (U.S. 3,576,760);
or fragrances (U.S. 3,567,11~i 3,697j643).

Their uses as antifogging coatings (U.S~ 3,488,215), body implants and bandages have also been described in U.S. 3,577,516i 3,695,921i 3,512,183i 3,674,901. The -wi.dely used soft contact lens consists of this material (U.S. 3,4~8,111; 3,660,545).

In ~he pharmaceutical field the main interest lies in the slow and controllable release of drugs from such hydrogels. Drug-containing hydrogel preparations have been described as being in the form of bandages;
subcutaneous i~plants; buccal devices, intrauterine devices, eye inserts. They are made by complicated fabrication procedures which usually involves casting the monomer solution into a suitable mold and polymeri~ing in the presence of a free radical generating initiator.

The use of drug loaded hydrogel granules as an oral dose form has also been suggested ~U.S. 3,551,556).
It is indeed one of the most useful applications of this concept in medicine since it allows the delivery into the , .,. , : . : ,. .:.. : .. ,. , .. ~ ::

~13~31t7 bloodstream of an oxally taken drug to be spread out over several hours in a reproducibl~e manner. This eliminate~
wasteful and potentially dangerous peak drug concentra-tions in the blood, while prolonging the time dur1ng which preferred and effective drug levels in the blood are main-tained.

There are two methods, by which hydrogel granules can ~e prepared. (1) One method consists of dicing or granulating a hydrogel sheet cast in the conventional manner and screening out the proper particle size. This method has several disadvantages: (a) It involves time consuming bulk polymerization o~ large amounts of materials in the form of relatively thin sheets; (b) the final pro-duct consists of jagged, rough particles with large surface area and sharp edges which are not only objectional from -the aesthetic standpoint, but also are ill-suited ~or the controlled release of a drug, which depends on a uniform diffusion rate and therefore on uniform particles with well-defined surface and volume.

(2) The second method of making hydrogel granules, --and ~y far the superior one, is suspension polymerization.
Suspension polymerization consists of suspending a liquid --monomer phase in a nonsolvent medium by stirring and with the aid of a protective colloid as a stabilizer, and pol~merizing the stirred suspension by conventional means.

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Polymerization is heat induced or catalyzed by decomposition of a free radical chemical initiator. This method yield uniformly spherical beads in a one-step process and i.s widely used in the production of polystyrene, poly(vinyl chloride) and polyacrylates, and poly~vinyl acetate). A good summary of the present state of the art is given by E. Farber in the Encyclopedia of Polymer Science and Technology, Vol. 13, pp 552-571, (1970), Interscience, New York. In case of water-soluble monomers used in the production of hydrogels, such as 2-hydroxyethyl methacrylate and N-vinyl-pyrrolidone, the nonsolvent medium is usually an organic liquid or an aqueous salt solution.
ln In United States 3,390,050 suspension polymerization of water-soluble monomers in the presence of large amounts of active ingredients is described. This process is, however, not suitable for the preparation of hydrogel beads for an orally administered drug since it is impossible to purify the polymer without leaching out the drug.
Most references to suspension polymerization of a 2-hydroxyethyl methacrylate refer to silicone oil or organic media such as mineral oil or xylene as the insoluble suspending phase ~nited States 3,567~118;
3,574,826;

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31 3L363~L7 3,575,123; 3,577,~18; 3,~7a,822; 3,583,g57). These pro-cesses give generally particles with very irregular, imperfect and porous su~aces, ~nsuited for uses where diffusion rather ~han adsorption and desorption is the working mechanism. Besides th~se fact~rs, the workup ~f the polymer on a technical scale wDuld pose a problem.

Suspension polymerization o~ 2-hydroxyethyl methacrylate (~IEM~) in the presence of 0.5 to 2~ of short-chain cross-linkiny agents (a composi-~ion conventionally named "Hydron"~ and using an a~ueous ~alt solution as medium has been described in U.S. 3,~9,634, ~ut there is no mention of a suspending agent as being a necessary ingredient of the ~ecipe. However, it can be d~nonstrated that without such a suspending agent no useful particles or beads are obtained, only large agglomerations o~ polymer.

It is, however, well-Xnown in the prior art that certain water-soluble polymers, ~uch as polyvinyl-pyrroli.done and hydroxyethyl cellulose are excellent suspending agents for suspension polymerization. It is also kno~n that certain highly insoluble inorganic com-pounds such as calcium sulfate, barium sulfate, calcium phosphate, magnesium phosphatel calcium carbonate and magnesium hydroxide ar~ also useful.

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, 1~13631 ~ 6 --The use~ of magnesium h~droxicle as the suspen-sion stabilizer in the suspension polymerization of vinyl monomers is disclosed in U.S. 2,801,992, but with the explicit teaching that excess alkali or free hydroxyl ions must be present. The magnesium hydroxide in the abs~nce of excess alkali is ineffective as a suspension stabilizer Indeed, even a stoichiometric amount of alkali to form magnesium hydroxide is insufficien-t to produce an effec-tive stabilizer.

While the presence of excess alkali and free hydroxyl ions (high p~ values) would cause no deleterious side effects with some suspension polymerization systems, there are many vinyl monomers, such as the acrylic esters, vinyl acetate and the like, which could undergo undesired base catalyæed hydrolysis in such systems at high pH values.
It is certainly preferred to polymerize such vinyl monomers under essentially neutral conditions not within the purview of the teachings of U.S 2,801,~92.

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~3~i3~L7 It was found when water-soluble polymers were used as suspendiny agents -that the hydrogel granules were of irregular shape and with ~ery porous surfaces.
If uniform beads were formed, they were of such small size (e.g., <0.3 mm diameter) as to be of no practical ~alue for the slow release of active ingredients. The same was true for the inorganic suspending agents, except that even more agglomeration occurred. Of all inorganic compounds only the insoluble gelatinous metal hydroxides gave smooth beads. In the case of poly(2~hydroxyethyl methacrylate) or "Hydron" these beads were of unusable small sizes and not uniformly spherical. But in the presence of macromeric crosslinking agents as described in this invention, regular, uniformly smooth spherical beads of up to 5 mm diameter could be obtained.

In -the course of these investigations it was now unexpectedly discovered that it is the simultaneous presence of at least 5% by weight of 2-hydroxyethyl methacrylate (HEMA) or another hydroxy substituted vinyl monomer and at least 5% by weight of a polyolefinic macromeric crosslinking agent in the polymerizing mixture, and insoluble gelatinous metal hydroxides in the absence of excess alkali or free hydroxyl ions in the suspending aqueous medium which allows the manufacture of uniform sp~rical beads with up to 5 mm diameter. The suspending medium is an aqueous salt ~36;~Jl7 solution dissolving HEMA to not over 10%. The particle size is easily con~rolled by stirring, slow stirring speeds resulting in large beads and higher speeds in small beads.
Although the instant process can be modified to make small beads ~<0.3 mm) by high speed stirring, no other known process is known to make uniform beads of over 0.3 mm other than the present invention. The pre-ferred bead size for the controlled delivery oE oral medications is from 0.6 mm to about 1.5 ~n.
Some of the hydrogel compositions of this invention are the subject of Canadian Patent No. 1,097,448.
It is an object of the present invention to provide an improved process for the preparation of uniform, spherical hydrogel beads of up to 5 mm diameter having a host of pharmaceutical and indus~rial uses.
It is a further objective of the present invention to provide uniform, spherical hydrogel beads comprising a crosslinked polymer pre-pared by suspension polymerization in an aqueous salt solution of 95 to 30%
by weight of a hydrophilic monomer ~A) which consists of 5-100% of a hydroxy substitu~ed vinyl monomer; and 5 to 70% by weight 1~ .

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~L3~3~7 g of a terminally substituted polyolefinic macromer crosslin~ing agent (B) in the presence of a suspending agent selected from the water-insoluble, gelatinous, strongly water-bonding, inoxganic metal hydroxides and :metal hydroxy salts in the absence of excess alkali.

The instant process involves the combined use of the particular gelatinous inorganic hydroxides, the monomer crosslinking compound and hydroxy substituted monomer in order to produce the uniform sperical hydrogel beads with up to 5 mm diameter. Each of the three ingredients was ~ound, unexpectedly, to be necessary for the preparation of up to 5 ~n large beads.

Detailed Description The instant invention pertains to an improved process for preparing essentially uniform sperical beads of up to 5 mm diameter of a crosslinked, water-insoluble hydrogel by suspension polymerization of (A) 95 to 30~ by weight of the hydrogel of a water-soluble monoolefinic monomer or mixture of ... . . .
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said water-soluble monomers, and from 0-70 by weight based on the total monomex of a water-insoluble monoolefinic monomer or mixture o said water-insoluble monomers, with the proviso that the final hydrogel does not contain over GO% by weight of said water-in-soluble monomer components, with (B) 5 to 70~ by weight of the hydrogel of a poly~
olefinic crosslinking agent, with a polymerization initiator in a concentrated aqueous inorganic salt solution wherein the improvement comprises carrying out the suspension polymerization with monoolefinic monomers containing at least 5~ by weight of the total monomers of a hydroxy substituted hydrophilic ~inyl monomer;

employing as the crosslinking agent a polyolefinic macromer having a molecular weight from about 400 to about 8,000, and : utilizing from 0.01 to 5% by weight, based on the hydrogel, of a suspending agent selected from the water-insoluble, gelatinous strongly water~bonding, inorganic metal hydroxides and metal hydroxy salts in the absence of excess alkali or ree hydroxy ions.
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9Ll36~i31 7 The hydrophilic portion of the hydrocJel composi-tion is prepared by the polymerization of a water-soluble monoolefinic monomer or a mi~ture of said monomers contain~
ing at least 5% of a hydroxy substituted vinyl. monomer and which can con-tain from O to 70%, and preferably at most 50~, .by weight of the total amount of the monomers, of a water-insoluble monoolefinic monomer or mixture of said water-insoluble monomers.

The process employs as ~ater-soluble, hydroxy substituted monomers water-soluble derivatives of acrylic and/or methacrylic acid, such as hydroxyalkyl esters where al~yl is of 2 to 4 carbon atoms, e.g., 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl or 2,3 dihydroxypropyl esters.

. Still another group of water soluble hydroxy sub stituted esters of acrylic or methacrylic acid are the .

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~1~3~ 7 ethoxylated and poly-ethoxylAted hydroxyalkyl esters, such as esters of alcohols of the formula HO-Cm~ m-O- (CH2C~2-o) n~H

~here m represents 2 to 5 and n represents 1 to 20 or esters of analogous alcohols, wherein a part of the ethylene oxide units is replaced by propylene oxide units. Further suitable esters are 3-(dimethylamino)-2-hydroxypropyl esters.

hno~her class of suitable derivatives of acrylic or methacrylic acid are their water-soluble amides or imides substituted by lower hydroxy-alkyl groups where alkyl is of 2 to 4 carbon atoms such as N-(hydroxymethyl)-acrylamide and -methacrylamide, N-(3-hydroxypropyl)-acrylamide, N-(2-hydroxyethyl)-methacrylamide and N-[l,l-dimethyl-2-(hydroxymethyl)-3-oxabutyl~-acrylamide; water-soluble hydrazine derivatives, such as dimethyl-(2-hydroxypropyl)amine methacrylimide ana the corresponding derivatives of acrylic acid.

Also useful, in combination with comonomers, are for instance, the hydroxyal~yl esters of maleic and fumaric acids with alkyl o~ 2 to 4 carbon atoms, such as di-(2-hydroxyethyl) maleate, and ethoxylated hydroxyalkyl maleates, hydroxyalkyl monomaleates, such as 2-hydroxye~hyl monomaleate and alko~ylated hydroxyalkyl monomaleate with vinyl ethers, vinyl esters, styrene or generally any monomer which ~7ill easily copolymerize with maleates or fumarates.
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~3~3~q Still other preferrecl water-soluble monomers are hydroxyalkyl vinyl ethers wi-th alkyls of 2 to 4 carbon atoms, such as 2-hydroxyethyl vinyl ether, 4-hydroxybutyl vinyl ether, in comhination with maleate.s, fwnarates, or generally all monomers which will easily copolymerize ~7ith vinyl ethers.

E.specially valuahle as hydroxy-substitutcd, water-soluble monomers are hydroxyalkyl acrylates and methacrylates, such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate and 2,3-dihydroxypropyl methacrylate. Especially preferred hydroxy substituted vinyl monomers are 2-hydroxyethyl methacrylate and 2- or 3-hydroxypropyl methacrylate.

Most preferred is 2-hydroxyethyl methacrylate.

Water-soluble comonomers, which do not contain hydroxy groups are: acrylic and methacrylic acid and alkyl ethers of polyethoxylated hydroxy alkyl esters thereof, such as esters of alcohols of the formula HO CmH2m~(CH2CH2~~nCH3 where m = 2 to 5 and n = 4 to 20 .

,, ~ - ' , ~ , .: , ~ 7 Dial~yl amino a].kyl esters and amides, such as 2-(dimethyl-.amino)ethyl,- or 2-(diethylamino)ethyl acrylate and methacrylate, as well as the corresponding amides; amide.s substituted by lower oxa-alkyl or lower dialkylamino alkyl groups,. ~uch as N-(l,l-dimethyl-3-o~.a-butyl) a~ryl.amide;
water-soluble hydrazine derivatives, such as trialkylamine methacrylamide, e.g., triethylamine-methacrylimide and the corresponding derivatives of acrylic acid. Mono-olefinic sulfonic acids and their salts, such as sodium ethylene sulfonate, sodium styrene sulfonate and 2-acrylamido-2-methylpropanesulfonic acid; N-[2-(dimethylamino)-ethyl]-acrylamide and -methacrylamide, N-[3-(dimethylamino)-2-hydroxypropyl]-methacrylamide.

Still another class of water-soluble monomers are the monoolefinic, monocyclic, azacyclic compounds such as N-vinylpyrrole, N-vinylsuccinimide, N-vinyl-2-pyrrolidone, l-vinylimidazole, l-vinylindole, ~-vinylimidazole,

4(5)-vinylimodazole, 2-vinyl-1-methylimidazole, 5-vinyl-pyrazoline, 3-methyl-5-isopropenylpyrazole, 5-methylene-hydantoin, 3-vinyl-2-oxa201idone, 3-methacrylyl-2-oxazolidone, 3-methacrylyl-5-methyl-2-oxa~olidone, 3-vinyl-5-methyl-2-oxazolidone, 2- and 4-vinylpyridine, 5-vinyl-2-methyl-pyridine, 2-vinyl-pyrîdine-l-oxide, 3-isopropenylpyridine, 2- and 4-vinylpiperidine,.2- and 4-vinylquinoline, 2,4-dimethyl-6-vinyl-s-triazine and 4-acrylylmorpholine.

The preferred monomer is N-vinyl-2-pyrrolidone.

.

., :., 36 1l r ~l7 ~ 15 w Preferxed amon~ these monomers which can be used at a level of from O to about 15~ by weight of the total monomers are acrylic acid, methacrylic acid, 2-vinyl pyridine, 4-vinyl-pyridine, 2-(dimethylamino)ethyl methacrylate, N-[2-dimcthyl-amino)ethyl] methacrylamide and sodium styrene sulfonate.

Preferred 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 mathacrylate, N-.vinyl 2-pyrrolidone and N-methylolacrylamide. It is noted that, when N-vinyl-2-pyrrolidone or any other ~on-hydroxy bearing water-soluble monomer is used, a second monomer containing hydroxyl groups must also be used concomitantly in the instant process.

Suitable hydrophobic comonomers, which may be incorporated into the reaction mixture, are for example, 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 ~ r -- ~ ~ _ .~
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` ~L3~;33~7 esters derived from alkane-carboxylic acids having 2 to 7 carbon atoms, e.g., vinyl acetate and vinyl propionate, or vinyl benzoate; acrylonitrile; styrene; and vinyl alkyl ethers in which the alkyl portion o~ the ether chain has 1 to 5 carbon atoms, e.g., methyl, ethyl, propyl, butyl or amyl vinyl ether.

Preferred embodiments are the alkyl acrylates or metacrylates where alkyl is 1 to 18 carbon atoms.

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~3~ 7 Other pr~ferred embodim~nts are the vinyl alkyl ethers wherein alkyl is from 1 to 5 carbon atoms.

Still other preferred water-insoluble monomers are acrylonitrile and styrene.

The terminal polyolefinic macromer crosslinking agent (B) olefinic moieties are preferably provided by acy] groups of lower ~ mono-unsaturatecl aliphatic monocarboxylic or dicarboY~ylic acids or by vinyloxy moieties.
These vinyl moieties are linked by a macromolecular chain containing repeating ester, amide or urethane, but particu-larl~ ether linkages. The molecular weight of the chain may vary from about 400 to about 8,000, preferable between about 600 and 5,000 and, especially, between about 1,500 and 3,000. Thus, the macromer preferably corresponds to the formula j3 12 1 12 13~

HC _ C _X _Y_ Rl~ Y_ X _ C = C~ or HC -CO CH- CH
/a Bl 2 wherein a is 1 or 2; Rl is a polycondensate chain having a mole-cular weight from about 200 to about 8,000 which contains hydro-caxbon residues connected via ether, ester, amide or urea ,. . . . .

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., :, ~L~3~17 linkages or is a polysiloxane of molecular weiyht between 400 and 8,000; R2 is hydrogen, methyl or -CH2COOR~;

R~ is hydrogen or alkyl of 1 to 10 carbon atoms;
R3 is hydrogen or -COOR~ with the proviso that at least one of R2 and R3 is hydrogen; X is an oxy~en atom, -COO
or -CONR5-;

R5 is hydro~en or alkyl of 1 to S carbon atoms;
Y is a direct bond or the radical -R6-Z CONH-R7-NHCO-Z~;

R6 is linked to X and represents branched or linear alkylene of 1 to 7 carbon atoms; Zl is an oxygen atom or -NR5~ 2 is Zl or a sulfur atom; and R is the diradical of an aliphatic, alicyclic or aromatic diiso~
cyanate with the proviso that in case X is oxygen, Y is different from a direct bond and R2 and R3 are hydrogen.

Preferably a is 1.

In the compounds of formula Bl and B2, Rl is in particular a polyethylene oxide chain, a polypropylene oxide chain or a polytetramethylene oxide chain, or a chain consisting of a polyethylene oxide-polypropylene oxide block copolymer, but it can also represent a chain derived from dicarbo~ylic acids, diols, diamines ox diisocyanates etc., by well known methods o poly-conden-sation. Rl can also be a polysiloxane containing chain.
The terminal radicals of the compounds o formula Bl are according to the definitions of R2 and R3 and if X
r~presents -COO- or CONR5-, the ac~l radicals of acrylic .. . . ,: . . ... .

~3~ 7 or methacrylie acid or the monoacyl raclicals of ma]eie, fumaric or itaconic acid, or of monoalkyl esters of the~e aeids t~ith straight or branched chain alkanols of 1 to 10 earbon atoms, such as methanol, ethanol, butanol, diisobutyl alcohol or decanol, or if X represents oxygen, the vinyloxy ~adical of vinyl ethers. Compounds of the formula ~1 with Y being a direct bond are diesters of maeromolecular diols, wherein two hydroxy groups are attached to the polycon-densate ehain Rl in opposite terminal or almost terminal positions, with ~,~-unsaturated acids. Such diesters ean be prepared from said macromolecular diol by well-known aeylation methods usiny reactive functional derivatives or suitable aeids, e.g., acid chlorides of acrylic or methacrylic acid, or of monoalkyl esters of maleie, fumarie or itaconic acid, or the anhydride of maleie or itaeonic acid. Compounds of formula Bl with amide group X are diamides obtained from macromolecular diamines by well-~nown aeylation reaetions using, e g., the acid ehlorides or anhydrides mentioned above. The maeromoleeular diamines are prepared, e.g., by reacting eorresponding maeromolecular diols with twice the molar amount of an alkylenimine, e.g., propylenimine.

The macromoleeular bis-maleamie aeids obtained by the above reaction when maleic acid anhydride is used as the aeylating agent for macromolecular diamines can be . .. ~ . - ;, . .
- ..

~L3~ 7 fu~ther heated or ~eacted with dehydrating agents to yield the macxom~lecular bis maleimido cornpounds o~ ~orrnula B2.
In these compounds, Rl thus may be, e.g., one of the macromolec~lar pvlycondensate chains named ~s moieties of compounas of *hE for~ula ~1 ~ ccording to the definition of ~ormula Bl, y can ~urther be a ~ivalent radical -R6-Zl-CON~-R7-NH-C0-æl-.
Thelein R6 is, e.g~, meth~lene, propylene, trimethylene, tetramethylene, pentame~lylene, neopentylene (2,2-dimethyl-trimethylene~, 2-hydroxytrimethylene, 1,1-dimethyl-2-(1-~xo-ethyl)trimethylene or l-(di-~ethylaminomethyl)eth~ylene and particular ethylene. The divalent radical R7 is derived ~rom an organic diisocyanate and is an aliphatic radical -such as alkylener e.g., ethylene, tetramethylene, hexamethylene, 2,~,4-trimethylhexamethylene, 2,4,4-trimethyl-hexamethylene; fumaroyl~iethylene or l-carboxypentamethylene;
a cycloaliphatic ~adical, e.g., 1,4-cyclohexylene or 2-methyl-1,4-cycloh~xylene; and 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-~hloro-1,8-nap~thylene, 1-methyl-2,4-, 1-methyl-2,7-, -4-me~hyl-17 2-, 6 methyl-1,3-, and 7-methyl-1,3-naphthylene, 1,8-dini~ro-~,7-naphthylene, 4,4'-biphenylene, 3,3'-dichloro-4,4'-~iphenylene, 3,3l-aimethoxy-4,4'-biphenylylene, 2,2'-dimét~yl- ~nd 3,3'-dimethyl-4,4'-~iphenylylerle, 2,2'-dichloro-~ ~.. ,. -. . .

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S,5'-dimethoxy--~,4'-biphenylene, methylenedi-p-phenylene, methylenebis-(3-chlorophenylene), ethylenedi-p-phenylene -or oxydi-p-phenylene. If in structure Bl, Y is no direct bond, R6 is al~7ays connected to X.

Thus, compounds of the formula Bl, in which Y
is said divalent radical, are, if X represents oxygen, bis-vinyl ethers or, if X represents -COO- o.r CONR5, bis-acrylates, bis-methacrylates, bis-maleates, bis fumarates and bis-itaconates.

Rl is in particular derived rom macromeric diols and diamines of 200 to 8000 molecular weight (MW).

Useful macromeric diols are polyethylene oxide diols of 500 to 3000 MW, polypropylene oxide diols of 500 to 300 MW, poly-n-butylene oxide diols of 500 to 3000 l~W, poly(- block-ethylene oxide -co-propylene oxide) diols of 500 to 3000 MW, wherein the percentage of ethylene oxide : . units can vary from l0 to 90%; polyester diols of 500 to 3000MW
obtained by the known methods of polycondensation from diols and diacids, for instance, from propylene glycol, ethylene glycol, butanediol or 3-thia-pentane diol and adipic acid, terephthalic acid, phthalic acid or maleic acid, and which may also contain macromeric diols of the polyether type mentioned above.

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~3fi31 More.yenerally/ any cliol of MW 500 to 3000 is use~ul, ~7hich can be obtained by polycondensation of diols, diamines, diisocyanates, or diacids and thus contain ester, urea, urethane or c~mide linkage ~roups.

Similarly useful are diamines of 500 to 4000 M~1, especially the bis-aminopropyl ethers of the above-mentioned diols, especially the bis-3-aminopropyl ethers o~ polyethylene oxide and polypropylene oxide diols.

~ preferred embodiment o~ the instant process employs a macromer (B) wherein Rl is a poly(ethylene oxide), poly~propylene oxide) or poly(tetramethylene oxide) chain ~ith a molecular weight of about 600 to about 4,000.

Another preferred embodiment of the process employs a macromer (B) wherein Rl is a chain obtained by the condensation reaction of an aliphatic, alicyclic or aromatic dicarboxylic acid or diisocyanate with an aliphatic diol or diamine.

.
A particularly preferred embodiment of the instan process uses as the macromer (B) a reaction pro~
. duct of a polyalkylene ether glycol, particularly poly-(tetramethylene oxide) glycol with a molecular weight o about 600 to about 4,000, firs~ terminated with . ' ; ~ ~ : , - , ., . -~L3~3~7 tolylene-2,4-diisocyanate or isophorone diisocyanate, and then endcapped with a hydro~yallcyl acrylate or me~hacrylate where alkyl is of 2.to 4 ~arbon atoms.

~ specially use~ul are the macromers (B) ~here the poly(tetramethylene o}ride~ glycol has a molecular weight of ~bout 1,~00 to ~bout 3,000 and the hydro~yal~yl methacrylate is 2-hydroxyethyl methacrylate.

Other preferred macromers (Bl~- are those wherein Rl can also be derived flom a polysiloxane containing diol, triol, or ait~iol, with a molec~lar weight of 400 to B,0~0. These di- or polyfunc-tional polysi.loY.anes can be of ~wo different struct~res:

( 3)3 ~ Si(C~3)z ~ IS (C~3)O ~ si(CH3)3 or --R8~Sitc~3)2o3~ Si(C~3)2 R8 whe~ein ~8 is a br~nched or lin~ar alkylene of 1 to 7 c~r~on atoms or -~CH2C~O~ , n is 1 to 20, Rg is hydrogen Rg or m~thyl~ x is 3 to 12D and y is 2 to 3.

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31 ~L.3~ L7 These polysiloxane macromers are preferably endcapped with iso-phorone diisocyanate or tolylene-2,4-diisocyanate followed by reaction with excess 2-hydroxyeth~l. methacrylate, 2-hydroxyethyl acrylate or 2-hydroxyprop~l acrylate.
Compounds of the formula Bl, wherein Y is -R6ZlCONHR7-NII-CO-Z2-are obtained in a 2-step reaction by first reacting macromolecular diols or diamines, i.e., compounds which contain two hydroxy or amino groups attached to the polycondensate chain, Rl, in opposite terminal or almost terminal positions, with at least twice the molar amount of an aliphatic, cycloaliphatic or aromatic diisocyanate consisting of two isocyanate groups attached to the radical R7, and, second, reacting the macromolecular diisocyanates so obtained with a compound of the formula R13 .1R2 HC - C-X-R6-ZlH (C) wherein R2, R3, X, R6 and Zl have the meaning defined for ~Bl) above.
If X represents oxygen, ~C) is vinyl ether containing an active hydrogen, for instance an hydroxyalkyl vinyl ether or an aminoalkyl vinyl ether; if X represents -COO- or -CON-R5, ~C) is an acrylate, methacry-. ~
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late, mal~ate, f~arate, itacon~te or the corresponding amide, containing an active hydrogen in the alkyl yroup.
The macromolecular diol or diamine is preferably used in a small excess, i.e., the ratio of isocyano groups to hydroxy or amino groups during the first step of the macromer synthesis should be at least 1:1, but is prefer-ably at least 1:1.05. If the compound o-E formula C used during the second step of the macromer synthesis, is identical with the hydrophilic monomer comprising (A), then a larye excess of this compound can be used, so that the resulting solution of macromer Bl dissolved or dispersed in Compound C can be used directly for the preparation of the final hydrogel.

The synthesis of the macromer, B, is suitably carried out at a temperature in the range of from about room temperature to approximately 100C. Preferably, the temperature employed is within the range of about 30-60C.
The conversion of the isocyanato group is followed by in~rared spectroscopy or by titration.

Preferred diisocyanates for preparing the macromer are tolylene-2,4-diisocyanate and isophorone diisocyanate.

Poly(tetramethylene oxide) glycol chain ~erminated with tolylene-2,4-diisocyanate is commercially available as "Adiprenel' from DuPont.

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~ L13~ 7 Tolylene~2,4-diisocyanate and isophorone diisocyanate are available commercially.

Another method for preparing the macromer is by reacting a hydroxyl-terminated prepolymer, e.g., polybutylene or polypropylene oxide, with acryloyl chloride, methacryloyl chloride or maleic anhydride and thus forminy a macromer without connecting urethane linkages as, for example, a macromer of the formula B2 or B1, where Y i5 a direct bond.

Following synthesis of the macromer, it is dissolved and diluted with monomers to make the final polymerizable mixture.

This monomer - macromer mixture may consist of 95-30% by weight of monoolefin vinyl monomers, which contain at least 5~ of a water-soluble: hydroxy substituted vinyl monomer and may contain from 0-20% of a water-insoluble vinyl monomer. Preferably it contains 20-100 of a hydroxy substituted vinyl monomer and 0-40% of a water-insoluble vinyl monomerî most preferably, it contains 40-100% hydroxy substituted vinyl monomer and no water-insoluble monomer at all. B is 5-70% by weight of a terminal polyolefinic macromer crosslinking agent; the preferred amount of macromer is 15-100~, with 25-45~ being most preferred.

.
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~3~ 7 The improvcd process of l:he instarlt invention pertains to the synthesis of uniform spherical hydrogel beads of up to 5 mm diameter ~y the suspension polymeri-zation of the monomer (A) - macromer (B) mixtures described above. The suspension polymerization is carried out in a medium ~hich comprises an a~ueous solution o~ a water-soluble inorganic salt in which is suspended a water-insoluhle, gelatinous, strong water-bonding inorganic metal hydroxide or metal hydroxide salt as the suspending agent in t~le absence of excess alkali or free hydroxyl ions.

The free radical polymerization is started by an initiator capable of generating ~ree peroxy or alkyl radicals in hi~h enough concentration to initiate polymeri-zation of the vinyl monomers employed at the synthesis temperature. These initiators are preferably peroxides or azo catalysts having a half-life at the polymerization temperature of at least 20 minutes. Typical useful peroxy compounds include: isopropylpercarbonate, tert.-butyl peroctoate, benzoyl peroxide, lauroyl peroxide, decanoyl peroxide, acetyl peroxide, succinic acid peroxide, methyl ethyl ketone peroxide, tert.-butyl peroxyacetate, propionyl peroxide, 2,4-dichlorobenzoyl peroxide, tert.-butyl peroxypivalate, pelargonyl peroxide, 2,5-dimethyl-2,5-bis f2-ethylhexanoyl-peroxy~hexane, p-chlorobenzoyl peroxide, tert.-butyl peroxybutyrate, t.-butyl peroxymaleic acid, :, :
- . . .
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~3~ L7 t.-butyl-p~roxyisopropyl carbonate, bis(l-hydroxy~
cyclohexyl)peroxide; azo compounds include: 2,2'-azo-bis-isobutyronitrile; 2,2'-azo-bis-(2,4-dimethylvaleronitrile);
l,l'-azo-bis-(cyclohexane carbonitrile); 2,2'-azo-bis-(2,4-dimethyl-4-methoxyvaleronitril~e).

The amount of initiator can vary from 0.01~ to 1 by weight of the monomer (A) and macromer (B), but is preferably from 0.03 to 0.3% by weight thereof.

Polymerization occurs in the monomer-macromer droplets which are insoluble in the a~ueous salt solution.
The droplets are stabilized, that is prevented from coalescing, by the presence of the suspending agent. The size of the droplet and hence of the ultirnate hydrogel bead is determined by the rate of stirring. Fast stirring tends to give smaller beads, slow stirring tends to give bigger beads, which are, howe~er, non-unifor~ and irregular in the absence of the instant gelatinous metal hydroxide suspending agents.

The gelatinous metal hydroxide or metal hydroxide salt is dissolved at the end of the suspension polymerization by the addition of acid such as hydrochloric acid. The hydrogel beads are isolated hy filtration.

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The process is normally carried out in a reaction vessel equipped with a condenser, nitroyen sparge, therrno-regulator and, most important, a stirrer and baffle of a design which will insure good rnixing at slow st~rring speeds.
Preferred in the laboratory are anchor-type glass stirrers connected to stirring motors whose speed can be carefully controlled. For a typical synthesis, the salt water solu-tion is first charged into the reactor together with a soluble magnesium or aluminum salt. The solution is then heated to the polymerization temperature and khe yelatin-ous metal hydroxide is precipi.tated by a prescribed amount of aqueous base during rapid stirring. Following this step, the stirring speed is reduced to whatever speed is neces-sary to yield beads of a given size, slow speeds leading to large sizes, high speeds to small ones. The monomer-macromer mixture containing the dissolved initiator is now adaed and the reaction kept at constant temperature and stirring speed for at least three hours, followed by an -- optional one hour reaction time at 100C at reflux.
nitrogen blanket is maintained at all times. The reaction muxture is then cooled to room temperature and enough acid, either organic such as acetic acid, or mineral acid, is added to dissolve the metal hydroxide. The beads are now filtered off, washed free of surface salt water and soaked in water " , ~; '` '' '~'~
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~3G31 or alcohols to extract unconverted mon~mers. Aftcr they are dried and weighed, their particle ~ize and particle size distribution can be measured by sc~eening and t~eir degree o~ swelling (DS) in various solvents can be deter-mined. Many parts of this very general process can, of course, be altered so as to suit special product requirements.
For instance, precipitation of th~ suspendiny agent can be carried out after addition of the monomer-macromer mixture and monomers can be added continuously during the polymerization. These monomers may be the same throughout the course of the reaction, or they may change, with the result, that the beads of heterogeneous composition can be produced.

The non-solvent ,aqueous phase for the process of the present invention is an aqueous salt solution. The salt can be theoretically any water-soluble inorganic salt at about 5 to about 25% by w~ight concentrations, ~ut in practice only the cheap, commercial chlorides and sulfates of alkali and alkaline earth metals are important, for instance: sodium chlo-ri~e potassium sulfate, magnesium chloride and magnesium sulfate.
These can be employed alone or as mixtures and in concentrations up to their solubility limit in ~ater. The preferred salt is sodium chloride or sodium sulfate and concentrations (in percent by weight) from 5~ up, preferably 10~ and up and with concen-, 3~

trations of 15~ or more being most preferred. ~s a general rule, the higher the sale concentration, the lower is the amount of water-soluhle monomer dissolved in the aqueous phase and concomitantly the more uniform is the ~inal spherical hydrogel bead. Sodium chloride at 20~ concen-tration in water is very preferred.

The ratio of aqueous phase to monomer-macromer phase can vary from 2:1 by volume to 15:1. For a highly swellin~ polymer it should be high, for a less s~elling polymer it can be low. Preferably it is from 2.5:1 to 3:1.

The heart of the instant process lies iIl the use of the particularly efficacious suspending system w~ich comprises the ~ater-insoluble, gelatinous, strong water-bonding inorganic metal hydroxides or metal hydroxide salts in the absence of excess alkali or free hydroxyl ions, a macromer (B) and a small amount ~at least 5~) of a hydroxy-substituted vinyl monomer. The preferred metal atom is one with a stable valency state so that it will not tend to participate in oxidation-reduction reactions. Such materials would typically be magnesium, aluminum and zirconium.

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The metal hydroxide suspending agents of the instant process are prepared by adding to an aqueous solution of a soluble metal salt (chloride, nitrate, sulfate, etc.) up to, but not exceeding a stoichiometric amount of alkali to form the metal hydroxide or a metal hydroxide salt where all valences of the metal ion are ~ot satisfied with hydroxyl groups. Such a metal hydroxiae salt would be aluminum hydroxy chloride or magnesium hydro~y chloride. The exact struc-ture of the water-insoluble, gelatinous precipitate prepared cannot be depicted, but such materials all work effectively as suspen-sion stabilizers in the instant process.

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~3t~3~L7 It is important, that the metal hydroxide ~e a strongly water-bonding type, as indicated by khe form~tion of a voluminous gel. Crystalline, l~ighly insoluble salts ~r oxides, which are commonly used as suspending agents, for instance, in the manufacture of polystyrene or poly-(vinyl chloride) beads, are totally ineffective in the production of uniform and large beads of pol~ners contain-ing 2-hydro~yethyl methacrylate (~IEMA) or N-vinyl-2~
pyrrolidone. It appears that a strong interaction involving hydrogen bonding bet~een the hydroxy groups of EE~, water, and the hydroxyls of the hydroxides is responsi~le for the outstanaing stabilizing action.

The choice of metal hydroxide is determined solely as to whether it forms a voluminous, gelatinous precipitate in the aqueous medium. The metal hydroxiaes of magnesium, aluminum, zirconium, iron, nickel, chromium, zinc, lead, calcium, cobalt, copper, tin, gallium, manganese, strontium, barium, uranium, titanium, lanthanum, thorium and cerium are effective suspending agents for the instant process.

The hydroxides of certain transition metals, such as manganese, iroIl and chromium are excellent suspendin~
agents, but are generally not the hydroxide of choice because they can interfere with the free radical polymeri-zation through electron transfer reactions. Their color also limits their utility to end-uses where some color is not a deterrent in the hydrogel bead.

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3L~3!Ei3~7 ~ 34 -The preferred suspencling agent is m~gnesiumhydIoY~ide or aluminum hydroxide in the absence of excess al~ali or free hydroxyl ions.

The amount of suspending agent ranyes from O.Dl to 5~ by weight based on 1he hydrogel of the water-insoluble, gelatinous metal hydroxide.

The suspending agent is preferahly prepared in situ by adding a prescrihed amount of aqueous base (usually l-normal sodium hydroxide solution~ to the aqueous salt solution containing dissolved therein a metal salt (such as l~ magnesium, aluminum, nickel, and ~le li~e~. Common useful salts are magnesium chloride, magnesiwm sulfate and aluminum sulfate, but any source of magnesium~+ or aluminum+*~ ions can be used equally as well.

The monomers useful in this process are general items of commerce as are the inorganic salts required for preparing the gelatinous metal hydroxide suspending agents.

The degree of swelling (DS) in water is determined by ~welling a given weight of beads in water till equilibrium is esta~lished, weighing the swollen beaas and weighing the dried beads. Degree of swelling is defined as DS = weight of swollen beads - weight of ~ x 100 weight of dry beads - , : - : . . ~ ~
.

~13~ 7 The average medium paxticle size (M.P.S.) is defined as the number (mm~, at which the cumulative particle size distribution plot, as measured by screening the total yield of beads through a series of screens with mesh sizes from 8 50, cuks through the 50% line.

The following examples are presented for the purpose of illustration only and are not to be construed to limit the nat.ure or scope of the instant invention in any manner whatsoever.

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~3~317 Example 1 Preparation of Hydrogel A smooth wall, l,000-ml resin ~lask was equipped . with a reflux condenser, nitrogen inlet tube, thermometer attached to a thermoregulator, baffle and anchor-type stirrer driven by a variable speed motor. A slow flow of nitroyen was maintained through the reaction flask at all times.

To the ~lask were charged 360 grams of a 20% by weight aqueous sodium chloride solution followed by 23 grams ~0.114 moles~, of ma~nesium chloride-hexahydrate. The solu-tion was heated slowly to 80 with rapid stirring. To this .solution was then added dropwise 123 ml (0.123 moles) of a l-normal sodium hydroxide solution to form a fine, gelatinous precipitate of magnesium hydroxide in the reaction flask.

~ ~fter all the sodium hydroxide was added, the : stirring speed was reduced to 150 rpm and a mixture of monomer (A) and macromer ~B) containi.ng dissol~ed therein 0~2 gram of tert-butyl peroctoate as a free radical polymeri-zation initiator was added. (The mix-ture of monomer and macromer was prepared by dissolving 60 grams (ca. 0.024 moles) of a poly(tetramethylene oxide~glycol (average molecu-lar weight of 2,000~ endcapped with isophorone diisocyanate ~ in 140 grams (1.08 moles~ of 2-hydroxyethyl methacrylate : :
.

~3~i33L7 (HEMA) and allowing said miY~ture to react for 72 hours at room temperature. At the end of this period the disapperance of the terminal isocyanate groups was verified by noting the absence of the characteristic infrared spectral band at 2270 cm~1 associated with the -NCO group.) The reaction mixture was stirred under nitrogen at 150 rpm and a-t 80C for three hours. The temperature was then raised to 100C for 1 hour after which time the flask was cooled to room temperature. 10 ml of concentrated hydrochloric acid was then added to dissolve the magnesium hydroxide suspending agent. The reaction mixture was then filtered through fine cheesecloth. The isolated product beads were washed with 2,000 ml of water and soaked over-night in 500 ml of ethanol to extract any residual monomer.
The beads were then isolated by filtration through a poly-ester cloth bag, which is then sewn closed, and dried in a home clothes dryer. Uniform spherical beads were obtained in a yield of 193 grams (96.5%) which had an average diameter of 1.02 ~ 0.3 mm and exhibited a degree of swelling in water ~DSH O) of 37~.

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~L3~3~t7 Examples 2-4 Effect of Monomer (A) - Macromer (B) Ratio_on Elydrogel P~eparation Using the procedure of Example l, hydroyel beads were prepared with different ratios of monomer (A) and macromer (B).

~verage % Endcapped Beads DS
% HEM~ Macromer Size H O
Example Iby wei-ght) (A) (by weight) (B) ~mm) (mm~

2 ~0 10 0.~8 51 1 . 70 30 1.02 37 - ~ 3 60 ~0 l.l9 ~4.3 4 40 60 2.05 15 .
It.appears as the amount of macromer ~B) is increased the average head size also increases lunder the same reaction conditions) and the DSH O decreases.

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~3~3~7 Examples 5-13 Effect of N-Vinylpyrrolidone (NVP) as Component of Monomer (~) - Macromer ~B) on Hydrogel Preparation Using the procedure of Example 1, but with dif-ferent stirring speeds and with clifferent mixtures of H~
and NVP as monomer (A) with macromer (B), hydrogel beads were prepared as seen below:

Endcapped Average Stirring% HEMA % NVP Macromer Bead DS
Speed(by ~eight) (by weight (by weight) Size H O
Exam~ rpm (A) (A) (B) (mm) _ ( 150 47.5 5 ~7.5 1.121 6 110 54 10 36 1.136 7 150 34 15 51 1.32~
8 110 40 20 40 1.236 9 100 55 25 2g 1.057 100 35 ~5 20 1.2103 11 110 35 25 40 1.440 12 120 10 75 15 1.5212 13 110 30 25 45 1.336 An increase in the NVP content of the hydrog~l increases the degree of swelling other polymerization conditions being held constant.

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3~7 Also if the one plots composition of Examples 1, 6, ~ and 13 on a triangular grid, where the thxee coordinators are % NVP, ~ HEM~ and ~ Macromer, a straight line is obtained, which represents composition of equal degree of swelling.

The same set of examples show that with increas-ing NVP content, the average bead size increases.

EY.amples 1~-19 Use o~ Other Macromers in Hydrogel Bead Formation -- Using the preparative method of E~ample 1, but substituting for the macromer t~) based on poly(tetra-methylene oxide)glycol endcapped with isophorone diiso-cyna~e (IPDI) the macromers shown below, hydrogel beads were prepared with the properties shown.

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- '~2 -Use of Aluminum ~l~d:coxide as Suspending -Agent and Acrylic Acid as a Commonomer Using the process of EY.ample 1, 3.15 grams (O.005 moles) of aluminum sulfate-hexadecahydraté was substituted for the magnesium chloride-hexahydrate and 31 ml (0.031 moles) of l-normal sod.ium hydroxide 501u-tion was used to prepare the aluminum hydroxide suspend-ing agent.

The mixture of monomer (A) and macromer (B) was prepared by dissolving 96 gr~ms of the poly(tetra-methylene oxide~gl.ycol (average molecular weight about 2,000~ endcapped with isophorone diisocyanate in 64 grams of 2-hydroxyethyl methacrylate and 40 grams of acrylic aci;d neutralizing any hydroxyl ions present before polymerization occurred.

- Uniform spherical beads were obtained which had an average diameter of 1.02 + 0~2 mm in a yield of 180 grams (90~. The swelling of the beads was dependent on pH with the DSpH being 65.4 and DSpH being 75.8.

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' ' ~. ~ . "' " ' . ' ~3L3~ L7 ~xample 21 Use of an Azo PolymerLzation Initiator and Other ~later-Soluble Monomers Follo~ling the procedure of Example 1, 0.2 grams of azobisisobutyronitrile was substituted for the pexoxy catalyst.

The monomer (A) - macromer (B) mixture used was prepared by dissolving 84 grams of poly(tetramethylene oxide)glycol (average molecular weiyht 2,000) endcapped : with isophorone diisocyanate in 56 grams of 2-hyaroxyethyl methacrylate and 60 grams o~ N-(2-dimethylamino)ethyl-methacrylamide.

Uniform spherical beads were obtained in a yield of 193 grams (96.5%) which had an average diameter of 1.02 ~ 0.4 mm. The degree of swelling was pH dependent with the DSpH being 83.2 and the DSp~ being 71.1.

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~31 3~3 - '~4 -E ample 22 ~se of Other ~ater-Soluble Monomers in ~rogel Formation When the exact procedure of Example 1 was used except that the 140 grams of 2-hydroxyethyl methacrylate was replaced by a mixture of 40 grams of 2~hydroxyethyl methacrylate and 100 yrams of 3-hydroxypropyl methacrylate, uniform spherical beads were obtained in a yield of 193 grams (96.5%) which had an average diameter of 1.02 ~ 0.3 mm and exhibited a degree of swelling in water (DSH 0) of 37.9~.

Example 23 According to the process of Example 1, hydrogel beads were prepared using as monomer - macromer mixture 24 grams poly(tetramethyleneoxide) glycol of MW Z000 endcapped with isophorone diisocyanate in ~ss2 grams 2-hydroxyethyl ~ methacrylate, _34s grams N-vinyl-2-pyrrolidone and 80 grams ; methoxy-polye~hylene glycol methacrylate containing an average of 9 ethoxy units. Uniform round beads were obtained having an average d:iameter of 0.72 mm and degree of swelling in Ss~ater (DSH 0) of 272~ss.

S ~ ~r~ ~"~,"~S~ S~ J.~,.~ 3v;-~ r~ {~ S~,-S~ 3s,~ s - , ~13~3~7 ~5 Example 24 Using the procedure of Example 1, hydrogel be~ds were made by the reaction of 33.3 grarns o~ a 60~ aqueous solution of N methylolacrylamide with 171 grams of a mixture of 40~ poly(tetramethylene oxide)glycol (MW 2000), endcapped with ~ moles of isophorone diisocyanate and 60~ 2-hydroxyekhyl methacrylate in a yield of 180 grams (85%) of uniformly round beads having an average diameter of 1.10 mm and a degree of swelling in water (DSH2o) of 32%^

Example 25 Use of a Polysiloxane Macromer The general procedure of Example 1 was used substituting the monomer (A) - macromer (B), seen before for that described below.

The monomer (A) - macromer (B) mixture used in this example was prepared by dissolving 80 grams of the polysiloxane polyol :

~3~7 - '~ 6 ~ 5 ~0 Si(~H3)3 (o-si~o SilC-:13)3 H (OCH2CH) -Si~ O ~Si-O ~ Si-O) - ( si 3 (1 2 ) 1 4 CH3 Cl~3 CH3 ¦ 3 (CH-CH2-0) H
CH3 1~4 1 X2 ~ X3 ~ X4 = 6-8 available from Dow Corning as Q4 3557, endcapped with isophorone dilsocyanate in 83.2 grams of 2-hydroxyethyl methacrylate and 30.8 grams of N-vinylpyrrolidone.

Uniform spherical beads were obtained in a yield of 192 grams (96~) which had an average diameter of 1.02 0~4 mm and a degree of swelling DSH O of 39.8%.

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~L~3~3 E mple 26 Use of ~nother Polysiloxane Macromer Following the procedure of Exarnple 1, 115 grams of sodium chloride dissolved in 310 grams of water followed by 25 grams (0.247 equiv) of magnesium chloride hexahydrate.
A fine gelatinous precipitate of magnesium hydroxide was formed upon addition of 123 ml (0.123 equiv) of l-normal sodium hydroxide solution with rapid stirring.

The monomer ~A) - macromer (B) mixture used in this example was prepared by dissolving 107.5 grams of the polydimethyl siloxane diol H~CH2CH2~ ~ Si O ~ Si-/CH C~I O) ~ H
CH3 ~10 CH3 ' y + yl = 26 available from Dow Corning as Q4-3667, endcapped with isophorone diisocyanate, in 107.5 grams of 2-h~fdroxyethyl methacrylate.

Uniform spherical beads were obtained in a yield of 200 grams (93~) which had an average diameter of 1.66 ~ 0.5 m~ and a degree of swelling DSH O of 28.1%.

~L~3~3~7 - 4~ -Examples 27-31 Use of Various Gelatinous Me~al Hydroxide Suspending Agents Using the general procedure of Example 1 and the same reactants except for the suspend.ing agent metal hydroxide, hydrogels wexe preparcd as seen below:

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In order to minimize hydrolysis of 2-~ydroxyethyl methacrylate and other sirnilar acrylic ester monomers, it is desirable to run the suspension pol~merization at an essen-tially neutral p~i or as near thereto as possible by never using more al~ali than neces~ary to form and precipita~e the metal hydroxide or metal hydroxide salt.

In Example 1 with magnesium chloride, approximately half thr stoichiometric amount of alkali required to form magnesium hydroxide was used to give a precipitate which for-mally may be considered magnesium hydroxy chloride. The final pH of the suspension polymerization system was 7.8.

Fxample 3la Aluminum ion can also be used in excess to pre-pare the instant hydrogel beads. In Example 30 a stoichio-metric ~equivalent) amount of alkali was used to prepare the aluminum hydroxide suspending agent.

Example 30 was repeated, but with only 90% of the stoichiometric (equivalent~ amount of alkali (sodium hydrox-ide 0.112 equiv.~ being used with aluminum sulfate hexa-decahydrate (0.123 equiv.) to form the aluminum hydroxy sulfate suspending agent. The pH of the suspension poly-merization system was 7.0 and round b?eads of 1 mm average diameter were obtained in good yield.

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_ 5l _ When in another experiment a 5~ stoichiometric excess of al~ali (sodium hydroxide) ~as used to precipitate aluminum hydroxide, the pH of the suspension polymeriæation system ~as 10.5, far too al~aline, and presenting the risk of ester monomer hydrolysis side reactions.

Example 32 Use of Non-Gelatinous Suspending Agents When the water-insoluble, gelatinous, strong water-bonding inorganic hydroxides of Examples 1 and 27-31 were replaced by various finely divided inorganic products such as ealei~un phosphate, ealeium earbonate, magnesium earbonate, magnesium phosphate or calcium oxalate, polymerization took place, but agglomeration o~ the pro-ducts into large irregular chunks occurred. No uniform, spherical hydrogel beads were observed.

The following examples show that commonly used polymerie suspending agents do not give useful hydrogel beads.

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Example 33 The process of Example 1 was repeated, but instead of using magnesium hydroxide as suspending agent, polyvinyl-pyrrolidone (PVP-K90, from G~F Corporation) was dissolved in the aqueous phase at a concentration of 0.08% (by weight of monomer~macromer mixture).

Polymerization occurred and conversion to polymer was essentially 100~, but in form of uneven granules rather than smooth round beads and with a considerable amount of coagulated material, especially around the stirrer shaft and the reactor wall.

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~3~3~7 E~ le 34 The process of Example 1 was repeated, but instead of using magnesium hydroxide, h~droxyethylcellulose ~HEC QP32000; Union Carhide) was dissolved in the aqueous phase at a concentration of 0.01~ (by weight of monomer-macromer mixture). Pol~nel-ization occurred and conversion was essentially complete. 68~ of the ~eads obtained were <0.4 mm in diameter~

Reducing the stirring speed and increasing or decreasing the amount of dispersant did not lead to larger round beads, but produced heavy agglomeration into clusters and granules.

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-3'~'~7 Examples 35-~1 Hydrogels Prepared Usiny Various -Wa~er Insolub71e Comollomers The general procedure of Exc~mple 1 was used to prepare hydro~el beads from a monomer (A) - macromer (B) mixture of a solution o~ 24 grams o poly(tetram~thylene oxide)glycol of MW 2000 endcapped with isophorone diisocyanate, in 42 grams of 2-hydroxyethyl methacrylate, 54 grams of N-vinyl-2-pyrrolidone and 80 grams o~ one of the ~ater-insoluble comonomers listed in the following table:

Bead Size DS
Example Comonomer Yield % (mm) H2 ~ . . _ ethyl acrylate 90 0.90 63 36 2-ethylhexyl acrylate 975 0.86 32 37 ethyl methacrylate 91.5 0~92 61 38 methyl methacrylate 93 0.52 60 39 methyl acrylate 9S 0.78 83 octadecyl methacrylate 95 0~50 41 41 dioctyl fumarate 95 0.85 32 :

All reactions proceeded smoothly and gaYe beads ~ith the DS~12o values and of average diameters.

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E~E~es 42-46 Use of Salts Other Than Sodium Chlori.de in the Polymerization Medium The procedure of Example 1 was repeated excep~
that salts other than sodium chlorlde were used in the aqueo~;s polymerization medium. The effect of using other salts on the average medium bead size (MBS) and the aegree of swelling (D5H O) in water i5 seen below:

% DS
Aqueous MBS H O
Example Salt Solution (mm) (%)2 42 Sodium Sulfate (10) 0.65 35 43 Magnesium Sulfate (10) 1.00 47 44 Potassium Sulfate (10) 0.88 36 ~;: 45 Potassium Chloride (10~ 0.75 36 46 Sodium Chloride (10) 0.68 32 Uniform spherical hydrogel beads were formed in each case with excellent yields (96-97%).

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1~3~3~7 ~ 56 -Examples 47-49 E~fect of Sodium Chloride Salt Concentration on Hydrogen Properties . The process of Examp:le 1 was repeated usiny several concentrati.ons of sodium chloride in the aqueous polymerizati.on medium. The effect of this on hydrogel yield, medium bead si.ze (MBS) and degree of swelliny in water (DS~ O) is given below:

% Sodium Chloride MBS DS O Yield Examplein Aqueous Medium (mm) (~)H2 t%) -47 5 1.00 31.5 95 46 1~ 0.68 32.0 96 .
~8 15 0.99 37.9 ~7 ~9 20 1.~ 37.8 9 : ' .

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E amples Using Low MW Crosslinking Ayents Examples 50~51 describe the preparation of hydro~
gels using the general procedure o Example 1 with the instant monomer (A) - macromer (B) mixture substituted by a conventional hydrogel composition, namely, a monomer, 2-hydroxyethyl methacrylate, crosslinked by a monomeric crosslink.ing agent divinylbenzene or ethylene bls-methacrylate. No macromer (B) is present in the composi~
tion of Examples 50 and 51. Hydrogel products were formed, but they were in each case very irregular in size and also small.

~3g~3~7 Examp:le 50 The general procedure of Example l was followed~
The monomer mixture used consisted of 199.4 grc~ms of 2-hydroxyethyl methacrylate with 2 grams of divinylbenæene with 0.2 grams of tert-butyl peroxypivalate as the free radical catalyst. The polymer:iæation reaction was carried out at 70C for 3 hours with a 100 rpm stirring speed after which the temperature was raised to 100C for l hour.

Small irregular shaped beads were isola-ted in a yield of 190.8 grams (95%) having an average diameter of 0.48 + 0.2 mm and a degree vf swelling in water (DSH2O) of 78%-:;~: : .:. : ~ . .

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- s9 -Exam~le 51 The procedure of Example l was followed. The monomer mixture used consisted of 199.7 grams of 2-hydroxy-ethyl methacrylate with 2 grams of ethylene bis-methacrylate and 0.2 gram of tert-butyl peroxypivalate and 0~1 yram of tert-butylperoctoate as free radical cakalysts. The poly-merization was carried out at 65C for l hour, at 85C
for 2 houxs and finally at 100C for l hour with a lO0 rpm stirring speed.

Irregular shaped beads were isolated in a yield of 195.3 grams (97%) having an average diameter of 0.62 f 0.2 mm and a degree of swelling in water (DSH O) of 79~.

The following example demonstrates, that it is the combination of an hydroxy-substituted monomer such as 2-hydroxyethyl methacrylate (HEMA) with a gelatinous hydroxide such as magnesium hydroxide and a macromeric crosslinking agent, which is essential to make round beads.

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EYample 52~a-c) __ ~ l-liter resin flask with smooth walls was equipped with a reflux condenser, nitrogen inlet tube, thermometer with thermoregulator, baffle and anchor~t~pe stirrer driven by a variable speed stirrer. 180 ml of a 20% solution o sodium chloride in water was charged, followed by 12.5 grams of magnesium chloride hexahydrate.
The solution was slowly heated to 85C and 62 ml of 1 N
sodium hydroxide solution was added dropwise during rapid stir-ring. A slow flow of ni.trogen through the flask ~as maintainec at all times. After all sodium hydroxide was added, the stirring speed was reduced to 150 rpm and 100 grams of a fully reacted mixture consisting of 20~ by weight of poly-(n-butylene oxide) glycol (MW 2000) which had been reacted with 2 moles of isophorone diisocyanate and then end-capped with 2 moles of 4-hydroxybutyl vinyl ether and 80~ by weight of monomer mixture as tabulated below, and having dissolved in it 0.065 grams of tert-butyl peroctoate as a free radical generating initiator, were added. For three hours, the temperature was maintained constant at 85C, the stirrin~
speed at 150 rpm under a nitrogen blanket. After three hours, the temperature was raised to 100C for one hour, after which time the flask was cooled to room temperature.

Five ml of concentrated HCl was added to dissolve the magnesium hydroxide and the content was filtered through :, , .

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t ~ ' ' ' ' ~ ''' ' ' ', ' ' ' . ~: ' 1~3~3~7 - 61 ~

a fine cheese cloth, washed, with 2 1 of water and soaked overnight in 500 ml of ethanol to extract residual monomers.
The beads were filtered through a polyester cloth bag which was sewn closed and dried in a home clothes dry~r.

~ % ~ ~ Yield of Med. Bead DS 2 Example ~IEMA MMA NVP Macromer _ eads Size (mm) ~1 a 40 -- 40 20 72 0.62 304 b -- 40 40 20 none obtained c 10 30 40 - 20 79 0.92 169 Only examples a and c produced beads, whereas example b led to total agglomeration.

HEMA is 2-hydroxyethyl methacrylate MM~ is methyl methacrylate NVP is N-vinyl-2-pyrrolidone Macromer is the terminal vinyl ether macromer aescribed above.

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Exampl 53 A 1~ resin ~lask with smooth walls ~7as equipped with a reflux condenser, nitrogen inlet tube, thermometer with thermoregulator,b~f~le and anchor-type stirrer driven by a variable speed stirrer. 360 grams of a 20~ii solution of sodium chloride in water were charged, ~ollowed by 13.2 grams of aluminum sulfate hexadecahydrate. The svlution ~Jas slo~ly heated to 80C and 160 ml l-N sodiwn hydroxide was added dropwise during rapid stirring. A slow flow of nitrogen through the 1ask was maintained at all times. A~ter all the sodium hydroxide was added, the stirring speed was reduced to 150 rpm and 196 grams of ~ully reacted mixture, consisting of 29.4~ poly-n-butylene oxide (M~ 000), end~
capped with ~ moles of isophorone diisocyanate, 68.6~
2-hydroxyethyl methacrylate, and 2% sodium styrene sulfonate and having dissolved in it 2 grams of water and 0.2 gram of tert.-butyl peroctoate as a free radical ~eneratin~ initiator r were added. For three hours the temperature was maintained constant at 80C; with the stirring speed at lS0 rpm under a nitrogen blanKet. After 3 hours the temperature was raised to 100C for one hour, after which time the flask was cooled to room temperature. 10 cc concentrated hydrochloric acid was added to dissolve the al~minum hydroxide and con-ents .

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~3~7 were filtered througll a fine cheeseclo-th, washed with 2Q water and soa~ed overnight in 500 ml of ethclnol to extract residual monomer. The beads were filtered throu~h a polyester cloth bag which was sewn closed and dried in a home clothes dryer.
180 grams of uniformly round beads were obtained with an average diameter o~ 0.85 m~l. Swelling of the polymer was dependent on the pH; DSp~l=l was 30.7 7 DSpH 8 was 51.1.

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Claims (25)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An improved process for preparing essentially uniform spherical beads of up to 5 mm. diameter of a crosslinked, water-insoluble hydrogel by suspension polymerization of (A) 95 to 30% by weight of the hydrogel of a water-soluble monoolefinic monomer or mixture of said water-soluble monomers, and from O to 70 by weight based on the total monomer of a water-insoluble monoolefinic monomer or mixture of said water-insoluble monomers, with the proviso that the final hydrogel does not contain over 60% by weight of said water-insoluble monomer components, with (B) 5 to 70% by weight of the hydrogel of a polyolefinic crosslinking agent, with a polymerization initiator in a concentrated aqueous inorganic salt solution wherein the improvement comprises carrying out the suspension polymerization with monoolefinic monomers containing at least 5% by weight of the total monomers of a hydroxy substituted hydrophilic vinyl monomer;
employing as the crosslinking agent a polyolefinic macromer having a molecular weight from about 400 to about 8,000, and utilizing from 0.01 to 5% by weight, based on the hydrogel, of a suspending agent selected from the water-insoluble, gelatinous, strongly water-bonding, inorganic metal hydroxides and metal hydroxy salts in the absence of excess alkali or free hydroxyl ions.

2. A process according to Claim 1 wherein the water-soluble monomer is a monoolefinic, monocyclic, azacyclic compound.

3. A process according to claim 1 wherein the water-soluble monomer is a hydroxyalkyl ester of acrylic or methacrylic acid in which alkyl is of 2 to 4 carbon atoms.

4. A process according to claim 1 wherein the water-soluble monomer is an acrylic or methacylic acid ester derived from an alcohol of the formula . Ho-CmH2m-O-(CH2CH2O)n- R

where R is hydrogen or methyl, m is 2 to 5 and n is 1 to 20.

5. A process according to Claim 1 wherein the water-soluble monomer is an N-substituted amide or imide of acrylic or methacrylic acid in which the N-substituent is hydroxyalkyl, wherein alkyl is of 2 to 4 carbon atoms.

6. A process according to Claim 1 wherein the water-soluble monomer is a hydroxyalkyl diester of maleic or fumaric acid, wherein alkyl is of 2 to 4 carbon atoms.

7. A process according to Claim 1 wherein the water-soluble monomer is a hydroxyalkyl vinyl ether, where the alkyl is of 2 to 4 carbon atoms.

8. A process according to Claim l wherein the water-soluble monomer is 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 or N-methylolacrylamide.

9. A process according to Claim 8 wherein the water-soluble monomer is 2-hydroxyethyl methacrylate.

A process according to Claim 9 wherein the water-soluble monomer is N-vinyl-2-pyrrolidone.

11. A process according to Claim 1 wherein the water-insoluble monomer is an alkyl acrylate or methacry-late where alkyl is of 1 to 18 carbon atoms.

12. A process according to Claim l wherein the water-insoluble monomer is a vinyl alkyl ether, wherein alkyl is of l to 5 carbon atoms.

13. A process according to Claim l wherein the insoluble monomer is acrylonitrile or styrene.

14. A process according to Claim l wherein the macromer has the formula or wherein a is 1 or 2, R1 is a polycondensate chain having a mole-cular weight from about 200 to about 8,000 which contains hydrocarbon residues connected via ether, ester, amide or urea linkages or is a polysiloxane of molecular weight between 400 and 8,000; R2 is hydrogen, methyl or -CH2COOR4;
R4 is hydrogen or alkyl of 1 to 10 carbon atoms; R3 is hydrogen or -COOR4 with the proviso that at least one of R2 and R3 is hydrogen; X is an oxygen atom, -COO- or -CONR5; R5 is hydrogen or alkyl of 1 to 5 carbon atoms;
Y is a direct bond or the radical R6-Z1-CONH-R7NHCO-Z2-;
R6 is linked to X and represents branched or linear alkylene of 1 to 7 carbon atoms; Z 1 is an oxygen atom or -NR5-; Z2 is Z1 or a sulfur atom; and R7 is the diradical of an aliphatic, alicyclic or aromatic diisocyanate with the proviso that in case X is oxygen, Y is different from a direct bond and R2 and R3 are hydrogen.

15. A process according to Claim 14 wherein R1 is a poly(ethylene oxide), poly(propylene oxide) or poly(tetramethylene oxide) chain with a molecular weight of about 600 to about 4,000.

16. A process according to Claim 14 wherein, R1 is a chain obtained by the condensation reaction of an aliphatic, alicyclic or aromatic dicarboxylic acid or diisocyanate with an aliphatic diol or diamine.

17. A process according to Claim 14 Wherein R1 is a polysiloxane chain of the structure or wherein R8 is a branched or linear alkylene of 1 to 7 carbon atoms or , n is 1 to 20, R9 is hydrogen or methyl, x is 3 to 120 and y is 2 to 3.

18. A process according to Claim 1 wherein the macromer is a reaction product of a poly(tetramethylene oxide) glycol with a molecular weight of about 600 to about 4,000, first terminated with tolylene-2,4-diisocyanate or isophorone diisocyanate, and then endcapped with a hydroxyalkyl acrylate or methacrylate, where alkyl is of 2 to 4 carbon atoms.

19. A process according to Claim 18 wherein the poly(tetramethylene oxide) glycol has a molecular weight of about 1,500 to about 3,000 and the hydroxyalkyl methacrylate is 2-hydroxyethyl methacrylate.

20. A process according to Claim 1 wherein the suspending agent is an insoluble, gelatinous metal hydroxide or metal hydroxide salt selected from the group consisting of the hydroxides or hydroxide salts of magnesium, aluminum, zirconium, iron, nickel, chromium, zinc, lead, calcium, cobalt, copper, tin, gallium, manganese, strontium, barium, uranium, titanium, lanthanum, thorium and cerium.

21. A process according to Claim 20 wherein the suspending agent is magnesium hydroxide, aluminum hydroxide, magnesium hydroxy salt or aluminum hydroxy salt.

22. A process according to Claim 1 wherein the water-soluble inorganic salt is dissolved in water at a concentration of about 5 to about 25% by weight.

23. A process according to Claim 1 wherein the water-soluble inorganic salt is selected from the chlorides and sulfates of the alkali and alkaline earth metals.

24. A process according to Claim 23 wherein the inorganic salt is sodium chloride or sodium sulfate.

25. A process according to Claim ] wherein from 0.01 to 1% by weight based on monomer of a polymerization catalyst. selected from the organic peroxides and azo initiators is used.