Note: Descriptions are shown in the official language in which they were submitted.
~3~3~
- 1 -
-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
. ' ~
. ~
. ~ ~ , . .
.. . .
9L~L3631
- 2 ~
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
-- 3 --
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.
. . . : - . ::: , ::
- .
~363~
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;
` v~
:
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.
T~e ~
.
,
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.
~ ,: ,: :.,. :
~3~i3~L7
7 --
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~ .
:
~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
... . . .
.,
~36~1~
- 10 -
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.
.~
: . . . . . .
: .
. ., -~- : :
, .::: . .:
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
.
.
~1~3~ 7
- 12 -
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.
.
,,
~: : , ~ , . . . ....... .
~3~3~q
- 13 -
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
- 14 -
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
- 16 -
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.
!~
` ': '' , ,' : : ``
`: ~ ' ' ` ' , . , . ' ` ' :
~3~ 7
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
,. . . . .
: , - - - :
., :,
~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
9 -
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
- 20 -
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-
~ ~.. ,. -. . .
~3~
- 21 -
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.
:
.,, : . , ~ :
~3fi31
22 -
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
- 23 -
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.
: .
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-
-24-
. ~
:
- . - , . .
~3~i3~
- 25 -
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.
. ~e~
'
.
:
:
; .
~ L13~ 7
- 26 -
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.
.
, ' : ' ' ' ' ~
~3~ 7
- 27 -
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,
:, :
- . . .
.. ~ ~ , . .:
~3~ L7
28 -
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.
j
...
..
1~3S3~
- 29 -
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
" , ~; '` '' '~'~
,: , ' : : ,, ; ,,, ,:
' ' ' ' , '`
~3G31
- 30
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~
- 31 -
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.
:- "
.: , ,: :
. .. .. : ,
3~
- 32 -
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.
: . , ,, ~: : ,. . - ;: . .
~3t~3~L7
- 33 -
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.
,
,, , . - : 1 .: , .~ .
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
- 35
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.
~: :- . ................ . .
.
~, . ;
~3~317
- 36 -
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
- 37 -
(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~.
'
: ~ : , :: .~ ~.
~L3~3~t7
- 38 -
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.
:
.
:
~3~3~7
- 39 -
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.
:~ - ,. : ~ , , , :: . : . :
3~7
- 40
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.
.
.
~L3~ '7
O ~ 0~ ~ ~D ' Lr~
~,
~ o~oo ,~ ~ Ln
UJ --' N ~ CO 01:) ~ ,.
n
a)
In ~ 0~ ~ O r~
N E~ .
N ~ ~l t~) N N
f~
.~
~ e~ ~ O O
d~ O
O
U~ o a) ,_ cn
~O Ul ~ O ~I
r~
~ r~
--' G4 H
n r~
`~ O`~ .~ rl rl ,~
O ~ .C
h ~ ~ c) ~:4 a) X Q~ a~ O O ~ rl rl
V r~ r~ ~ ~ O ~ ~ h ~ Q~
.,1 O X O X ~O X r~ r-l O ~ X
~1 ~1 0 ~ O OPl O ~ P~ O o o
t~
a
o
~J N ~
,_ ~ 11 ~I
p,~ O O O
~ rl _ 11 IL1 ~1
Z ~¢ O ~ O
~ 0
a) o o
~`3
q~ o
_
~ ~ X ~ ~
~ ~ ~ ~D n o ~ o o ~
d~ ~ ~ ~ ~r
rCt P~
: ~ '~t
f~ ~ ~ r' ~ cs~ h
~ ~ ~1 ~1 ~ ~1 ~
~ P~t
:
. ~, . ~ .
' "
' ' ' ~ ' . ' ', . .' . '
~3t~
- '~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.
.
' ' ~ ~ ..
. . ' ' . ,. ~ '' . '' :
' ' ~. ~ . "' " ' . '
~3L3~ L7
- 43 -
~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.
~ `''`
:~
.. ..
':.: ~ - :-; . :
....:
~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%.
.
: . " ~ ,
: :
~L~3~3
- 47 -
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:
`: '~ ' ' ' ' , ' ' ~ . ' ' '. ' ' ' ' ' '
~3~3~
~,.9
d. ¦ U-) , ,
O 1~ 11'1 U~
~ ~ ~ ~ ~ ~ ~"
tn
a
~r o 1` c~ ~D
o ~ o cn c~
r; O r~i O O G
,~
a
,1 ~ ~9 ~ a~ ~D
a) a~ cn cn
~a
o r~
h ~)
~ ~1 0 t
.
p:~
O
Z ~1 ~ ~ ~ f')
Ei
'
O O O O
~ O t`~
P
U~
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- 50 -
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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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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- 53 -
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
- 54 -
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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- 55 -
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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- 57
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
- 58 -
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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- 60 -
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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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.
`: :
- 62
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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- 63 -
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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