Note: Descriptions are shown in the official language in which they were submitted.
202811~
- 1-
V-17531/+lllT 8
Hvdro~els based on su~ar alcohol mon ers
The present invention relates to novel hydrogels, a process for their preparation, uses of
the hydrogels, for exarnple as contact lenses, intraocular lenses or in other areas of
application in which biocompatible rnaterials are necessary, and to the abovementioned
articles essentially comprising the novel hydrogels. The novel hydrogels are distinguished
by particular advantages with respect7 for example, to oxygen permeability, water content
and mechanical stability.
It is known that hydrogels (crosslinked polymers which are swellable in water to a limited
extent) have an oxygen permeability which depends on the water content. It increases with
increasing water content. The high oxygen permeability which is fundamentally desired is
norrnally achieved in the known polymers by accepting other severe disadvantages. Thus,
hydrogels having a high water content normally have low mechanical stability, such as
tear strength.
DE-A-3,215,918 ~has already disclosed hydrogels, and contact lenses made therefrom,
which contain a copolymer of a methacrylate of a xylitol whose hydroxyl groups are in
ketal form, and at least one hydrophobic and/or hydrophilic comonomer. However, these
copolyrners either contain no hydrophilic copolymer component or, if they do, contain a
hydrophobic comonomer component in a relatively small amount, ie. at least in an arnount
lower than 25 mole per cent.
By contrast, the copolymers according to the invention always contain a hydrophilic
comonomer component besides the ester of an unsaturated carboxylic acid having 3 or 4
carbon atoms with a sugar alcohol whose hydroxyl groups are in protected form. Ahydrophobic comonomer component may be entirely absent or present in amounts of at
least 25 mole per cent. Insofar, the present invention enriches the state of the art, since
novel hydrogels are disclosed which, due to an appropriate choice of material, have an
extremely favourable combination of properties, such as high water content, good oxygen
permeability and high mechanical strength. The last-mentioned property may be still
further improved by adding at least 25 mole per cent of a hydrophobic component. In
2028112
par~icular, the oxygen permeability can be controlled even after the polymerization,
independently of the material composition, by modifying the water content.
The invention therefore relates to a hydrogel which is a copolymer of a polymerizable
monomer mixture which contains
a) 5-95 mole % of a hydrophobic polyhydroxyvinyl monomer whose hydroxyl groups
are in protected form,
b) 5-95 mole % of a hydrophilic vinyl monomer,
c) 0-40 mole % of a hydrophobic vinyl monomer containing a maximum of two
fluorine atoms, and
d) 0-5 mole %, relative to the total amount of monomers a)-c), of a crosslinking agent,
in which hydrogel the hydroxyl groups of the segments formed by the monomers a) are in
protected or free form, and the proportion of the hydrophobic vinyl monomer c), if it is not
zero, is at least 25 mole %.
In the context of this application, vinyl monomers are not taken to mean exclusively
monomers which contain the vinyl group (-CH=CH2), but generally those which contain a
carbon-carbon double bond. Specific preferred meanings of the word component "vinyl"
in vinyl monomers will become clear from the preferred embodiments below.
The polyhydroxyvinyl monomer a) whose hydroxyl groups are in p~otected form is a vinyl
monomer derived from a sugar alcohol. It has, in particular, the formula I
. Rl-COO-CH2(CHOH)p-CH20H (I)
in which Rl is C2-C3alkenyl, p is a number from 1 to 8 and the hydroxyl groups are in
protected form, and furthermore positional isomers thereof in which the Rl-CO~ group is
bonded to a different oxygen atom, and the oxygen atom to which this group is bonded in
the depicted formula I is one of the hydroxyl groups which are in protected form.
Monomer a) may be one of the above-defined monomers or a mixture of several different
monomers of those defined above.
The proportion of vinyl monomers a) in the monomer mixture is preferably 5-80 mole %
2028112
-3-
or 10-65 mole % and particularly preferably 20-60 mole % or 30-70 mole %, depending
on whether component c) is present.
In the vinyl monomer, derived from a sugar alcohol, of the formula I in which the
hydroxyl groups are in p~otected form, p is preferably a number from 2 to 4. Examples of
sugar alcohols from which compounds of the formula I are derived are xylitol, adonitol,
arabitol, sorbitol, mannitol or dulcitol. Xylitol is preferrçd. C2-C3Alkenyl is vinyl,
1-methylvinyl or 2-methylvinyl.
The protected hydroxyl groups of the compounds of the formula I are preferably protected
in pairs as acid-labile ketals, for example and preferably as addidon products with a
ketone. Two hydroxyl groups which are jointly protected as a ketal are protected, for
example, together by means of a preferably subsdtuted methylene group, such as by lower
aL~cylidene, for example isopropylidene, isobutylidene or 2-methyl-4-pentylidene,
cycloalkylidene, for example cyclohexylidene, or benzylidene.
Particularly preferred representadves of the vinyl monomers of the formula I are5-O-methacryloyl-1,2;3,4-di-O-isopropylidene-DL~xylitol (S-MDPXy) of the formula II
(Ra = methyl, Rb =H), 5-O-acryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol (5-ADPXy)
of the formula II (Ra and Rb = H) and
5-O-crotonyl-1,2;3,4-di-O-isopropylidene-DL-xylitol (5-CDPXy) of the formula II (Ra =
H, Rb = methyl)
H2C-O-C C < ' ~C~ -TH2
H C O\ ~CH3 H3 ~ ~H
-T H CH3 H3 H 1
H-C-O~ ~CH3 H3C~CC H
H2C- CH3 H3C/ -CH2
and the positional-isomeric compounds
3-O-methacryloyl- 1 ,2;4,5-di-O-isopropylidenexylitol and
2028~2
-4-
3-O-acryloyl- 1 ,2;4,5-di-O-isopropylidenexylitol.
The hydrophilic vinyl monomers b) which can be used according to the invention are
preferably acrylates and methacrylates of the formula
R2
I
H2C=C-CooR3,
in which R2 is hydrogen or methyl, and R3 iS a hydrocarbon radical having 1 to 10 carbon
atoms which is monosubstituted or polysubstituted by a water-solubilizing group, such as
carboxyl, hydroxyl or tert-amino, for exarnple tert(lower aL1cyl)amino having 1 to 7 carbon
atoms per lower alkyl group, by a polyethylene oxide group having 2-100 recurring units,
preferably having 2-40 recurnng units, or by a sulfate, phosphate, sulfonate or
phosphonate group, for example a correspondingly substituted aL~cyl, cycloaLtcyl or phenyl
radical or a combination of such radicals, such as phenylaL~cyl or aLtcylcycloaLkyl,
furtherrnore acrylamides and methacrylamides of the formula
H2C=C-CON<
R4
in which R4 is hydrogen or Cl-C4aLI~yl;
acrylamides and methacrylamides of the formula
CH2=f-CONHRS
R2
in which Rs is as defined for R3 or R4;
maieates and fumarates of the forrnula
R300C CH=CH-CooR3;
crotonates of the formula
202~112
CH3-CH=CH~ooR3;
vinyl ethers of the formula
H2C=CH-oR3;
vinyl-substituted five- or six-membered heterocyclic compounds having one or twonitrogen atoms, and N-vinyllactams, such as N-vinyl-2-pyIIolidone, and vinylically
unsaturated carboxylic acids having a total of 3 to 10 carbon atoms, such as methacrylic
acid, crotonic acid, fumalic acid or cinnamic acid.
Preference is given to for example hydroxyl-substituted CrC4aL~cyl (meth)acrylates, five-
to seven-membered N-vinyllactams, N,N-di-CI-C4alkyl(meth)acrylamides and vinylically
unsaturated carboxylic acids having a total of 3 to 5 carbon atoms.
The proportion of the vinyl monomer b) in the monomer mixture is preferably 20-95 or
10-65 mole % and particularly preferably 10-50 or 30-70 mole %, depending on theproportion of the vinyl monomer c). The monomer b) may be one of the above-defined
monomers or a mixture of several different monomers of those defined above.
The water-soluble monomers b) which can be used include: 2-hydroxyethyl acrylate and
methacrylate, 2- and 3-hydroxypropyl acrylate and methacrylate, 2,3-dihydroxypropyl
acrylate and methacrylate, polyethoxyethyl acrylate and methacrylate, and
polyethoxypropyl acrylate and methacrylate, and the corresponding acrylamides and
methacrylamides, acrylamide and methacrylamide, N-methylacrylamide and
N-methylmethacrylamide, bisacetoneacrylamide, 2-hydroxylethylacrylamide,
dimethylacrylamide, dimethylmethacrylamide, methylolacrylamide and
methylolmethacrylamide, N,N-dimethyl- and N,N-diethylaminoethyl acrylate and
methacrylate, and the corresponding acrylamides and methacrylamides,
N-tert-butylaminoethyl methacrylate, N-tert-butylaminoethyl methacrylamide, 2- and
4-vinylpyridine, 4- and 2-methyl-5-vinylpyridine, N-methyl-4-vinylpiperidine, l-vinyl and
2-methyl-1-vinylimidazole, dimethylallylamine and methyldiallylamine, para-, meta- and
ortho-aminostyrene, dimethylaminoethyl vinyl ether, N-vinylpyrrolidone and
2-pyrrolidinoethyl methacrylate, acrylic acid and methacrylic acid, itaconic acid, cinnamic
acid, crotonic acid, fumaric acid, maleic acid and the hydroxy(lower alkyl) monoesters
and diesters thereof, such as 2-hydroxyethyl fumarate, maleate and itaconate and
2028112
-6-
di-(2-hydroxy)ethyl fumarate, maleate and itaconate, 3-hydroxypropylbutyl fumarate and
di-poly(aLIcoxyaL~yl) fumarates, maleates and itaconates, maleic anhydride, sodium
acrylate and sodium methacrylate, 2-methacryloyloxyethylsulfonic acid,
2-acrylamido-2-methylpropanesulfonic acid, 2-phosphatoethyl methacrylate, vinylsulfonic
acid, sodium vinylsulfonate, p-styrenesulfonic acid, sodium p-styrenesulfonate and
allylsulfonic acid, N-vinylpyrrolidone, N-vinylpyridone, N-vinylcaprolactam, andfurthermore the quaternized derivatives of cationic monomers obtained by quaternization
using selected alkyladng agents, for example halogenated hydrocarbons, such as methyl
iodide, benzyl chloride or hexadecyl chloride, epoxides, such as glycidol, epichlorohydrin
or ethylene oxide, acrylic acid, dimethyl sulfate, methyl sulfate and propane sultone.
A more complete list of water-soluble monomers which can be used in connection with
this invention can be found in: R.H. Yocum and E.B. Nyquist, Functional Monomers,
Volume 1, pp. 424-440 (M. Dekker, N.Y. 1973).
Preferred monomers b) are 2-hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone,
N,N-dimethylacrylamide, acrylic acid and methacrylic acid.
Exarnples of suitable hydrophobic vinyl monomers c) which are in some cases usedaccording to the invention are:
acrylates and methacrylates of the formula
H2Cl-COOR6
acrylamides and methacrylamides of the formula
H2Cl CONH R6
maleates and fumarates of the formula
R600C-CH=CH-COOR6,
2028112
-7 -
itaconates of the fo~nula
CH2
R600CSSH2-COOR6
crotonates of the formula
H3CSH=CHSOOR6,
vinyl esters of the formula
R6soosH=cH2
and vinyl ethers of the formula
H2C=CH-O-R6,
in which R2 is hydrogen or methyl, and R6 is a linear or branehed aliphatie, eyeloaliphatic
or aromatie group having 1 to 21 earbon atoms, for exarnple an appropriately substituted
aL~yl, eyeloalkyl or phenyl radical or a combination of such radicals, such as phenylaLl~yl
or aLkylcycloallyl, which may eontain ether or thioether bonds, sulfoxide or sulfone
groups or a carbonyl group; or R6 is a heterocyclic group wh*h contains oxygen, sulfur or
nitrogen atoms and 5 or 6 or, if it is bicyclic, up to 10 ring atoms, or a polypropylene oxide
or poly-n-butylene oxide group having 2 to 50 recurring aL~coxy units, or R6 is an aLkyl
group having 1 to 12 carbon atoms which contains halogen atoms, of which, however, at
most two are fluorine atoms, or R6 is a siloxane group having 1 to 6 Si atoms.
Preferenee is given, in particular, to Cl-C4alkyl esters or Cs-C7eycloalkyl esters of
vinylically unsaturated earboxylie acids having 3 to 5 earbon atoms.
The proportion of the vinyl monomers c) in the monomer mixture is either O mole % or in
a preferred embodiment 25-35 mole % and in a specific embodiment 30 mole %. The
monomers c) can also be one of the above-defined monomers or a mixture of several
different monomers of those de~lned above.
202811~
- 8 -
Examples of suitable hydrophobic monomers are: methyl acrylate and methacrylate, ethyl
acrylate and methacrylate, propyl acrylate and methacrylate, isopropyl acrylate and
methaclylate, butyl acrylate and methacrylate, isobutyl acrylate and methacrylate,
tert-butyl acrylate and methacrylate, ethoxyethyl acrylate and methacrylate, methoxyethyl
acrylate and methacrylate, benzyl acrylate and methacrylate, phenyl acrylate andmethacrylate, cyclohexyl acrylate and methacrylate, trimethylcyclohexyl acrylate and
methacrylate, isobornyl acrylate and methacrylate, dicyclopentadienyl acrylate and
methacrylate, norbornylmethyl acrylate and methacrylate, cyclododecyl acrylate and
methacrylate, 1,1,3,3-tetramethylbutyl acrylate and methacrylate, n-butyl acrylate and
methacrylate, n-octyl acrylate and methacrylate, 2-ethylhexyl acrylate and methacrylate,
decyl acrylate and methacrylate, dodecyl acrylate and methacrylate, tridecyl acrylate and
methacrylate, octadecyl acrylate and methacrylate, glycidyl acrylate and methacrylate,
ethylthioethyl acrylate and methacrylate, furfuryl acrylate and methacrylate, tri-, tetra- and
pentasiloxanylpropyl acrylate and methacrylate, and the corresponding amides;
N-(l,l-dimethyl-3-oxobutyl)acrylamide; mono- and dimethyl fumarate, maleate and
itaconate; diethyl fumarate; isopropyl fumarate and itaconate and diisopropyl fumarate
and itaconate; mono- and diphenyl fumarate and itaconate, and methylphenyl fumarate
and itaconate; methyl crotonate and ethyl crotonate; methyl vinyl ether and methoxyethyl
vinyl ether, vinyl acetate, vinyl propionate, vinyl benzoate, acrylonitrile, styrene,
a-methylstyrene and tert-butylstyrene.
Preferred monomers c) are methyl methacrylate, n-butyl methacrylate, isopropyl
methacrylate, isobutyl methacrylate, cyclohexyl methacrylate or a mixture thereo
"
The crosslinking agents d) are, in particular, diolefinic monomers, for example allyl
acrylate, allyl methacrylate, ethylene glycol diacrylate and dimethacrylate, diethylene
glycol diacrylate and dimethacrylate, triethylene glycol diacrylate and dimethacrylate,
tetraethylene glycol diacrylate and dimethacrylate and generally polyethylene oxide glycol
diacrylate and dimethacrylate, 1,4-butanediol diacrylate and dimethacrylate,
poly-n-butylene oxide glycol diacrylate and dimethacrylate, propylene glycol diacrylate
and dimethacrylate, polypropylene oxide glycol diacrylate and dimethacrylate,
thiodiethylene glycol diacrylate and dimethacrylate, di-(2-hydroxyethyl)sulfonyldiacrylate and dimethacrylate, neopentyl glycol diacrylate and dimethacrylate,
trimethylolpropane triacrylate and tetraacrylate, pentaerythritol triacrylate and
tetraacrylate, divinylbenzene, divinyl ether, divinyl sulfone,
disiloxanylbis-3-hydroxypropyl diacrylate and methacrylate, and related compounds.
2028112
g
Ethylene glycol dimethacrylate is preferr~d.
If present, the crosslinldng agent is preferably added in amounts of from 0.01-1 mole %,
particularly preferably in an amount of from 0.2-1 mole %, in each case relative to the
total amount of monomers a) to c).
A preferred hydrogel comprises a monomer mixture containing
S-80 mole % of vinyl monomer a),
20-9S mole % of vinyl monomer b) and
0 mole % of vinyl monomer c).
f
A further preferred hydrogel comprises a monomer mixture containing
10-65 mole % of vinyl monomer a)S
10-65 mole % of vinyl monomer b) and
25-35 mole % of vinyl monomer c), in pardcular 30 mole % of c).
A particularly preferred hydrogel comprises a monomer mixture containing
30-70 mole % of vinyl monomer aj,
30-70 mole % of vinyl monomer b) and
0 mole % of vinyl monomer c).
A likewise particularly preferred hydrogel comprises a monomer mixture containing
20-60 mole % of vinyl monomer a),
10-S0 mole % of vinyl monomer b) and
30 mole % of vinyl monomer c).
The hydrogels according to the invention are produced, for example, by therm~l
polymerizadon or by free-radical copolymerization, either in bulk or in the presence of
small amounts of solvent. Polymerization is expediently carried out at elevated
temperature, preferably in the presence of an inidator which forms free radicals, for
example at a temperature in the range of about 30C to about 105C. These inidators are
preferably peroxides or azo catalysts having a half-life drne period of at least 20 minutes
at the polymerization temperature. Typical exarnples of peroxy compounds which can be
used are isopropyl percarbonate, tert-butyl peroctanoate, benzoyl peroxide, lauroyl
peroxide, decanoyl peroxide, acetyl peroxide, succinyl peroxide, methyl ethyl ketone
peroxide, tert-butyl peroxyacetate, propionyl peroxide, 2,4-dichlorobenzoyl peroxide,
202~112
- 10-
tert-butyl peroxypivalate, pelargonyl peroxide, 2,5-dimethyl-2,S-bis(2-ethylhexanoyl-
peroxy)hexane, p-chlorobenzoyl peroxide, tert-butyl peroxybutyrate, tert-butylperoxy-
maleic acid, tert-butyl peroxyisopropylcarbonate and bis(l-hydroxycyclohexyl) peroxide.
The azo compounds include 2,2-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethyl-
valeronitrile), l,l'-azobis(cyclohexanecarbonitrile) and 2,2'-azobis(2,4-dimethyl-
4-methoxyvaleronitrile).
It is also possible here to use other mechanisms which form free radicals, such as
irradiation with, for example, X-rays, electron beams and UV radiation.
The amount of initiator can vary between 0.001 and 1 mole %, relative ~o components a)
to d), but is preferably 0.01 to 0.3 mole %.
The monomers to be polymerized are expediently purified before the polymerization, in
particular to remove inhibitors with which they are stabilized. Thus, for example, they are
washed with suitable dilute aqueous bases, such as aLlcali metal hydroxides, for example
sodium hydroxide solution, and purified by distillation under gentle temperaturecondidons.
The polymerization mixtures are polymerized on a laboratory scale in a manner known per
se, for example in a cylindrical mould, by subjecting them, in plastic syringes, to a
temperature programme in which the temperature is increased from 30C in steps to about
100C. The temperature steps can be, for example, between S and 10C, with a residence
dme of 1 to 12 hours per temperature. Two- or five-hour intervals are customary, but
individual temperatures can also be mauntained for up to 20 hours. Condidoning at the end
for S to 20 hours at temperatures between 70 and 100C is usual.
In order to obtain hydrogels according to the invention, the copolymers obtainable as
described above must be hydrated. This is expediently carried out by storing them in
aqueous buffered saline solution, which is preferably isotonic. Before the hydration, the
polymers are normally cut into thin discs.
The above-described hydrogels contain, in the segments formed by the vinyl monomers a),
the hydroxyl groups which are present there still in protected form, for example as
isopropylidene ketals. They are therefore still relatively highly hydrophobic. They can be
~028112
converted into hydrogels according to the invention which contain, in the segments
formed by the vinyl monomers a), dhe hydroxyl groups present dhere in free form by
removing the protecting groups. This can be accomplished by introducing them into an
acidic medium, as is generally known for acetal cleavages, for example in accordance
with GB 2,091,750 (Tanaka et al.).
The protecting-group removal causes the segments formed by the vinyl monomers a) to
become hydrophilic to highly hydrophilic. The ability of the hydrogels to absorb water can
thereby be significandy increased. In this way, dhe oxygen permeability can still be
affected after the polymerization while the material composition remains fundamentally
dhe same. The hydrogels according to the invention dherefore have the advantage dhat the
oxygen permeability can be controlled by two mutually independent measures: the content
of vinyl monomers a), b) and c) on dhe one hand, and dhe hydrolysis of the
hydroxyl-protecting groups of dle vinyl monomer a) on the odher hand.
A further surprising aspect of dhe invention is dhat the hydrophilic monomers b) with the
hydrophobic monomers c) and the sugar alcohol monomers give polymers at all which,
both in the unswollen and in the swollen state (hydrogel), do not have phase separation
and are dhus optically clear.
The hydrogels according to the invention have very good oxygen permeabilities and are at
the same time hydrophilic and, in addition, mechanically stable, ie. they have, for
example, a high tear strength. They are therefore highly suitable as materials for contact
lenses or intraocular lenses and as other biocornpatible materials, for example implants,
eye bandages, transdermal systems or other forms of medicament carriers.
The production of contact lenses from the hydrogels mentioned can be effected in a
manner known per se. To this end, the mixtures to be polymerized are polymerized, for
example, in a cylindrical mould, and the rods obtainable are cut, after being released from
the mould, into discs or buttons, which can be further processed mechanically.
Alternatively, the polymerization can be carried out in lens moulds, so that lens blanks are
obtained directly as polymers.
The reaction is preferably carried out under an inert atmosphere if it is carried out in open
moulds. As is known, oxygen inhibits the polymerization and results in longer
polymerization times. If closed moulds are used to form the polymer, the moulds comprise
2028112
inert materials having low oxygen perrneability and non-stick properties. Examples of
suitable mould materials are polytetrafluoroethylene, such as Teflon~, silicone rubber,
polyethylene, polypropylene and polyesters, such as Mylar~. If a suitable release agent is
used, glass and metal moulds can also be used.
The monomers b) and c) used are known, are in some cases commercially available, or
can be prepared by processes known per se.
The monomers of the formula I can be prepared, for example, by reacting a compound of
the formula m
HOCH2(CHOH)p-CH20H (m)
in which p is a number from 1 to 8, and in which (p+l) hydroxyl groups are in protected
form, or, if appropriate, a mixture of two or more different compounds of the formula m
as defined above, but which differ in that a different hydroxyl group is in each case not in
protected form, or a reacdve derivative of a compound of the formula m or of a mixture of
compounds of the formula III, with a reactive derivative of a compound of the formula IV
Rl-COOH (IV)
.~ .
in which R1 is C2-C3aL~cenyl, and, if necessary, an isomer mixture obtained is resolved.
A reactdve derivative of a compound of the formula IV is, in pardcular, a carboxylic
anhydride, such as an internal anhydride or an anhydride with a hydrohalic acid, such as
with hydrochloric acid. Compounds of this type are, for example, acrylyl chloride,
methacrylyl chloride or crotonyl chloride or methacrylic anhydride.
A reactive derivadve of a compound of the formula m is, for example, a metal salt of a
compound of the formula m, for example an alkali metal salt, such as a sodium salt.
The reaction is carried out, starting from a compound of the formula III having one free
hydroxyl group, preferably in an inert solvent, such as an organic base, for example a
tertiary amine, such as pyridine, at temperatures between -40 and 100C, in particular with
exclusion of moisture, such as by working under a protective-gas atmosphere, for example
with nitrogen gas. Starting from a reactive derivative of a compound of the formula III, the
202811~
inert solvent used is preferably a hydrocarbon or a hydrocarbon mixture whose boiling
range is advantageously above 50C. Otherwise, the process conditions are essentially
identical. Specific advantageous process parameters are given in the examples.
For the resolution of isomer mixtures obtained, chromatographic methods are suitable, in
particular those using water/lower aL~canol mixtures as the eluent, for example
water/methanol mixtures. High-pressure liquid chromatography (HPLC) is particularly
suitable. Specific advantageous process parameters are given in the examples.
The starting compounds of the formula m, as defined above, can be prepared in a manner
known per se, for example from compounds of the formula m in which (p+2) hydroxyl
groups are in free forrn, by reaction with a ketone, for example acetone.
The examples below illustrate the subject-matter of the invention, but without representing
a limitation, for example to the scope of the examples. Percentages in amount data are
mole per cent, unless expressly stated otherwise. Temperatures are given in degrees
Celsius.
The abbreviations used have the following meanings:
AIBN azoisobutyr~nitrile
BuMA n-butyl methacrylate
EGDMA ethyleneglycoldimethacrylate
HEMA 2-hydroxyethyl methacrylate
MMA methyl methacrylate
Regarding the abbreviations of the monomers a) used, reference is made to the
explanations in connection with formula I.
General information on Examples 1-7:
GC: Perkin-Elmer Sigma 1, glass column (length: 1250 mm, internal diameter 3mm)
Packing material Chromosorb G containing 5 % of polyethylene succinate
35, column temperature 170C, carrier gas He, 25 ml/min.
Analytical HPLC:
Steel column (length 250 mm, 0 4.6 mm)
~2811~
- 14-
Packing material 5 C18 Nucleosil, Macherey and Nagel, Integrator
Chromatopac C-R 3A
Shimadzu, 20C.
reparative HPLC:
Steel column (length 250 mm, 0 32 mm)
Packing material 7 C18 Nucleosil, Macherey and Nagel, 20C.
.
Example 1: 1.2;3,4-Di-O-isopropvlidene-DL-xvlitol
300 g of xylitol (1.97 mol) are reacted at 25C with acetone by a method of R.S. Tipson
and L.H. Cretchcr, J. Org. Chem. 8, 95 (1943) and P.A. Levenne and R.S. Tipson, J. Biol.
Chem. 115, 731 (1936) and ibid. 106, 113 (1935). The product is disdlled in an oil-pump
vacuum (75C, 0.03 hPa). The syrup obtained contuns about 90 % of the title compound
as the major product and 1,2;4,5-di-O-isopropylidenexylitol as a by-product.
In order to isolate the title compound, the syrup is distilled over a 70 cm packed column
filled with Brunswick coils (diameter: 4 mm) in an oil-pump vacuum (0.03 hPa) (head
temperature: 75C; bottom temperature 135C; withdrawal dripping rate: 1 drop/3 s). The
syrup is withdrawn in 10 fractions of about 30 g each. As the GC of the first fiaction
shows, the by-product (retention dme: 6.3 min) is highly concentrated in the first fracdon
(peak area propordon 30 %). The proportion of the by-product considerably decreases
condnuously from the 1st ! the 4th fraction. It is no longer detectable in the GC in the 6th
fracdon. Fractions 6 to 10 comprise GC-pure 1,2;3,4-di-O-isopropylidene-DL-xylitol
(retendon time: 10.5 min; Rf: 0.69 in absolute ethanol; Rf: 0.65 in absolute methanol).
m.p.: 36-37C; m.p. (lit): 36C (N. Ba~ett et al., J. Chem. Soc. 1965, 3382) or m.p. (lit):
32-34C ~ et al., Carbohydr. Res. 67, 117 (1978).
Example 2: 1.2:4,,~-Di-O-isopropvlidenexvlitol
This compound is separated from 3.00 g (12.9 mmol) of the first fraction from the
Brunswick coil distilladon described in Example 1 by means of preparative HPLC (eluent:
mixture of 30 % by volume of methanol and ? % by volume of water, flow rate 42
mVmin; amount injected: 300,ul of substance; pressure 140 bar; detection: Knauerrefractometer).
The methanol and the wator are stripped off from a total of I I of the resultant solution on
2028112
- 15-
a Rotavapor. The syrup which remains is distilled using a bulb tube column in an oil-pump
vacuum (75C, 0.03 hF~a). The 1,2;4,5-di-O-isopropylidenexylitol obtained has the
following chromatographic characterisdc data:
Rf: 0.60 (in absolute ethanol); 0.58 (in absolute methanol); GC: retention time: 6.3 min.
Example 3: 5-O-MethacrYlovl-1.2:3.4-di-O-isoproPYlidene-DL-xvlito!
a) Synthetic route I: 10 rnl of methacrylic anhydride (0.071 mol) are added at 20C to 8.94
g (39 mmol) of 1,2;3,4-di-O-isopropylidene-DL-xylitol, dissolved in 50 rnl of pyridine.
The reaction mixture is stirred at 80C for 4 hours with exclusion of moisture and, after
cooling to 20C, mixed with 50 ml of water. This solution is extracted three times with
100 ml of petroleum ether (boiling range 90-100C) in each case. The combined
petroleum ether phases are washed by shaking once with 300 ml of 5 % sodium hydroxide
solution and once with 300 ml of water and are subsequently dried over sodium sulfate.
0.03 g of tert-butylpyrocatechol is added, the petroleum ether is removed, and the residue
is distilled on a Rotavapor in a water-pump vacuum without a condenser, the receiving
flask being cooled with ice water (b.p. 93C/0.05 hPa, bath temperature 130C).
S-O-Methacryloyl- 1,2;3,4-di-O-isopropylidene-DL-xylitol is obtained as a colourless
syrup which begins to crystallize after storage at 0C for two months. The crystals are
dissolved in 6.5 ml of petroleum ether (boiling range 80-100C) at 20C and recrystallized
as described under b).
b) Synthetic route II: 13.2 g of 60 % sodium hydride/mineral oil dispersion ( ^ 7.9 g, 0.33
mol of sodium hydride) from Janssen Chimica are washed twice with petroleum ether
under a nitrogen atmosphere in order to remove the mineral oil. To do this, the sodium
hydride dispersion is stirred for 15 minutes at 60C with 200 ml of petroleum ether
(boiling range: 90-100C3. When, after a further 15 minutes, the sodium hydride has
settled on the flask bottom, the petroleum ether is decanted off and the sodium hydride is
again washed in the same way with 200 ml of petroleum ether. The petroleum ether is
again decanted off. 225 ml of petroleum ether (boiling range 90-100C) are added to the
washed sodium hydride, and 75 g (0.325 mol) of syrupy
1,2;3,4-di-O-isopropylidene-DL-xylitol are subsequently added slowly at 20C in a stream
of nitrogen (evolution of hydrogen!).
This reaction mixture is stirred for 2 hours at 60C under nitrogen and subsequently
cooled to -10C. 31.5 ml (0.33 mol) of methacrylyl chloride (from Fluka), dissolved in
202~1~2
- 16-
150 ml of petroleum ether (boiling range 90-100C), are then slowly added dropwise
(exothermic reacdon!) with sdrring and with exclusion of moisture at a rate such that the
temperature remains between -5C and -10C. The flask is kept at -10C overnight. The
mixture is subsequently stirred at 60C for 1 hour and cooled to 20C, and the precipitate
is filtered off. The precipitate is washed with 150 ml of petroleum ether. The combined
filtrates are washed once with 750 ml of 5 % sodium hydroxide soludon and once with
750 ml of water and are dried over sodium sulfate. 0.25 g of tert-butylpyrocatechol is
subsequently added (as inhibitor). The petroleum ether is removed on a Rotavapor in a
water-pump vacuum at 30C, and the syrup which remains is distilled in an oil-pump
vacuum without condenser. The receiving flask is cooled with ice water (b.p. 98C/0.07
hPa, bath temperature 130C). S-O-Methacryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol
is obtained as a colourless syrup.
Seed crystals can be obtained, as described in Example 4, using a sublimation apparatus.
60 ml of petroleum ether (boiling range 80- 100C) are dissolved in 78 g of the syrup
obtained. The soludon is cooled to -20C and then, after a seed crystal has been added, left
to crystallize for 24 hours. The petroleum ether, cooled to -20C, is subsequently poured
quickly off the crystals. The crystals are dried at 20C in an oil-pump vacuum and
comminuted. The crystals obtained in this way are subsequently crystallized again as
described.
M.p.: 35-35.5C; m.p. (lit.): 33C (A.N. Anikeeva arid S.N. Danilov, Zh. Obshch. Khim.
34 (4), 1063-4 (1964); Chem. Abstr. 61, 1929 f (1964)).
GC: Retention time: 8.0 min; analytical HPLC: retention dme: 24.5 min.
Example 4: S-O-AcrvloYl- 1.2:3.4-di-O-isopropvlidene-DL-xYlitol
8.75 g of 60 % sodium hydride/mineral oil dispersion ( ^ 5.25 g of sodium hydride, 0.219
mol) are washed twice analogously to Example 3 with 65 ml of petroleum ether (boiling
range: 90-100C) in each case under nitrogen. 400 ml of petroleum ether (boiling range
90-100C) are added to the washed sodium hydride, and 50.0 g (215 mmol) of syrup-form
1,2;3,4-di-O-isopropylidene-DL-xylitol are subsequently added slowly at 20C in a stream
of nitrogen (evolution of hydrogen!). This reaction mixture is stirred at 80C for 4 hours
under nitrogen and subsequently cooled to -35C (with stirring). 17.5 ml (215 mmol) of
distilled acrylyl chloride from Fluka are then dissolved in 250 ml of dry petroleum ether
and slowly added dropwise (exothermic reaction!) with sti~ing (about 2 hours) and with
exclusion of moisture at a rate such that the temperature remains between -30 and -35C.
202811~
- 17-
The flask is kept at -10C overnight. The mixture is then stirred at 20C for 1 hour, and the
precipitate is filtered off with suction using a D4 frit. The solution is concentrated to 150
ml on a Rotavapor (water bath 27C) in a water-pump vacuum, washed by shaking twice
with 150 ml of 5 % sodium hydroxide solution in each case and dried over sodium sulfate.
0.25 g of tert-butylpyrocatechol is added to this solution; the petroleum ether is stripped
off on a Rotavapor (water bath 27C). The syrup which remains is distilled in an oil-pump
vaccum without condenser. The receiving flask is cooled with ice water, b.p. 81C/0.08
hPa, bath temperature 110C. 5-O-Acryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol is
obtained as a colourless syrup.
In order to produce crystals, the following procedure is adopted: 0.5 g of the syrup
obtained is transferred into a sublimation apparatus. The cold finger is cooled to -50C,
and the syrup is warmed to 70C in an oil-pump vacuum (0.04 hPa). After about 1 hour,
the syrup has distilled onto the cold finger. The syrup crystallizes slowly on the cold finger
while the cold finger is warmed to 20C.
22 g of the syrup obtained are dissolved in 100 rnl of petroleum ether (boiling range
80-100C) at 20C, and this solution is washed by shaking twice with 100 ml of 5 %
sodium hydroxide solution in each case and once with 100 ml of water. The solution is
dried over sodium sulfate, subsequently concentrated to 65 ml on a Rotavapor (water-bath
temperature 27C) in a water-pump vacuum, and recrystallized as under Example 3b.
l4H22O6(286-3) calc. C58.73 H7.75
found C59.18 H 7.72
M.p.: 32-33C, white crystals, n2D0 = 1.4561 (syrup)
Rf: 0.90 (in absolute ethanol),0.90 (in absolute methanol), GC: retention tilne 7.8 min.
Example 5: 5-O-Crotonovl- I ~2:3.4-di-O-isopropvlidene-DL-xvlitol
1.6 g of 60 % sodium hydride/mineral oil dispersion ( ^ 0.96 g of sodium hydride, 40
mmol) are washed as described in Example 3. 30 ml of petroleum ether (boiling range
90- 100C) are added to the washed sodium hydride, and 10.0 g (43 mmol) of syrupy
1,2;3,4-di-O-isopropylidene-DL-xylitol are subsequently added slowly at 20C in a stream
of nitrogen (evolution of hydrogen!). The mixture is then stirred at 70C for 3 hours under
a nitrogen atmosphere. The mixture is cooled to 20C and 4 ml (40 mmol) of crotonyl
2028112
- 18-
chloride, dissolved in 20 ml of petroleum ether (boiling range 80- 100C), are added
dropwise a~ 20C with exclusion of moisture. This reaction rnixture is stirred at 20C for 1
week with exclusion of moisture, and the precipitate is subsequently filtered off. The
filtrate is washed by shaking twice with 30 rnl of 5 % sodium hydroxide solution in each
case and once with 30 ml of water, and is dried over sodium sulfate. The petroleum ether
is subsequently stripped off on a Rotavapor in a water-pump vacuum. The syrup which
remains is distilled in an oil-pump vacuum without condenser (b.p. 95C/0.09 hPa, bath
temperature 135C). S-O-Crotonoyl-1,2;3,4-di-O-isopropylidene-DL-xylitol is obtained as
a colourless syrup which crystallizes slowly at 20C.
The syrup obtained is dissolved in 7 ml of petroleum ether (boiling range 80-100C),
cooled to -20C and, after a seed crystal has been added, left to crystalliæ for 24 hours.
The crystals, cooled to -20C, are subsequently filtered off quickly under suction using a
frit and dried at 20C in an oil-pump vacuum.
l5H24O6 (300-4) calc. C S9.99 H 8.05
found C 59.84 H 8.08
M.p.: 41.5-42.5C, white crystals n2D0 = 1.4610 (syrup),
f: 0.89 ffn absolute ethanol), 0.87 (in absolute methanol).
Example 6: 3-O-MethacrvloYI-1.2:4.5-di-O-isopropvlidenexylitol
7.5 g (32 mmol) of the isomer rnixture from the fi1rst fracdon of the Brunswick coil
distilladon from Example 1 are reacted analogously by synthedc route I (see Example 3)
and a further 7.5 g by synthedc route II (see Example 3). The syrup obtained by synthetic
route I (6.00 g, 67 %) and the syrup obtained by synthetic route II (6.50 g,73 %) each
contain S-O-methacryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol as the major product
and contain the title compound as a by-product. The methanol is stripped off from the total
of 2 1 of resultant solution on a Rotavapor in a water-pump vacuum (bath temperature
30C). The aqueous soludon which remains is extracted twice with 1 1 of petroleum ether
(boiling range 80-100C) in each case. The combined petroleum ether phases are dried
over sodium sulfate. Petroleum ether is stripped off on a Rotavapor in a water-pump
vacuum (water-bath temperature 27C). The syrup which remains crystallizes slowly at
20C. The crystals of 3-O-methacryloyl-1,2;4,5-di-O-isopropylidenexylitol are dried at
20C in an oil-pump vacuum.
~028112
,9
M.p.: 69-70C; GC: retention dme: 5.7 min.
The title compound can also be separated off from
5-O-methacryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol by preparative HPLC (eluent:
soludon of 60 % by volume of methanol and 40 % by volume of water, flow rate: 50mVmin, amount injected 1 ml, pressure 140 bar, detection UV 254).
Rf: 0.86 (in absolute ethanol, 20C), 0.78 (in absolute methanol, 20C), analydcal HPLC:
retendon time 20.8 min, same conditions as in Example 3.
Example 7: 3-O-Acrvlovl-1.2:4.5-di-O-isoPropvlidenexvlitol
7.5 g (32 mmol) of the isomer rnixture from the first fraction of the Brunswick coil
distillation from Example 1 are reacted analogously to Example 4. The syrup obtained
contains S-O-acryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol as the majorproduct and
contains the title compound as the by-product. The title compound is separated off from
S-O-acryloyl-1,2;3,4-di-O-isopropylidene-DL-xylitol by preparative HPLC. The solution
obtained (1 1), comprising 3-O-acryloyl-1,2;4,5-di-O-isopropylidenexylitol, methanol and
water, is worked up as described in Example 6.
M.p.: 65-66C; GC: retention dme 6.0 min.
General data regarding the examples below:
HEMA (Rohm GmbH) - stabilized with hydroquinone and hydroquinone monomethyl
ether - is freed from the inhibitors by washing the pertinent monomer (100 ml amounts)
with 3xlO0 ml of 5 % sodium hydroxide solution and lxlO0 ml of water, drying thesolution over Na2SO4 and disdlling the product without inhibitor, avoiding overheating
due to the headng bath. The cloudy inidal fraction (about 10 ml) is discarded. When
weighing out HEMA, the EGDMA content (on average 0.14 mole %) determincd by gas
chromatography in the starting monomer is taken into account. The initial weight of
monomers is a total of 11.00 g per batch. S.S mg of AIBN are added to all the batches. The
AIBN is only added last to samples 8,9,17, 18, 26, 33, 34,41, 42, 49 and 50 after the
S-MDP-Xy or S-ADP-Xy crystals have been rapidly melted at 50C and after the melts
have cooled to 20C.
Example 8: (described for sample 21 as an example): 4.611 g of HEMA, 2.124 g of MMA,
2Q28~12
- 20 -
4.247 g of 5-MDPXy, 18.2 mg of EGDMA and 5.5 mg of AIBN are weighed out into a 25
ml conical flask. The polymerization batch is then stirred at 20C for 1 hour until all the
crystals have dissolved completely in the mixture. When a homogeneous liquid mixture
has been produced, it is transferred into 10-ml plastic syringes (Henke-Sass Wolf,
Tuttlingen, material: polyethylene and polypropylene, melting point about 140C, internal
diameter: 16 mm). The air is forced out, the syringe batches are melted, and the stamp is
fastened by a wire. The syringes sealed in this way are placed in a water bath, it being
ensured that the water surface always has a higher level than the surface of the monomer
mixture in the syringe. The polyrnerization is then carried out for 12 hours at 30C, 5
hours at 40C, and 2 hours at each of 50C, 60C and 70C. The syringes with their solid
contents are then post-polymerized in a drying oven for 2 hours at 80C and then for 5
hours at 90C. The polymers obtained are removed from the syringes and conditioned for
8 hours at 90C. A cylindrical, hard polymer is obtained. The polymer sample is hard and
glass-clear.
Tables Ia and Ib below indicate the material composition of the monomer mixtures, which
are reacted analogously to the procedure described above for sample 21. Polymer samples
35-40, 43-48,51-55 and 59-62 are hard and cloudy. All the other samples are hard and
glass-clear. The initial weight of AIBN is always 5.5 mg.
2~2~
Table Ia: Composi~ion of samples 1-34
Sampl~ EGDMA HEMA 5 MDP-Xy MMA (a) or Bu~LA (b)
No. [mole %]tmgl tmole %]tg] tmole %] tg][mole 9~o] [g]
1 0.2 10.0100 109900'
2 0.2 105 95 9.802 S 1.188
3 0.2 109 90 8.75010 2.239
4 0.2 11.~ 80 6974 20 4.015
S 0.2 123 70 S530 30 5.458
6 0.2 125 65 4.90535 6.083
7 Q2 13.2 S0 3326 S0 7.661
8 0.2 13.9 25 1389 75 9.597
9 0.2 14.5 0 100 10.986
1.0 1419100 10.858 0
11 1.0 134A 95 9.691 5 1.175
12 1.0 127.890 8.65710 2.215
13 1.0 1165 80 6.90720 3.977
14 1.0 107A 70 SA82 30 5.411
IS 1.0 103A 65 4.86535 6.032
16 1.0 93A S0 3302 S0 7.605
17 1.0 81.0 25 1381 75 9.538
18 1.0 72.1 0 100 10.928
19 0.2 183 70 8.263 0 30 2.719 (a)
0.2 183 60 6.21310 2.385 30 2385 (a)
21 0.2 18.2 S0 4.61120 4.247 30 2.12A (a)
22 0.2 18.2 40 3325 30 5.743 30 1914 (a)
23 0.2 18.2 30 2.27040 6.970 30 1.742 (a)
24 0.2 18.2 20 1389 S0 7.994 30 1599 (a)
0.2 18.1 10 0.64160 8.863 30 lA77 (a)
26 Q2 18.1 70 9.609 30 1373 (a)
27 0.2 16.6 70 .7A86 O 30 3.173 (b)
28 Q2 16.7 60 5.69410 2.185 30 3.104 Cb)
29 0.2 169 S0 4.26520 3.929 30 2.790 (b)
0.2 17.0 40 3.09830 S.3Sl 30 2.534(b)
31 Q2 17.0 30 2.12840 6.535 30 2320 (b)
32 0.2 17.1 20 1309 S0 7.534 30 2.140 (b)
33 0.2 17.2 10 0.60760 8.390 ` 30 1986 (b)
34 0.2 17.2 O 70 9.130 30 1.853 (o)
202811~
-22 -
Table Ib: Composition of samples 35-66
Sannple EGDMA HnE~fA S-ADP-Xy ~ A(a) or Bu~L~ ~b)
No. [mole %] Im8] Imolc %] IEd [mole ~o] Lgl tmole %] 18]
350.2 10.0 100 10990 0
360.2 10.6 95 9.851 5 1.138
370.2 11.0 90 8.834 10 2.155
380.2 11.9 80 7.094 20 3.894
390.2 12.8 65 5.035 35 5.952
400.2 13.6 S0 3.438 S0 7.548
410.2 14.5 25 1.448 75 9.537
420.2 15.2 0 100 10.985
43 1-0 141.9 100 10.858 0
441.0 135.1 9S 9.740 S 1.125
451.0 129.0 90 8.739 10 2.132
461.0 118.5 80 7.026 20 3.856
471.0 106.1 65 4992 35 5.902
481.0 96.5 50 3A12 S0 7.491
491.0 84.4 25 1.439 75 9A77
S01.0 75.6 0 100 10.~24
Sl0.2 18.3 70 8.263 0 30 2.719 (a)
520.2 18.4 60 6.276 10 2.296 30 2A09 (a)
530.2 18.6 S0 4.695 20 4.123 30 2.163 (a)
540.2 18.7 40 3A08 30 S.611 30 1.962 (a)
55` 0.2 18.7 30 2339 40 6.847 30 1.796 (a)
S60.2 18.8 20 lA37 S0 7.889 30 1.655 (a)
570.2 18.8 10 0.667 60 8.780 30 1535 (a)
580.2 18.9 0 70 9.550 30 lA31 (a)
S90.2 16.6 70 7A86 O 30 3.498 ~b)
60 02 16.9 60 S.747 10 2.103 30 3.133 ~b)
610.2 17.1 S0 4337 20 3.809 30 2.837 ~b)
620.2 17.4 40 3.170 30 S.220 30 2592 ~b)
~r 630.2 17.S 30 2.189 40 6.407 30 2387 Cb)
640.2 17.7 20 1352 S0 7.420 30 2.211 ~b)
650.2 17.8 10 0.630 60 8.293 30 2.059 ~b)
660.2 17.9 o 70 9.055 30 1.927 ~b)
Example 9: Hydration of the polvmer discs
The polymers from Example 8 are cut into discs (diameter: 11.9 to 12.1 mm, thickness:
0.137 to 0.256 mrn) and polished. The di~neter Dp, the ~hickness dp alld the weight Wp of
the discs are determined. Dp is determined using a magnifying glass with measurement
scale and dp is determined using a rnicrometer screw. The polymer discs obtained in this
way are stored for 10 days at 35C in aqueous "buffered isotonic saline solution" (300
mosmol; pH 7.2; 3.04 g of Na2HPO4 x 2H2O, 0.84 g of NaH2PO4 x H2O and 8.00 g of
NaCI per 1 1 of solution), which is replaced twice.
202811 2
- 23 -
ExamDel 10: Hydrolvsis of the polvmer discs
In accordance with the method of Tanaka et al. (German Offenlegungsschrift 3,200,479),
the polymer discs from Example 9 are stored at 20C for 30 minutes in a 50 % aqueous
formic acid solution and then for 2 hours in 6N hydrochloric acid at 20C in order to
remove isopropylidene protecting groups. After hydrolysis, the discs are placed in 2 %
aqueous soda solution at 20C for 15 minutes and then stored for 10 days at 35C in
"buffered isotonic saline solution" (as in Example 8), the soludon being replaced twice.
With the exception of polymers 37-40, 45-48,52-54 and 60-62, which are slightly to very
cloudy, the other polymer discs are glass-clear and colourless.
Hydrolysis proceeds very easily in all the polymers - in some cases even in only 50 %
formic acid. This can be detected from the increasing swelling.
The removal of the isopropyUdene protecting groups, and thus liberation of the OH groups
on the saccharide molecules, by 6N HCl at 20C has been studied in detail. The question
of whether cleavage of the ester bond via which the saccharide unit is bonded to the
polymer structure also occurs under the given conditions has also been clarified here.
It is known [T. Tanaka, Spektrum der Wissenschaft 78 (March 1981)] that hydrogels
containing carboxyl groups have a higher water content and a greater linear expansion on
transfer from aqueous saline solution into distilled water. Accordingly, the values for
water content and linear expansion should increase when the polymer discs are transferred
from "buffered isotonic saline solution" into distilled water. In addition, the IR spectra of
these samples (washed undl salt-free and then dried) should contain absorptions ~or
carboxyl and maybe also carboxylate groups if ester cleavage has taken place to a
considerable extent (sensitivity of IR spectroscopy) during removal of the protecting
groups.
Most of the samples from the sample series Nos. 35-66 exhibit this type of increase in the
linear expansions and the IR absorptions in the range from 2500 to 2700 cm-l and at 1570
cm-l which are typical for carboxyl groups, while the band at 3000 cm-l is covered by the
strong CH2 band at 2490 cm~l and the very strong, broad OH band at 3400 cm~l andcannot therefore be evaluated with certainty. For polymer sample Nos. 1-34, neither an
increase in the linear expansion nor the appearance of IR bands characteristic of carboxyl
or carboxylate groups were found.
202~112
-24-
This allows the conclusion that ester cleavage of this type occurs significantly more
quickly in acrylic esters containing saccharide units, while it is not observed under the
hydrolysis conditions used here in the case of methacrylates.
Example 11: Water content and linear swellin~ of the hvdrated polvmer discs
(unhvdrolvsed)
Unhydrolysed polymer discs from the examples above are investigated for water content
(H) at 35C after swelling in "buffered isotonic saline solution" and for linear expansion
(LE). The values deterrnined are surnmarised in Table 2. The water content drops with
increasing proportion of hydrophobic di-O-isopropylidene-DL-xylitol units in thepolymer. This also applies to the linear expansion.
`" 202g~
Table 2
Polymer H [%] Polymer LE [%]
sample from at 35C sample from at 35C
Example 8 Example 8
38.4 35 17.5
2 31.5 36 lS.0
3 26.9 37 13.4
4 18.7 38 8.8
S 14.0 39 5.8 -
6 ll.S 40 3.5
7 6.6 41 1.0
9 1 43 16.7
35.5 44 13.4
11 28.5 45 12.1
12 25.5 46 8.4
13 18.0 ~ 47 5.8
14 13.8 48 2.1
lS ll.S 49 1.0
16 6.6 S0 0
18 1 Sl 7.5
19 19.9 52 5.8
14.5 53 2.5
21 9.8 54 2.5
22 . 6.5 55 2.1
23 4.2 56 1.6
24 2.9 57 1.0
2.0 58 0.8
26 1.2 59 5.0
27 12.0 60 3.6
28 8.9 61 2.5
29 6.0 62 2.5
4.0 63 0.8
64 0.6
Example 12: Water content and linear expansion of the hvdrolYsed and swollen polYmer
sarnples
Table 3 below shows the values for the water content and the linear expansion for the
hydrolysed polymer samples in which the isopropylidene protecting groups on the
S-MDPXy units (or analogous units) have been removed. The water content and the linear
swelling increase considerably with increasing proportion of xylitol units in the hydrogel.
The values for the water content are also given for the commercially available lenses W
38 and WCE.
~28112
- 26 -
Table 3
Polymer sample H ~%] LE [%]
from Example 8 at 35C at 35C
37 19
2 45 23
3 52 28
4 65 41
74 50
6 76 54
7 ~3 72
9 88 97
17
11 42 20
12 48 26
13 58 34
14 66 43
69 47
16
17 82 64
18 83 68
19 20 7
33 14
21 47 22
22 59 32
23 69 42
24 75 53
64
26 84 72
27 12 4
28 21 6
29 31 12
. 44 18
31 56 25
32 64 32
33 71 37
34 74 44
37 ~7
2028112
- 27 -
Polymer sample H [%] LE [%]
from Example 8 at 35C at 35C
.
36 43 20
37 S0 27
38 64 40
39 78 62
87 88
41 94 106
43 33 16
44 39 18
n 23
46 60 34
47 73 49
48 81 61
49 -- 74
S0 90 87
Sl 20 S
52 34 13
53 49 21
54 61 33
SS 72 48
56 80 62
57 84 75
58 88 88
S9 12 4
23 8
61 35 lS
62 47 20
63 57 27
64 - 65 33
W38 38
WCE 57
Exam~le 13: Transmission of visible li ht
The hydrogel discs from samp1es 1-34 of Example 8 are placed between quartz plates, and
the transmission of visible rays is measured between wavelengths 400 and 800 nm. The
transmission for visible light increases continuously between 400 and 800 nm and is
greater than 90 % for all thc samples. Tbus, for example, a transmission of 92 % at 400
nm, 94 % at 600 nm and 95 % at 800 nm is measured on the hydrolysed polymer disc No.
22 (thickness 0.209 mm).
Example 14: Content of extractable components
For samples 1-34 of Example 8, the content of extractable components (E~) is low, ie. a
maximum of 4.5 %, and in most samples is 2 % or less. R increases only relatively little
2028112
- 28 -
with increasing xylitol content and thus increasing water content. Comparable polymers in
which the xylitol units have been replaced by N-vinylpyrrolidin-2-one units have, by
contrast, up to 30 % by weight of extractable components at significandy lower water
contents. In view of the hydrolysis carried out in accordance with Example 10 and in view
of the high water contents, these are astonishingly low R values. This speaks both in
favour of very good copolymerization and against ester cleavage during the hydrolysis.
The situation is different in the case of samples 35-64 of Example 8, for which the R
values are up to 17 % by weight. Even in the case of these samples, however, they are
usually 10 % or significantly less. Here, R increases relatively fast with increasing xylitol
content, and thus increasing water content. It may be assumed that this high percentage of
extractable components is also attributable to partial cleavage of the ester bonds during the
hydrolysis (see comments in Example 10).
Example 15: Determination of the oxv~en permeabilitv
The measurement is carried out using a Createch permeometer, model 201 [1032 Neilson
St., California 94706) with an Ag anode and a Pt cathode by the method of J. Fatt (Am. J.
Optom. and Physiol. Opdcs, 48, 545 (1971)] at 35C. The electrodes are positioned in a
plexiglass holder. The atmospheric humidity is greater than 90 % for the measurements.
The values for oxygen permeability of some hydrated and/or hydrolysed polymer discs
from Example 8 are shown in Table 4 - expressed as the permeation coefficient P
transmissibility T and as the oxygen flow JO . For the purposes of comparison, the
values for two commercially available hydrogel materials (W38 = polyHEMA crosslinked
with EGDMA, WCE = copolymer of VP and methyl methacrylate, both Ciba Vision) areadded.
The thicknesses df of the discs with water contents greater than 40% are determined via
the linear swelling LE. The thicknesses of the other discs are measured using a
thickness-measuring instrument. Table 4 contains the values for the oxygen permeability
of the polymer samples 20, 37, 39 and 41 after hydration and for the polymer samples
20-22, 25, 35, 54-56 and 58 after hydrolysis.
2028112
-29 -
Table 4
Polymersamph: from Po 10-11 To 10-9 Jo
E:~ampleNo. 8 2 2 2
~y~o- d f H [%] LE [%] r ml (2) cm2 1 r ml (2) 1 r ~ (2)
~drud) ly~ed) km3 _ l ml s mm (Hg)~L cm2 s mm (Hg)~ L al~2 . h
0.0216 33 6.4 3.0 1.7
0.0233 14 1.0 0.4 0.2
21 0.0393 47 2215.4 3.9 2.2
22 0.0354 59 3227.8 7.8 4.4
0.0366 80 6454.6 14.9 8.3
0.0239 37 37 8.6 3.6 2.0
37 0.0213 29 4.8 23 1.3
39 0.0196 15 2.0 1.0 0.6
41 0.0168 3 1.3 0.8 0.5
54 0.0254 61 3324.4 9.6 5.4
0.0327 72 4836.8 11.3 6.3
56 0.0343 80 6259.2 173 9.7
58 0.0348 88 8864.2 185 10.3
W38 8.3 4A 2.5
WCE 22.9 10.9 6.1
Example 16: Bal_indentation hardness
Sample cylinders ~0 130 mm, D = 4.0 mm) are machined from the polymer discs fromsome of the above examples and polished. The ball indentation hardness K is determined
at 23C using an apparatus from Zwick. The K values of the polymer discs investigated,
measured 60 seconds after commencing loading, are summarised in Table 5.
Table 5
Polymer sample K[N/mm2]
from Example No. 8
59 127
120
61 107
62 92
63 75
64 52
.
