| Full Text |
USE OF TOCOPHEROL
I
The invention relates to the use of tocopherol as v^/eli as to a method for manufacturing hydrophilic polysiloxanes. The invention aiso relates to hydrophiiic polysiloKanes, to a method for manufacturing hydrophilic sitoxane eiastorners, as we!! as to hydrophilic siloxane elastomers.
BACKGROUD
Polysiloxanes are applied in many ways in industry e.g. as suffactants, coatings, dispersion agents, dispersion stabilisers, release agents, food additives, sealants, tubes and medical applications. Polysiloxanes are aiso applied in many ways in medical industry, e.g. in drug delivery applications, both as coatings In conventional pills and as implantable, intravaginat or intrauterine devices. The most commonly used poiysiloxane is polydimethyisiloxane (PDMS), which is a highly hydrophobic, stable and temperature resistant materia!. PDMS is especially suitable for use as membranes regulating the release rate of drugs. However, as PDfvIS is hydrophobic, it cannot be used for all drugs, depending of the hydrophiiicity or hydrophobicity of the drug.
However, when preparing polysiloxanes by ring opening polymerisation of cyclic siloxanes with phosphazene base catalysts, a large amount of catalyst is required, leading to cross-linking of the polymers during storage.
Sterically hindered phenols, such as a-tocopherols and their derivatives have been used in the polymerisation reactions to slow down the reaction and to prevent the formation of gels and oligomers. Tocopherol has also been used as a stabiliser in polyrriers due to its anti-oxidant effect.
There is, however, still a need to provide a co-catalyst suitable for reducing the amount of catalyst used during the ring opening polymerisation of cyclic siloxanes. There is aiso a need to provide a component capable of strongly reducing, if not compieteiy avoiding, the cross-linking of the polymers thus obtained during storage.
Concerning the medical applications, the release rate of the drug has traditionally been regulated by changing the parameters of the drug release system, for example by changing the surface area, the thickness of the membrane, the
quantity of the drug or the amount of fillers in the membrane regulating the release. However, if a significant change of the release rate is desired or if the dimensions of the delivery device cannot be modified, the constitution of the polymer needs to be modified.
it is known that the diffusion properties of polydimethyisiioxane can be varied by adding to the polymer substituent groups that decrease or increase the release rate.
The addition of polyethylene oxide (PEO) groups into PDMS poiymer can increase the release rate of drugs. Uliman et al, presents in Journal of Controlled Release 10 (1989) 251-260 membranes made of block copolymer comprising polyethylene oxide and PDMS, and the release of different steroids through these membranes. According to the publication, the release of hydrophilic steroids is increased and the release of lipophilic steroids is decreased, when the amount of PEQ groups increases. In that study the PEO groups are connected to the silicon atoms of the siloxane groups via a urea-bond.
Patent Fi 107339 discloses regulating the release rate of drugs by a siioxane-based elastomer composition comprising at least one elastomer and possibly a non-crossiinked polymer, as well as a method for manufacturing said elastomer composition. The elastomer or the polymer of the composition comprises poiyaikylene oxide groups as alkoxy-terminated grafts or blocks of the polysiloxane units, or a mixture of these, The alkoxy-terminated grafts or blocks are connected to the siloxane units by silicon-carbon-bonds.
Publication Hu et al. "Synthesis and drug release property of poiysiloxane containing pendant long aikyi ether group", Gaofenzi Xuebao, (1) 62-S7, 1997 Kexue (CA 126:200090} presents a silicone based poiymer that has been grafted with ether groups after the polymerization step, thus leaving the hydrosilation catalyst (Pt) inside the polymer. The polymer is useful when mixed with silicone rubber. The publication only discloses simple ether groups. The polymer grafted as disclosed decreases the release rate of the drugs.
US 6,346,553 discloses atkylmethyisiloxane-polyalkyleneoxide-dimethylsiloxane-copolymers, that are suitable for use as surface-active agent for both oil-water-emulsions and siiicone-water-emulsion, and a method for manufacturing said copolymers. The copolymers can be manufactured by a hydrosilyiation reaction between a straight chain or branched chain olefin and a cyclic siloxane, using
platinum catalyst, distilling the alkylated cyclic siloxane, polymerising the mixture of said tetramethyldisiioxane and possibly another cyclic siloxane in the presence of an acidic catalyst. The obtained polymer is finally hydrosilyiated with a terminally unsaturated poiyalkyleneoxide polymer.
US 6,294,634 presents a method for manufacturing siloxane compositions by heating a mixture of dimethylsiloxane, alkyl-substituted cyclic siloxane and a cyclic siloxane comprising a oxyalkylene-group, in the absence of solvent. The polymerisation catalyst can be, for example, alkaline metal hydroxide, aikoxide or silanolate, Lev^/is acids, acidic phosphazenes or basic phosphazenes. The composition comprises only small residues of platinum or is completely free from platinum.
US 3,427,271 discloses organic poiysiloxanes that are formed of dimethylsiloxane units, methyf-oxyalkylsiioxane units and siloxane units that are substituted with methyl group and a higher alkyl group. The polymerisation reaction uses platinum catalyst.
OBJECTS AND SUMMARY OF THE INVENTION
In view of the above-mentioned, it is an object of the present invention to provide a co-cata!yst suitable for reducing the amount of catalyst, it is also an object to reduce the cross-linking of the polymers during storage.
One object of the present invention is to provide a platinum free elastomer with which the release rate of the drug is easily controlled,
A yet another object is to provide an elastomer that also has sufficient mechanical properties.
The present invention thus relates to the use of tocopherol as a co-catalyst in the ring opening polymerisation of cyclic siloxanes.
The present invention further relates to a method for manufacturing hydrophiiic poiysiloxanes, wherein a hydrido-containing cyclic siloxane is reacted with a hydrophiiic molecule comprising a carbon-carbon double bond, having the general formula (1) or {!!)
(1) H2C=CH-(CHR)n-0-(CHRlCR2R3)f^R4
CO H2C=CH'(CHR)n-R5
wherein n is an integer from 0 to 4, m is an integer from 0 to 5, R, R', R^, R3 and R"^ are each independently hydrogen or a Ci to CQ alkyl, R^ is a saturated cyclic
hydrocarbon containing carbonyl group, in the presence of a first catalyst to obtain a monomer, and polymerising said monomer in the presence of a second catalyst and tocopherol as a co-cataiyst.
The present invention also provides a hydrophilic polysiloxane having the formula (Ml)
{HI) EB-[Bi-B2-B3]k-EB
wherein
EB is an end blocker group, B-j, 83 and B3 is independently selected from the group consisting of a -Si-0- chain comprising a hydrophilic group and a methyi group,a -Si-0- chain comprising two methyl groups and a -Si-0- chain comprising a vinyl group and a methyl group,
said B-j, B2 and B3 are randomly distributed along the chain of the polysiloxane, and k is an integer from 15 to 50 000, obtainable by the method according to the present invention.
The invention yet further relates to a method for manufacturing a hydrophilic siloxane elastomer, comprising cross-linking a polysiloxane according to the present invention, in the presence of a cross-linking catalyst, as well as to a hydrophilic siloxane elastomer obtainable by said method.
SHORT DESCRIPTION OF THE DRAWINGS
Figure 1 presents an example of monorTier synthesis according to an embodiment of the present invention.
Figure 2 presents an example of anionic ring-opening polymerisation according to an embodiment of the present invention.
Figure 3 presents an arrangement for measuring the drug release.
Figure 4 presents some drug permeation results measured with elastomers according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the use of tocopherol as a co-catalyst in the ring opening polymerisation of cyclic siloxanes.
As will be shown later in the Experimental part, using tocopherol as a co-catalyst in the ring opening polymerisation of cyclic siloxanes, the amount of catalyst needed for such reaction is reduced. Furthermore, the cross-linking of the polymers during storage is greatly reduced when tocopherol has been used as a co-catalyst in the ring opening polymerisation.
According to one embodiment of the present invention said tocopherol is selected from the group consisting of Dl-alpha-tocopherol, RRR-aipha-tocopherol, D'L-alpha-tocopherol acetate and RRR-alpha-tocopherol acetate. Mixtures of these compounds can naturally also be used.
According to another embodiment the cyctic siloxane is selected from the group consisting of heptamethy! cyclotetrasitoxane and tetramethyl cyclotetrasiloxane.
The present invention further relates to a method for manufacturing hydrophilic polysiloxanes, wherein a hydrido-containing cyclic siloxane is reacted wtth a hydrophilic molecule comprising a carbon-carbon double bond, having the general formula (I) or (II)
(I) H2C=CH-(CHR)n-0-(CHRlCR2R3)^R4
(iS) H2(>CH-(CHR)n~R5
wherein n is an integer from 0 to 4, m is an integer from 0 to 5, R, R'^, R2, R3 and R'^ are each independently hydrogen or a Ci to Cg alkyi, R^ is a saturated cyclic
hydrocarbon containing carbonyl group, in the presence of a first catalyst to obtain a monomer, and polymerising said monomer in the presence of a second catalyst and tocopherol as a co-catalyst.
The details and embodiments listed above also apply to the method according to the present invention.
The present invention thus relates to a method for manufacturing hydrophilic polysiloxanes that provides polydimethyl siloxane polymers that do not exhibit any undesired oross-iinking during the polymerisation and the storage of the polymer. These polymers can be cross-linked to form a more hydrophilic elastomer than
6
PDMS elastomers. Such an elastomer allows an easy and accurate control of the release rate of the drug from polymer based drug delivery system.
According to an embodiment of the invention the monomer containing hydrophilic moiety is purified before the polymerisation. This allows the manufacture of a hydrophilic silicone elastomer that is essentially free from catalyst residues from the hydrosilation reaction. When a platinum catalyst is used in this first step, the resulting elastomer made according to this embodiment is essentially platinum free, provided that no platinum is used in the cross-linking step.
The monomer obtained can be purified with any known method, such as by distillation under reduced pressure. The aim of the purification is the elimination of unreacted unsaturated starting material, alkylated products formed thereof and especially the elimination of the residues of the catalyst, such as platinum residues. At the moment, distillation is the simplest way to totally exiude the platinum catalyst from the final elastomers and is thus preferred method in the present invention.
According to an embodiment the hydrido-containing cyclic siloxane is selected from the group consisting of heptamethyl cyclotetrasiloxane and tetramethyl cyciotetrasiioxane. Also other further cyclic siloxanes can be used in the copolymerization, such as octamethyi cyclotetrasiloxane.
According to another embodiment the hydrophilic molecule is selected from the group consisting of allyl ethyl ether, allyl methyl ether, allyl propyl ether, ally! butyl ether, allyl penty! ether, butyl vinyl ether, propyl vinyl ether, tert-pentyl vinyl ether and ally! acetate.
The reaction temperature in the hydrosilation reaction can vary from room temperature up to 250-300 "C, preferably it is from 20 to 170 "C and more preferably from 50 to 170 "C, even more preferably from 50 to 95 '^C. it may be necessary to heat the reaction to 100 "C or above, especially if the activity of the catalyst has been reduced by the presence of water in the reaction mixture or by slurrying the catalyst into diluent.
Suitable catalysts are, for example, platinum based or platinum complex based hydrosiiyiation catalysts that are described for example in US 3,220,972; US 3,715,334; US 3.775,452; US 3,814,730; US 4,421,903 and US 4,288,345. Some suitable catalysts are chloroplatinate, piatinum-acetylacetonate, platinum divinyldisiloxane complex, hexamethyldiplatinum and complexes of platinum
7
haiides with different compounds having double bonds, such as ethylene, propylene, organic vinylsiloxanes or styrene. Also other catalysts, such as ruthenium, rhodium, palladium, osmium and iridium as well as their complexes, can be used.
According to a preferred embodiment the first catalyst is a platinum catalyst. As the monomer is preferably purified before polymerisation, the obtained polymer and further the obtained elastomer are platinum free, provided that piatinum is not used in the crosslinking step.
The polymerisation may be a homopolymerisation or a copoiymertsation, in which case a comonomer is present in the polymerisation step. The cornonomer can for example be a vinyl comonomer selected from the group consisting of vinyi containing cyclic and linear low molecular weight siioxanes, such as 1,3,5,7-tetraviny!-1,v3,5,7-tetramethyl cyclotetrasiloxane. The cyclic siioxane can thus be copolymerised with different cyclic siioxanes and/or linear siioxanes.
The ring opening polymerisation is typically catalysed by either acidic or basic catalysts. Examples of suitable basic catalysts are alkaline metal hydroxides and their complexes with alcohols, alkaline metal alkoxides, alkaline metal siianolates and different phosphorous nitric haiides. Preferred catalysts are potassium siianolates and phosphazene bases. Examples of suitable acidic catalysts are strong acids, such as sulphuric acid, acetic acid or trifluoromethane sulfonic acid, Lewis acids, such as boron trifluoride or aluminium chloride, or strongiy acidic ion exchange resins.
The polymerisation can, for example, be carried out in a solvent, without a solvent or as an emulsion. In some cases, a suitable solvent can be used in order to regulate the reaction rate and in order to achieve a certain degree of poiyrnerisation. If a solvent is used, some suitable solvents are liquid hydrocarbons such as hexane and heptane, silicones such as polydiorganosiloxanes, silanols such as tnalkylsilanol and in some cases alcohols, such as alcohols comprising 1 to 8 carbon atoms, in some cases, the water present in the reaction renders the controlling of the reaction easier.
According to yet another embodiment an end-blocker is present in the polymerisation step. Said end-blocker can be selected from the group consisting of linear iow molecular weight siioxanes, such as 1,1,3,3-tetravinyl dimethysiloxane.
8
The end-biocker can be used to regulate the molar mass of the polymer or to introduce functional groups to the ends of the polymer chain.
According to an embodiment of the invention said second catalyst is selected from the group consisting of phosphazene bases, ammonium silanolates, potassium silanoiates, sodium silanolates, lithium silanolates and mixtures thereof.
Phosphazene bases are efficient catalysts in polymerisation reactions and the amount of catalyst used can be rather small, for example 1-2000 ppm based on the amount of siloxane, preferably 2-1000 ppm and more preferably 2-500 ppm. in practice, the amount of catalyst is also dependent on the reaction rate and the desired molar mass of the polymer. The amount of catalyst can be, for example, from 2 to 200 ppm.
Any suitable phosphazene base can be used as a catalyst, especially those that
are in liquid form or that can be dissolved in a liquid. Some examples of
commercially available phosphazene bases are 1~tei1-butyi-4,4,4-
tris(dimethyiamino)-2,2-bfs[tris(dimethylamino)-phosphoranylidenamino]-2A",4A'-
catenadi(phospha2ene), 1-tert-butyl-2,2,4,4,4-pentakis(dimethyiamino)" 2A^4.'^'-
catenadi(phosphaz:ene) and 1-tert-octyl-4,4,4-tris(dimethylam(no)-2,2-
bis[tris(dimethyiamino)-phosphoranylidenamino]-2A"',4/V^-catenadi(phosphazene),
The reaction time in the polymerisation step can vary from 30 minutes to several hours, depending on the activity of the catalyst and on the desired product. The polymerisation temperature can vary from room temperature to 250 "C, preferably from 80 to 200 ^'C and more preferably from 120 to 150 "C.
The polymerisation reaction can be controlled by taking samples at regular intervals and by analysing them w/ith any known method, such as following the molar mass by gel permeation chromatography. The polymerisation reaction can be terminated by adding a suitable neutralising reagent that inactivates the catalyst. Typically, the reactions are performed under inert atmosphere, such as nitrogen.
The present invention also relates to hydrophilic polysiloxanes having the fonmula (III)
(ill) EB-{Bi-B2-B3]k-EB
wherein
9
EB is ar5 end blocicer group, B-t, B2 and B3 is independently selected from the group consisting of a -Si-O- chain comprising a hydrophilic group and a methyl group,a -Si-O- chain comprising two methyl groups and a -Si-0- chain comprising a vinyi group and a methyl group,
said 8-;, 82 and 83 are randomly distributed along the chain of the poiysiioxane, and k is an integer from 15 to 50 000.
This hydrophilic poiysiioxane can be obtained by the method according to the present invention.
According to one embodiment of the invention the hydrophilic group is selected from the group consisting of propyiethytether, ethyibutylether, propylcyclohexanone, propyimethylether, dipropylether, propylbutylether, propyipentyiether, ethylpropylether, ethyl-tert-pentylether and propylacetate.
According to another embodiment of the invention the end blocker group is selected from the group consisting of linear lovj molecular weight siloxanes.
According to an embodiment of the invention, the polymer materia! is curable, i.e. cross-linkable with a cross-linking catalyst. According to an embodiment, the cross-linking catalyst is peroxide. Should it not be necessary that the elastomer is platinum-free, a platinum-based cross-linking catalyst can be used, The details and embodiments listed above also apply to this hydrophilic poiysiioxane according to the present invention.
The invention yet further relates to a method for manufacturing a hydrophilic siloxane elastomer, comprising cross-linking a poiysiioxane according to the present invention, in the presence of a cross-linking catalyst, as well as to a hydrophilic siloxane elastomer obtainable by said method. According to one embodiment, the cross-linking catalyst can be for example a peroxide cross-linking catalyst or a platinum cross-linking catalyst. If platinum free elastomer is wanted, peroxide crossiinking should preferably be employed.
According to yet another aspect the present invention relates to hydrophilic siloxane elastomer obtainable by the method described above.
The details and embodiments listed above also apply to this method and to the elastomer according to the present invention.
10
The elastomer is typically manufactured by cross-linking using any known catalysts and/or initiators, such as peroxides, irradiation, hydrostlylation or condensation. For example, organic vinyl specific or non-specific peroxides can be used, such as di-tert-butylperoxide and 2,5-bis-(tert-butylperoxide)-2,5-dimethyihexane or benzoyiperoxide, tert-butyiperoxy-2-ethylhexanoate and/or 2,4-dichiorobenzoylperoxide. The amount of catalyst varies, for example, from 0.1 to 5 parts per weight per 100 parts of siioxane.
Siioxane-based elastomer as used here can stand for an elastomer made of
disubstituted siioxane units, wherein the substituents can be substituted or unsubstituted lower alkyls, preferably C-\ io CQ alkyls or phenyl groups. A certain
amount of the substituents attached to the silicon atoms are substituted oxyalkyi groups that are attached to the silicon atoms by a silicon-carbon bond.
By C-^ to CQ alkyls in this context are meant methyl, ethyl, propyl, butyl, pentyl and hexyl, and ail their isomers.
in the foibwing, when substituted oxyalky! groups are mentioned, it Is meant such substituted oxyalkyi groups that are attached to the silicon atoms by a silicon-carbon bond.
According to one embodiment the elastomer composition can be formed of one single cross-iinked siioxane based polymer. According to another embodiment, the elastomer composition can be formed of two interpenetrating eiastomers. The first elastomer can then comprise substituted oxyalkyi groups as described above, and the second elastomer can be a siioxane based elastomer such as PDMS. The second elastomer can also comprise substituted oxyalkyi groups as described above.
The elastomer composition according to the present invention can be used as a membrane (or film) or matrix for regulating the release rate of a drug. By drug it is meant any kind of pharmaceutically active ingredient that can be administered into mammals. The membranes or films can be manufactured by any known method, such as by casting, extrusion, pressing, moulding, coating, spraying or dipping.
The drug release rate of the elastomer may be controlled by the amount of substituted oxyaikyi groups and/or by the properties of the drug.
According to yet another embodiment the elastomer composition may be a mixture comprising a siioxane based elastomer (for example PDMS) and at least one
11
polysiloxane polymer or copolymer comprising substituted oxyalkyl groups. Also the siloxane based elastomer may comprise such substituted oxyalkyl groups.
According to an embodiment the elastomer composition aiso comprises a filler, such as amorphous silica, in order to increase the strength of the film made from the elastomer composition. Other possible fillers include aluminium oxide, titanium oxide, mica, calcium carbonate, various fibres and barium sulphate. The amount of filler depends on the nature of the filler and the use of the elastomer. Reinforcing fillers, such as silica, are typically used in an amount from 1 to 50, preferably from 15 to 40 parts per weight and the other fillers in an amount from 1 to 200 parts per weight.
EXPERIMENTAL PART
Polymerisations were carried out in an oil bath in a 100 ml round bottom glass
vessel with mechanical stirhng and under nitrogen atmosphere. Monomer and
other starting chemicals, such as D'La-tocopherol (0.01 wt-%), vinyl comonomer (e.g tetramethyltetravinyicydoterasiloxane (MV4), 0,01 mol-%) or vinyl copolymer
and end blocker (e.g. tetramethyl divinyl disiloxane) were introduced to the vessel. Through changing the stoichiometry starting chemicals with each other the molecular weight of the polymer and crosslinking density of the prepared elastomer cou\d be varied. Polymerisation temperature was 150 'C and mixing rather vigorous (200-400 rpm). When the temperature of the reaction solution reached 150 "C, 50 ppm of catalyst 1-tert-butyl-4,4,4-tris(dimethylarnino)-2,2-bis[tns(dimethylamino)-phosphoranylidenamino]-2A^',4A^-catenadi(phosphazene) was added with microsyringe through the septum below the surface of the solution. Ring opening polymerisation started either hght away and proceeded to the end fast or gradually during about 30 min. When polymerisation had reached the target, the catalyst was deactivated by the addition of an equivalent amount of tris(trimethylsilyl)phosphate. At the early stage of reaction the viscosity raised quickly and in some experiments the viscosity started to decline slightly during polymerisation. This phenomenon was attributed to the growing amount of low molecular weight cyclic molecules and linear molecules as polymerisation proceeded to its thermodynamic equilibrium.
Example 1
Starting chemicals
Substituent: Ailylethylether (Aldrich)
12
Starting siioxane; Heptamethylcyciotetrasiloxane (Clariant)
Catalyst of the monomer synthesis; Pt-divinyltetramethyldisiioxane, 2.3 wt-% of Pi in Xylene (ABCR)
Polymerisation catalyst; Phosphazene base (1-tert-butyl-4,4,4-tns(di.methylamino)-2,2-bisitris!dirnethy!amino)-phosphoranyiidenamino]-2A',4.';V'-catenadi(phosphazene) (Fluka Chimika)
Co-catalyst; D'L-a-tocopherol (Roche)
Vinylcomonomer; l3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane, MV4 (Gelest)
End blocker; Vinyl terminated poly(dimethyisiloxane), DMS-V21 (ABCR)
Polymerisation catalyst deactivator; tris(trimethylsilyl)phosphate (Fluka Chimika)
Monomer synthesis
Heptamethylcyciotetrasiloxane and altyiethylether were weighed in a 50 mi glass round bottom vessel equipped with reflux condenser, the stoichiometric relation used was 1.1;1 (vmyl;SiH). The vessel was placed in an oil bath and nitrogen was purged through the vessel. The oil bath was heated up to 65 "C and the catalyst (20 ppm Pt) was added with a microsyringe through the septum into the reaction soiution. After a few minutes there was an exotherm and the colour of the medium changed from clear to brownish. The reaction was followed with FT-iR by the disappearance of SiH (2100 cm'} and vinyl (1650 cm"') absorptions. Samples were taken regularly every hour and after 2.5 hours the reaction had finished according to FTIR (vinyl peak at 1650 cm' disappeared).
The monomer thus prepared (1,1-3,3-5,5-7-heptamethyl-7-propyiethylether~ cyclotetrasiioxane) was distilled under reduced pressure (P
13
Poivmerisation of 1.1-3,3-5,5-7-heptamethvl-7-propylet.hyiether-cvclotetrasiioxane
Ring opening polymerisation was carried out in a 100 mi glass round bottom vessel with overhead stirring, under nitrogen atmosphere. The temperature of the poiymerisation was set to 150 "C, The vessel was charged with 25 g of monomer (98.69 wt-%), 0,01 wt-% of D'L-(x-tocopheroi, 0.10 wt-% of MV4 and 1.20 wt-% of end blocker. When the reaction medium had reached the target temperature, phosphazene catalyst (50 ppm) was added through the septum, Poiymerisation initiated slowly, until after 10 minutes there was a notable rise in the viscosity. Poiymerisation was continued with a slower mixing for 30 min, after which the catalyst was deactivated with an equivalent amount of tris(trimethyl&iiyi)phosphate.
The polymer was then stripped from volatile components in a short path wiped film evaporator (P
Example 2
Starting chemicals
Substituent: n-Butylvinyiether (BASF)
Starting siloxane: Heptamethylcyclotetrasiloxane (Clariant)
Catalyst of the monomer synthesis; Pt-diviny!tetramethylidisiloxane, 2.3 wt-% of Pt in xylene (ABCR)
Poiymerisation catalyst: Phosphazene base (1-teft-butyi-4,4,4-tns(d(methyiamfno)-2,2-bis[tris(dimethyiamino)-phosphoranylidenamino]-2A^,4A^-catenadifphosphazene) (Fluka Chimika)
Vinylcomonomer; 1,3,5,7-tetravinyi-1,3,5,7-tetramethylcyclotetrasiloxane, MV,, (Gelest)
End blocker: l1,3,3-tetravinyld(methyldisiloxane (ABCR)
Poiymerisation catalyst deactivator: tris(trimethyisilyi)phosphate (Fluka Chimika)
!\/tonomer synthesis
The same steps as in Example 1 were used for the monomer synthesis. The substituerit (n-butylvinylether) used made the reaction proceed much faster (total
14
time 0.5 h) and complete. No extra Si-H were observed according to FTIR (at 2050 cm'^), Product l1-3,3-5,5-7-heptamethyl-7-ethylbutylether'Cydotetrasfloxane was purified by distillation.
Poiymerisation of 1 ,'1-3,3-5,5-7-heptamethvl-7-ethvlbutylether-cvciotetrasiioxane
The same steps as in Example 1 were used for the polymer synthesis. The charged starting chemicals were 25 g of 1,1-3,3-5.5-7~heptamethyt-7-ethylbutylether-cyciotetrasiloxane (99.4 wt-%), 0,10 wt-% vinyl comonomer (MV4) and 0,80 wt-% of end-blocker. To start the polymerisation the needed catalyst amount was 100 ppm that was charged in two steps through septum over a time of 30 minutes. Poiymerisation resulted in a polymer with lower molecular weight when compared to Example 1.
Example 3
Starting chemicais
Substituent: n-Butylvinyl ether (BASF)
Starting siloxane: Heptamethylcyciotetrasiloxane (Clariant)
Catalyst of the monomer synthesis; Pt-divinyltetramethy!disiloxane, 2,3 wt-% of Pt in xylene (.ABCR)
Polymerisation catalyst: Phosphazene base (1-tert-butyl-4,4,4-tris(dimethyiamino)-2,2-bis[tris{dimethyiamino)-phosphoranyiidenamino]-2A',4A®~ catenadi(phosphazene) (Fluka Chimika)
Co-cataiyst: Dla-tocopherol (Roche)
Vinylcomonomer; 1,3,5,7-tetravinyl-1,3,5,7-tetramethyfcyclot6trasitoxane, M\/4 (Geiest)
End blocker: 1,1,3,3-tetravinyldimethylsiloxane, (ABCR)
Polymerisation catalyst deactivator: tris(trimethyisityl)phosphate (Fluka Chimika)
15 Monomer synthesis
The same steps as in Example 1 were used for the monomer synthesis, This time with different substituent (n-Butylvinyl ether) the reaction was much faster and it was compiete after 0.5 h. No Si-H groups were remaining according to FT-IR.
Poiymerisation of 1,1-3.3-5,5-7-heptamethvl-7-ethvlbutvlether-cvclotetrasiioxane
The same steps as in Example 1 were used for the polymerisation. Polymerisation started faster (according to viscosity) and was more complete than in Examples 1 and 2.
Example 4
Starting chemicals
Substituent: 2-Ailylcyclohexanone (Aidrich)
Starting siioxane: Heptamethylcyciotetrasiloxane (Clariant)
Catalyst of the monomer synthesis: Pt-divinyltetramethyldisiloxane, 2.3 wt-% of Ft in xylene (A8CR)
Polymerisation catalyst: Phosphazene base (1-tert-butyl-4,4,4-tris(dimethyiamino)-2,2-bis[tris(dimethylamino)-phosphoranylidenamino]-2.A^,4A'" catenadi(phosphazene) (Fluka Chimil
Co-catalyst: D'L-a-tocopherol (Roche)
Vinyicomonomer: 1,3,57-tetravinyH ,3,5.7-tetramethylcyclot6trasiloxane, MV4 (Gelest)
Monomer synthesis
The same steps as in Example 1 were used for the monomer synthesis. Hydrosilation reaction happened gradually during 2 hours (according to F'TIR), the colour changed to yellowish concurrently. The product 11-3,3-5,5-7-heptamethy!-7-propylcyclohexanone-cyclotetrasitoxane was purified by distillation.
16
Polymerisation of. 1.1 -3.3--5,5-7-heptamethvi-7-propyicyciQhexanorie-
cyclotetrasiioxane
The same steps as in Example 1 were used for the polymerisation. Polymerisation did not start until the amount of catalyst, that was gradually added, was 600 ppm. Polymerisation proceeded slower than in experiments 1 to 3.
Example 5
Starting chemicals
Substituent; n-Butylviny! ether (BASF)
Starting siloxane: Heptamethylcyclotetrasiloxane (Clariant)
Catalyst of the monomer synthesis; Pt-divinyltetramethyldisiloxane, 2.3 wt-% of Pt in xylene (ABCR)
Polymerisation catalyst; Phosphazene base (1-tert-butyl-4,4,4-tris(dfmethylamino)-2,2-bisitris(dimethyiamino)-phosphoranylidenamino]-2A^,4A"-catenad!(phosphazene) (Fluka Chimika)
Co-catalyst: D'L-a-tocopheroi (DSM)
Vinylcomonomer: 1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane, MV4 (Geiest)
End blocker 1,1,3,3-tetravinyldimethylsiloxane, (ABCR)
Polymerisation catalyst deactivator: tris(trimethylsilyi)phosphate (Fluka Chimika)
Monomer synthesis
The same steps as in Example 1 were used for the monomer synthesis. Reaction time was faster than in examples 1 and 2, that is, approximately 10 minutes. At the end of the reaction, the medium did not contain any SiH groups according to FTIR. Product 1,1-3,3"5,5-7-heptamethyl-7-ethylbutylether-cyclotetrasiloxane was purified by distillation.
Poiymerisatjon of 1,1.3,3.5.5,7-heptamethvl-7-ethylbutvlether-cyclotetrasiloxane
The same steps as in Example 1 were used for the polymerisation. Poiymensation reaction was successful.
17
Example 6
Starting chemicals
Substituent: Allylethylether (Aldrich)
Starting sifoxane; Heptamethylcyclotetrasiloxane (Clariant)
Catalyst of the monomer synthesis: Pt-divinyltetramethyldisiloxane, 2.3 wt-% of Pt in xylene (ABCR)
Polymerisation catalyst: Phosphazene base (1-tert-butyl-4,4,4-tn's(dimethylamino)-2.2-bis[tris(dimethylamino)-phosphoranylidenamino]-2A■^4A'•• catenadi(phosphazene) (fiuka Chimika)
Co-catalyst; Dl~a-tocopherol (Roche)
Vinylcomonomer: l3,5-trivinyl-1,3,5-trimethylcyciotetrasi!oxane, MV;j (Geiest)
End blocker; Vinyi terminated poiy(dimethylsiloxane), DMS-V21 (ABCR)
Poiymerisation catalyst deactivator: tris(trimethylsily!)phosphate (Fluka Chimika)
Reinforcing fumed silica; Aerosil R106 (Degussa)
Curing agent; tertbuty!peroxy-2-ethylehexanoate TBPEH, (Interchim Austria)
Monomer synthesis
The aiiylethyiether and heptamethylcyclotetrasiloxane were charged in a round bottom glass vessel equipped with reflux condenser. The vinyl/SiH stoichiometry was 1.1:1. The vessel was set in an oil bath and the reaction was carried under nitrogen atmosphere. Oi! bath was heated to 65 'C and the catalyst (20 ppm Pt) was added through septum. After a few minutes an exotherm was noticed and concurrently the colour of reaction medium changed from clear to brownish. The reaction was followed with FT-!R by the disappearance of SiH (2100 cm"^) and vinyi (1650 cm"') absorptions. Samples were taken regularly every hour and after 2.5 hours the reaction had finished according to FTIR (vinyl peak at 1650 cm' had disappeared). The monomer thus prepared (1,1-3,3-5,5-7-heptamethyl-7-propyiethylether-cyciotetrasiloxane), was distilled under reduced pressure (p
18
platinum from the monomer (distillate). The purity of the monomer was analyzed with GC and it was found to be 95 % pure (area %),
Poiymerlsation of 1,1,3,3.5,5,7-heptamethvl-7-propYiethviether-cvciotetrasiioxane)
Ring opening polymerization was carried out in a 100 ml glass round bottom vessel with overhead stirring, under nitrogen atmosphere. The temperature of the polymerisation was set to 150 'C. The vessel was charged with 25 g of monomer {98.09 wt-%), 0.01 wt-% of D'L-a-tocopherol, 0.70 wt-% of MV^ and 1.20 wt-% of end blocker. When the reaction medium had reached the target temperature, phosphazene catalyst (50 ppm) was added through the septum. Polymerisation initiated slowly, until after 10 minutes there was a notable rise in the viscosity. Polymerisation was continued with a slower mixing for 30 min, after which the catalyst was deactivated with an equivalent amount of tris(trimethy!siiy!)phosphate.
The polymer was then stripped from volatile components in a short path wiped film evaporator (P
Elastomer preparation
The stripped polymer was compounded in a kneading mil! with 25 v^-% of fumed silica and 1.5 wt-% of TBPEH-peroxide. When the base in the mil! was homogeneous, it was used to prepare sheets of different thicknesses in a hot press (120 °C) between release films. These sheets were subsequently post cured in vacuum oven (100 "C, P
Examples 7-16
In these examples, different polymerisable hydrophilically modified monomers were prepared. These monomers were then copolymerised with vinyl-functional cornonomers. Prepared polymers were then mixed with silica and cured using a vinyl-specific peroxide, and tested for their use in medical appiications for releasing of drugs.
Monomer preparation
The monomers used were synthesised by hydrosilation of heptamethyl cyclotetrasiloxane {H!\/ICTS, Ciariant) and selected double-bond-containing
19
hydrophilic molecules. Hydrophilic groups were mostly ether-like structures with a terminal double-bond, Platinum-divinyl tetramethyl disiloxane {Pt~DVTMDS, ABCR) complex was used as a cataiyst for hydrosilation, in some occasions also solid platinum and palladium catalysts were tested. The vinyi/Si-H molar ratio was most often 1.1:1. Reactions were first carried out in 8 ml vials with simply heating the reaction mixture under stirring in oii bath. If this smaii scale experiment vvas successful, the next step was to scale up the reaction and to produce enough material to be distilled and polymerized. Most often temperature was about 65"C and used catalyst amount was 20 ppm.
Some components are mentioned below with their abbreviated names. For example,
HMCTS stands for heptamethyl cyclotetrasiloxane,
Pt-DVTMDS stands for platinum-divinyl tetramethyl disiloxane complex,
MV4 stands for 1,3,5,7-tetravinyl-1,3,5,7-tetramethyl cyclotetrasiloxane,
MV3 stands tor 1,3,5-i.riviny{-1,3,5-trimethyi cyclotrisiloxane,
D4gAMe stands for 1,1,3,3,5,5,7-heptamethyi~7-propyimett^ylether
cyclotetrasiloxane ,
D4gAEE stands for 1,1,3,3,5,5,7-heptamethyl-7-propylethylether
cyclotetrasiloxane,
D4g8VE stands for 1,1,3,3,6,r5,7-heptamethyl-7-ethylbutyiether cyclotetrasiloxane
D4gACHN stands for 1.1,3,3,55,7-heptamethyl-7-propy!cyciohexanone cyciotetrasiioxane,
DMS-V21 stands for vinyl terminated poiydimethylsiioxane, and
TBPEH stands for tert-butylperoxy-2-ethylhexanoate.
In these examples, four different derivatives were tested for monomer synthesis. Their structures, names, abbreviations and producers are presented in Table 1.
20
Table 1
Aiiyl ethvi ether
AEE
Aldnch
v.. ^...-'-^s.
Allyl methvl eth«
AME
vBCE.
,il
2- AHyl cytiohcxanons
ACHN
Aidsich
\o-
-^v
11-'Butyl
BVE
KASi-
As hydrosilation takes place most easily in tenninal double bonds, all of the tested molecules had one. Figure 1 presents a reaction scheme of synthesis of D4gAME-monomer from heptamethyl cyclotetrasiloxane and allyl methyl ether via hydrosilation as an example of monomer synthesis,
Hydrosilation reactions were monitored by FT-IR (Nicolet 760). The reaction was noted to be ready when strong SiH IR absorption at 2100 cm' or C=C absorption at 1650 cm ' disappeared. In most cases the reaction time was about three hours and stili some unreacted specimen remained, but butyl vinyl ether hydrosilated in less than half an hour completely leaving no leftover Si-H groups to the reaction mixture.
21
Table 2
Derivative Catalyst Temperature Reaction time Comments
AME Pt-DVTMDS 55-60 X 2.3h proceeded welf
AEE Pt-DVT-MDS 65 X 2,5h proceeded well
BVE Pt-DVTMDS 65 X 15min proceeded well
ACHN Pt-DVTMDS 70 "C 2,5h proceeded well
Monomer synthesis was successfully carried out with ailyl methyl ether, altyl ethyl ether, n-bulyi vinyl ether and allyl cyciohexanone. These all reacted well at 65 "C with 20 ppm of Pt-DVTMDS catalyst. Reaction times varied quite much as can be seen from Table 2. Larger scale (100 g) reactions were carried out in 250 ml round-bottomed flasics with reflux condenser and nitrogen inlet attached. Catalyst had to be added carefully to the reaction mixture, because of the notable exotherm during the first steps of hydrositation.
Monomer purification
Before polymerisation monomers had to be distilled to achieve at least 96 % purity (determined as area-% from gas chromatograph peaks). Distillation was performed using microdisttllation equipment, oil bath and vacuum pump. Pressure was reduced to below 10 mbar and most often oil-bath temperature had to be raised to about 110 'C until the main product was distilled. After the distillation, collected monomer distillate was revised for purity with GC-MS and dried with 4 A molecular sieves by adding about 20 volume-% of sieves to the monomer containers.
Poiymerisation
I Polymerisation experiments were started at 8 ml vials with approximately 2 g of dned monomer and 50 ppm of catalyst. Different monomers and reaction conditions were tested. The reaction was an anionic ring-opening polymerisation, where both potassium silanolate and phosphazene base catalysts could be useful. Figure 2 shows a simplified scheme of anionic ring-opening polymerisation of
i D^AEE. .After successful results in this small scale, bigger batches of 10-50 g were
'II
made in 30 ml vials and in 100 ml three-neck flasks with reagents, like end-blockers, vinyi comonomers and additive as D'L-a-tocopheroi.
All of the tested reagents and their purpose in poiymerisation are presented in Table 3. Only one of each type was used in one experiment.
Table 3
i Substance
I Purpose
I Amount used
i0.10wt-%
|l,3,5,7.tetraviny!-1,3,5,7-tetramethyl : cyciotetrasibxane (MVj, SOY)
vinyl-containing j
comonomer
! 1,3,6-thvinyi-1,3.5-trimethy! i cyclotrisiioxane (MV3, Geiest)
vinyl-containing comonomer
0.70 wt-%
dimethytsiloxane,
Vinylmethyisiioxane-dimethylsiloxane copolymer, (Geiest)
i1,1,3,3-tetravinyi i(ABCR)
vinyl-containing copolymer
end-blocker
10wt-%
0,80 wt~%
Vinyl terminated poiydimethyl siloxane, DMS-V21 (ABCR)
end-blocker
1.20 wt-%
D'L-c.i-tocopherol (Roche) \ Potassium silanolate (SOY)
additive catalyst
0.01 wt-% 50 ppm
I Phosphazene base (Fluka Chimika) catalyst
! 50 ppm
_ J
Poiymerisattons were carried out under nitrogen atmosphere and vigorous stirring. Temperature was set to ISOX. Polymerisation time varied from half an hour to two hours, depending on the monomer and temperature. Most of the reactions were quite fast, but stirring and heating was continued for half an hour after the polymerisation occurred to achieve best possible polymerisation degree and yield. At the end the reaction was quenched with tris(trimethylsilyl)phosphate (Fluka Chimika),
23
A vinyl comonorner, such as 1,3,5,7-tetravinyl-1,v3,57-tetramethy! cyclotetrasiloxane (MV,i), was added to the reaction medium. Also other vinyl-containing substances were tested (see Table 3). Good polymers were achieved using vinylmethyisiloxane- dimethylsiloxane--copolymer, but when these polymers were stored, some cross-linking occurred after a few days, A good solution to this problem was addition of D'L-a-tocopherol (vitamin E), that is an antioxidant and statJiiiser. it prevented the unwanted cross-linking and also had a cocataiysing effect on poiymerisation; lesser catalyst was needed to initiate the ring opening polymerisation. In Table 4 there are presented a few ring opening polymerisation experiments with D4gBVE, wtiere difference of experiments made with and without
D'L-(i-tocophero! can be easily seen.
Table 4
\ Example D'L-a-tocopherol Temperature Catalyst amount needed Vinyl compound Gel formation
7 8 no 1150 X
!
no 1150 "C 100 ppm no no
150 ppm 150 ppm 250 ppm 300 ppm yes (copolymer) yes
19 no no 150 X 150 X
"" I
yes (MV3) i no
ho
1
t
yes (MV4) \ yes
hi no 150 X
yes (MV4) no
\^2
[ yes 150 X 50 ppm yes (copolymer) no
r ^13 yes HSO'C 50 ppm yes (MV3) no
14 yes hsoX 50 ppm yes (MV4) yes (MV4) no
15 yes 150 X 50 ppm 50 ppm
no 1
16 yes 150X
yes (MV4) no i
i
J
In Table 5 there is a summary of the polymerisation experiments made for all of the derivatised monomers.
24
Table 5
Catalyst
Monomer
D.4gAEE
i D4gAEE
D4gBVE
[
D4gACHN
Catalyst amount
50-500 ppm
potassium silanolate
phosphazene 50-200
ppm
base
60-200 ppm
phosphazene base
50-600 ppm
phosphazene base
Temperature
100-150 °C
120-150 X
100-150 X
110-150 "C
Additive
compounds
tested
Dl-a-tocopherol
D'L-a-
tocopherol,
IVIV3, MV,,,
vinyl-
copoiymer,
end^^biockers
D'L-«-
tocopherol,
MV3, MV4,
vinyi-
copolymer,
®.0.d.:.!?]2Ckers ._
D'L-a-
tocopherol,
MV4,
Mw -
range
(weight
average
masses)
50000-140000 g/moj
120000-
190000
g/mol
120000-
200000
g/moi
) circa I 50000 i g/mol
Removal of low-moiecuiar weight compounds
Low-molecular weight compounds had to be removed from polymer before further processing. If these compounds were left in, resulting elastomer would have poor tensile strength and too large amount of extractable material. Low-molecular weight substances were evaporated from polymer using microdistitlation equipment and vacuum pump at small scale. This was not the most effective way to remove the volatiles, so some polymer samples were combined to be able to create large volume enough for using short path distillation device (VTA, VKL 70-4-SKR-T Short Path Distillation Unit). Short path distillation unit was equipped with
25
a vacuum- and diffusion pump and an oil circulating system (Huber, Unistat 385w Circulation Thermoiat).
In small scale when microdistillation apparatus was used, temperature was raised to 120 "C and pressure was less than 2 mbar. )n bigger scale when short path distillation equipment was used, temperature was 90 'C and pressure about 0.2 mbar.
Elastomer preparation
After stripping, the polymer was compounded in a small laboratory mixer with 25 wt'% of dried silica (Aerostl R 106) and 1.5 wt-% of tert-butylperoxy-2-ethylhexanoate (TBPEH). Silica was added gradually in half gram quantities, and the base was mixed for 15 minutes to achieve a homogenous material.
Sample membranes for permeability tests were prepared using laboratory thermal press (Enerpac) with 0.4 mm thick round spacer mould. Materia! was pressed between release iinere and metal plates with 100 bar oil pressure at 120 "C for six minutes.
Slabs for mechanical testing were prepared similarly to permeability samples, but a different, 2 mm thick rectangle shaped (6.1 cm x 8.2 cm) spacer was used.
Elastomer films were subsequently post-cured at 100X and under 10 mbar pressure for one hour. Especially Poly(D4gAEE) 2 mm thick films got a little yeiiowish colour during post-cure.
Characterisation
Monomer analysis with GC-MS
A gas chromatograph-mass spectrometry (GC-MS) equipment (Agilent Technologies) was used to characterise the synthesised monomers. Samples were diluted in n-hexane (approximately 0.1 mg/ml) and two injections were taken from each sample. Yields and purity were estimated as area-% of GO peaks and main impurities and side-products were identified from MS spectra, if necessary. The biggest impurity in all of the experiments was the starter material, heptamethyl cyclotetrasiloxane.
26
Polymer analysis with GPC
Number- and mass-average molar masses and polydispersity were determined from the synthesised polymers using gel permeation chromatography (GPC). Used GPC equipment consisted of pump (Waters 515), injector (Waters 717Pius), Ri-Detector (Waters 2414) and column oven (Perl
Samples were prepared by diluting polymer to toluene (J.T.Baker), Toluene was used also as a carrier solution. Flow was set to 0.3 ml/min. Toluene was run through the equipment the night before measurements were done to stabilise the flow, and to cleanse the columns and injector.
Analysis of drug permeability
Drug pe,mieab!lity measurements were carried out using side-bi-side diffusion cells presented schematically in Figure 3. The system consisted of two similar glass chambers, the donor cell 1 and the receptor cell 2, surrounded by water jackets 3 and equipped with magnetic stirrers 4. The donor cell 1 had saturated concentration of estradiol in 1 % cyclodextrin solution (reference number 6). Estradiol diffused through elastomer membrane 5 set between the ceils to receptor ceil 2 containing a solution (1 % cyclodextrin). Used membrane thicknesses were 0.2 and 0,4 mm, each membrane was measured accurately.
Testing time was five days, and every day two 2.8 (.d samples were taken from the receptor ceil solution via the sampling port 7. After sampling, the taken amount of solution was replaced with pure 37 "C cyclodextrin. Temperature was kept steady at 37 "C with water bath (Lauda) to simulate the conditions in human body.
Taken solution samples were analyzed for estradiol by high performance liquid chromatography (HPLC). From HPLC concentration results, the permeations were calculated by plotting measured concentrations towards time and finding the slope of linear trend-line of plotted points.
Tensile strength and elongation
Samples for tensile strength measurements were die-cut from pressed elastomer pieces with desired thickness (2 mm). Test samples were ISO 37 type 2 specimens. Tensile strength was measured using Monsanto T2000 apparatus with
27
100 N or 1 kN ceil. High extensiometer (Gauge length 20 mm) was attached to the equipment to be able to measure the elongation. Rate of extension was 500 mm/min. Before analysis the samples were kept at constant room temperature and moisture for 24 hours (23 X, 50 %).
Extractable material
Amount of hexane-extractable material from elastomer was determined by weighing 0.3 g of elastomer to 30 ml vial and adding 20 ml of n-hexane. Three parallel measurements were carried out. Samples were shaken for 24 hours at room temperature and on the next day hexane solution was decanted. Solid samples were rinsed with fresh hexane once more and dried in vacuum oven at 40 "C and at pressure lower than 10 mbar for an hour. After drying, samples were stabilised at room temperature for yet another hour and then weighed. Extractables were calculated as percentage of mass difference between samples before ar^d after treatment.
in addition extractions were analyzed with GPC and GC (Agilent Technologies 6890 N Network GC System, FID detector) to be able to evaluate the amount of common cyciics (D4-D5) in extracted solution and possible larger fragments of extracted species.
Results
Synthesis and polymers
From ail the four tested derivatised nionorner candidates two were eventually processed through the whole synthesis route from monomer to elastomer.
Polymer synthesis was carried out successfully with D4gAEE and D4gBVE. The molar masses were mostly of the order of 140 000 g/mol.
Drug permoabMy
Target permeation was ten times that of reference elastomer, an unmodified PDMS. In Figure 4 there is plotted results of the estradiol permeation measurements for poly(D4gAEE), poly(D4gBVE) and reference PDMS elastomer membranes. The time in hours in shown in abscissa and the amount of estradiol released in \\Q is shown in ordinate. The squares stand for poly(D4gAEE), the triangles stand for poly(D4gBVE) and the diamonds for the references PDMS elastomer.
28
Tensile strength and elongation
Results of tensile strength and elongation measurements are presented in Tabie 6. First samples were measured without post-curing and with 1 l
Tabie 6
Polymer post-cure Stress/MPa Eiongation
Po!y{D,g.AEE) no 2,8 190%
PolyCD^gBVE) PolyCDagAEE) no 2.3 158%
yes yes 2.6 3.2 127% 132%
Poiy(D.gBVE)
Extradable material
Extractables were measured both with and without post-curing. Results are presented in Tabie 7. Polymer used for post-cured samples were stripped with more effective short path distillation unit.
Table 7
Polymer \ post-cure
_ I__
Poly(D4gAEE) no i Poly{D4gBVE) | no
I Poly(04gAEE) | yes
\ Poiy(D4gBVE) I yes
extracted material, wt-% j
— H
15.70% 14.30 % 11.50% 6.90 %
29 CLAIMS
1. Use of tocopherol as a co-catalyst in the ring opening polymerisation of cyclic silcxanes.
2. Use according to claim 1, characterised in that said tocopherol is selected from the group consisting of D'L-a-tocopheroi, RRR-a-tocopheroi, D'L~a-tocopherol acetate and RRR-a-tocopherol acetate.
3. Use according to claim 1, characterised in that the cyclic siloxane is selected from the group consisting of heptamethyl cyclotetrasiloxane and tetramethyl cyciotetrasiloxane.
4. A method for manufacturing hydrophilic polysiioxane polymers, wherein a hydrido-Gontaining cyclic siloxane is reacted with a hydrophilic molecule comprising a carbon-carbon double bond, having the general formuia (I) or (II)
(!) H2C=CH-(CHR)n-0-(CHR' CR2R3)f^,R4
(") H2C=CH-(CHR)n-R5
wherein n is an integer from 0 to 4, m is an integer from 0 to 5, R, R', R2, R3 and R"^ are each independently hydrogen or a Ci to Cg alkyl. R^ is a saturated cyclic
hydrocarbon containing carbonyi group, in the presence of a first catalyst to obtain a monomer, and polymerising said monomer in the presence of a second catalyst and tocopherol as a co-catalyst.
5. The method according to claim 4, characterised in that the cyclic siloxane is selected from the group consisting of heptamethyl cyclotetrasiloxane and tetramethyl cyciotetrasiloxane,
6. A hydrophilic polysiioxane obtainable by the method of claim 4.
7. A method for manufacturing a hydrophilic siloxane elastomer, comprising cross-linking a polysiioxane according to claim 6 in the presence of a cross-linking catalyst.
30
8. The method according to claim 7, characterised in that the cross-iinking
catalyst is selected from the group consisting of peroxide cross-iini
platinum cross-iinking catalyst.
9. A hydrophilic siioxane elastomer obtainable by the method according to claim 7.
10. A hydrophilic siioxane elastomer according to claim 9, characterised in that it is
platinum free.
11. A hydrophilic polysiloxane having the formula (III)
wherein
EB is an end blocker group, B-f, B2 and B3 is independently selected from the
group consisting of a -Si-0- chain comprising a hydrophilic group and a methyl group,a -Si-0- chain comprising two methyl groups and a -Si-0- chain comprising a vinyl group and a methyl group,
said B1, 82 and B3 are randomly distributed along the chain of the polysiloxane, and k is an integer from 15 to 50 000, obtainable by the method according to claim
t.
|