WO2010054800A1

WO2010054800A1 - Triblock copolymer gelators

Info

Publication number: WO2010054800A1
Application number: PCT/EP2009/008031
Authority: WO
Inventors: Martinus Abraham Cohen Stuart; Franciscus Adrianus Maria Leermakers; Marc Leemers; Joris Henricus Bernardus Sprakel
Original assignee: Stichting Dutch Polymer Institute
Priority date: 2008-11-11
Filing date: 2009-11-11
Publication date: 2010-05-20

Abstract

The invention relates to a composition comprising water, a triblock copolymer and polyionic component C, wherein the triblock copolymer is an ABA copolymer, having two charged blocks A and a water soluble neutral block B, and the polyionic component C has a charge opposite to the charge of block A of the copolymer. The invention also relates to the use of the composition in drug delivery (controlled release agents), rheology modifiers in for example coating formulations, food and cosmetics.

Description

Triblock copolymer gelators

The present invention relates to triblock copolymer gelators.

Triblock copolymers are known in the art. Langmuir 2004, 20, 4306-4309 for example discloses ABA type triblock copolymer gelators. The A block consists of a 2(diisopropylamino) ethylmethacrylate block, while the B-block is derived from 2- methacryloyloxyethyl phosphorylcholine. At low pH, the triblock copolymer is ionic. At pH above 4, the A block becomes hydrophobic and a micelle is being formed. Comparable systems are disclosed in for example Biomacromolecules 2003, 4, 864- 868. Here a gel can be formed at amounts above 10w/v% around neutral pH.

MACohen Stuart made a review on diblock and triblock copolymers in "Current Opinion in Colloid & Interface Science 10(2005), 30-36". Triblock copolymers, having associative middle blocks, are disclosed, that can make flowerlike micelles, 3- dimensional networks, core shell corona micelles and the like. The formation of micellar or gel-like structure is highly dependent on conditions like pH, concentration and temperature. The triblock copolymers known in literature are associative thickeners, wherein the thickening action is based on hydrophobic interactions of the hydrophobic blocks of the copolymers. These hydrophobic interactions can be disturbed by interactions with other hydrophobic ingredients of a dispersion, like polymers, particles, fillers and the like. Application of these triblock copolymers is therefore limited.

US 2006-275337 discloses diblock copolymers used as complex coacervate core micelles as surface modification or surface treatment.

EP 0780419 discloses multi-functional site containing polymers, that form gels after chemical reaction between different polymers.

It is an object of the invention to provide water soluble systems showing gelation behavior, resulting in solutions having reversible viscoelastic properties. It is another object of the invention to provide gelators that avoid the hydrophobic interactions with fillers and other hydrophobic ingredients of a dispersion or with hydrophobic surfaces of containers and the like.

The di- and triblock copolymers of the state of the art also have a problem of difficulty to handle due to premature gelling under certain conditions. The invention relates to a composition comprising water, a triblock copolymer and a polyionic component C, wherein the triblock copolymer is an ABA copolymer, having a charged block A and a water soluble neutral block B, and the polyionic component C has a charge opposite to the charge of block A of the copolymer.

Such a composition has a number of advantages. The properties of the composition can be tuned by additives, like for example salts, acids and bases. Furthermore the composition is a two component system, which provides freedom to tune the properties of the composition, without the need to make a new triblock copolymer or a polyionic component C.

Another advantage of the composition of the present invention is that a gelation or thickening effect will only occur upon mixing of the two components of the composition. This allows for easy preparing the single components, without all kinds of problems with premature gelling of the components.

Still another advantage of the composition of the present invention is the fact that the composition acts as an associative thickener. This means that the gelation is reversible and after disturbance of a gel by for example shear, the gel will repair itself again and obtain similar properties as before the disturbance.

Detailed description of the invention.

The term "complex coacervation", as used herein, refers to the interaction of two macromolecules of opposite charge. In the literature coacervation addresses the separation of colloidal systems in liquid phases, wherein the phase more concentrated in hydrophilic colloid component is called the coacervate. The term "complex" indicates that the driving force for separation of colloids is of electrostatic origin.

In the present specification, the molecular weight of a polymer, copolymer, or block refers to the weight-average molecular weight of said polymer, copolymer, part or block. The weight-average molecular weight of the polymer or copolymer can be measured by gel permeation chromatography (GPC). In the present specification, the molecular weight of a block refers to the molecular weight calculated from the amounts of monomers, polymers, initiators and/or transfer agents used to make said block. The man skilled in the art knows how to calculate these molecular weights. The ratios by weight between blocks refer to the ratios between the amounts of the compounds used to make said parts or blocks, considering an extensive polymerization. Typically, the molecular weight M of a block: M_b|_Oc_k, is calculated according to the following formula:

u

, wherein Mj is the molecular weight of a monomer i, rij is the number of moles of a monomer i, and n_precusor is the number of moles of a compound the macromolecular chain of the block will be linked to. Said compound may be a transfer agent or a transfer group, or a previous block. If it is a previous block, the number of moles may be considered as the number of moles of a compound the macromolecular chain of said previous block has been linked to, for example a transfer agent or a transfer group. It may be also obtained by a calculation from a measured value of the molecular weight of said previous block. If two blocks are simultaneously grown from a previous block, for example at ends, the molecular weight calculated according to the above formula should be divided by two.

The composition of the present invention is water based, which means that the components of the composition are dissolved or dispersed in water as the main solvent component. At least 50% of solvent of the composition is water, more preferably at least 60% of the solvent.

The composition comprises at least two components that carry opposite charges. The first component, being the triblock copolymer and the second component C are oppositely charged, meaning that one component exhibits an overall anionic character and the other component has an overall cationic character. The ionic properties can be accounted for by groups that are permanently charged or "quenched" in aqueous environment, such as e. g. sulfonate groups, or by chargeable or "annealed" groups which are dependent on pH, such as e.g. amines and carboxylated groups. From hereon, the term "chargeable", as used herein, refers to both permanently charged groups and chargeable groups. It can be also referred to "ionic" (charged) units, monomers, blocks, or polymers, or to "potentially ionic" (chargeable) units, monomers, blocks, or polymers. For the sake of simplification, in the present specification, "ionic" (responsibly anionic or cationic) refers to both ionic and potentially ionic (responsibly potentially anionic or potentially cationic), unless otherwise specified. In a preferred embodiment of the present invention, the ionic units of the polymers are permanently charged groups. The first component is a triblock copolymer with two ionic blocks A comprising each independently at least 6, more preferably at least 10 ionic groups. Preferably the amount of ionic groups is less than 100, more preferably less than 50. The term "block polymer", as used herein, refers to polymers that are constructed from blocks of more than one monomer (or units deriving from monomer (s)). It does not comprise polymers with random distributions of more than one monomer. However a block can be itself a random distribution of units deriving from more than one monomer.

The block copolymers can be prepared from monomeric units by different polymerization methods, known to the skilled man. For example, polymerization can be performed using condensation reactions, radical polymerization, cationic polymerization or any other chain growth mechanism.

The first component according to the present invention is preferably an ABA block copolymer. The block copolymer may optionally contain other blocks or bridging groups between the A and B blocks, or at the end of an A-block, as long as the essential properties of the triblock polymer are not negatively influenced.

The term "ionic block", as used herein, is meant to include blocks of charged groups and chargeable groups. The block polymer can be overall cationically or anionically chargeable. The ionic block of the block polymer is preferably selected from the group consisting of poly-L-lysine or other poly (amino acids), polyacrylic acid (PAA), polymethacrylic acid (PMA), DNA-segments, poly (thiophene-3-acetic acid), poly (4- styrenesulfonic acid), poly (pyridinium acetylene), poly (ethylene imine), poly (vinylbenzyltriamethylamine), polyaniline, poly (alkylamine hydrochloride), poly- (dimethylamino ethylmethacrylate) (PAMA), polyaspartic acid, poly (N-alkyl-4- vinylpyridinium) (PVP), but it is not limited thereto. More preferably, the ionic block is selected from the group of polyacrylic acid (PAA), polymethacrylic acid (PMA), poly- (dimethylamino ethylmethacrylate) (PAMA) and poly (N-alkyl-4- vinylpyridinium) (PVP). The block can also be defined by the units it comprises and/or by the monomers the units derive from. Thus the ionic block can comprise anionic units or cationic units. Examples of cationic blocks are blocks comprising units deriving from cationic monomers such as: aminoalkyl (meth) acrylates; aminoalkyl (meth) acrylamides; monomers, including particularly (meth) acrylates, and (meth) acrylamides derivatives, comprising at least one secondary, tertiary or quaternary amine function, or a heterocyclic group containing a nitrogen atom, vinylamine or ethylenimine; diallyldialkyl ammonium salts - their mixtures, their salts, and macromonomers deriving there from. Examples of cationic monomers include: dimethylaminoethyl (meth) acrylate; dimethylaminopropyl (meth) acrylate; ditertiobutylaminoethyl (meth) acrylate; dimethylaminomethyl (meth) acrylamide; dimethylaminopropyl (meth) acrylamide; ethylenimine; vinylamine; 2-vinylpyridine; 4-vinylpyridine; trimethylammonium ethyl (meth) acrylate chloride; trimethylammonium ethyl (meth) acrylate methyl sulphate; dimethylammonium ethyl (meth) acrylate benzyl chloride; 4-benzoylbenzyl dirnethyiammoπium ethyi acrylate chloride; trimethyl ammonium ethyl (meth) acrylamido (also called 2- (acryloxy) ethyltrimethylammonium, TMAEAMS) chloride; trimethylammonium ethyl (meth) acrylate (also called 2- (acryloxy) ethyltrimethylammonium, TMAEAMS); methyl sulphate; trimethyl ammonium propyl (meth) acrylamido chloride; vinylbenzyl trimethyl ammonium chloride; and diallyldimethyl ammonium chloride.

Examples of pH responsive cationic blocks are: poly (dimethylaminoethyl) methacrylate (PDMAEMA), poly methacrylic acid / polymethacrylate (PMA).

Examples of cationic blocks that are non responsive to pH are: poly (trimethylaminoethyl) methacrylate (PTMAEMA), polypotassium vinylsulfonate (PKVS).

Most preferred cationic blocks are blocks comprising units derived from at least one monomer selected from the group consisting of dimethylaminoethyl (meth) acrylate, dimethylaminopropyl (meth) acrylate, ditertiobutylaminoethyl (meth) acrylate, dimethylaminomethyl (meth) acrylamide, dimethylaminopropyl (meth) acrylamide, or blocks of poly (dimethylaminoethyl) methacrylate (PDMAEMA), poly

(trimethylaminoethyl) methacrylate (PTMAEMA), or polypotassium vinylsulfonate (PKVS).

Examples of non-pH responsive anionic blocks are blocks comprising units derived from anionic monomers like monoalkylesters of alpha-ethylenically- unsaturated, preferably mono-alpha- ethylenically-unsatu rated, dicarboxylic acids; alpha-ethylenically-unsaturated, preferably mono-alpha-ethylenically-unsaturated, compounds comprising a sulphonic acid group, and salts of alpha-ethylenically- unsaturated compounds comprising a sulphonic acid group.

Examples of pH responsive anionic blocks are blocks comprising units derived from anionic monomers like alpha-ethylenically-unsaturated, preferably mono-alpha- ethylenically-unsaturated, monomers comprising a phosphate or phosphonate group; alpha-ethylenically-unsaturated, preferably mono-alpha-ethylenically-unsaturated, monocarboxylic acids; monoalkylamides of alpha-ethylenically-unsaturated, preferably mono-alpha- ethylenically-unsaturated, dicarboxylic acids; acrylic acid, methacrylic acid.

Preferred anionic blocks include blocks comprising units deriving from at least one anionic monomer selected from the group consisting of: acrylic acid; methacrylic acid; vinyl sulphonic acid, salts of vinyl sulfonic acid; vin.ylbenzene sulphonic acid, salts of vinylbenzene sulphonic acid; alpha-acrylamidomethylpropanesulphonic acid, salts of alpha- acrylamidomethylpropanesulphonic acid; 2-sulphoethyl methacrylate, salts of 2- sulphoethyl methacrylate; acrylamido-2-methylpropanesulphonic acid (AMPS), salts of acrylamido-2- methylpropanesulphonic acid; and styrenesulfonate (SS).

The ionic blocks A can also comprise neutral hydrophilic units.

In a preferred embodiment of the invention, the triblock copolymer is a linear polymer and the blocks are end-to-end linked, optionally with a spacer or bridging group. If the copolymer is branched, the chargeable groups could also be grafted onto a hydrophilic and neutral backbone.

The triblock copolymer comprises at least a block B that is hydrophilic and neutral. In principle any hydrophilic and neutral block 8 can be employed, the only restrictions being that it is water-soluble and can be connected to the ionic block. The hydrophilic and neutral block B of the block polymer can be selected from the group comprising polyethylene glycol (PEG), polyglyceryl methacrylate (PGMA), polyvinylalcohol, polyacrylamide (PAM), polymethacrylamid. Other examples of neutral hydrophilic blocks B are blocks comprising units derived from neutral hydrophilic monomers, like for example: - ethylene oxide, - vinyl alcohol, - vinyl pyrrolidone, - acrylamide, methacrylamide, - polyethylene oxide (meth) acrylate (i. e. polyethoxylated (meth) acrylic acid), - hydroxyalkylesters of alpha-ethylenically-unsaturated, preferably mono-alpha- ethylenically-unsaturated, monocarboxylic acids, such as 2- hydroxyethylacrylate, and - hydroxyalkylamides of alpha-ethylenically-unsaturated, preferably mono-alpha- ethylenically-unsaturated, monocarboxylic acids.

In a preferred embodiment, the hydrophilic and neutral block B is chosen from polyethylene glycol (PEG), polyglyceryl methacrylate (PGMA), polyvinylalcohol, polyacrylamide (PAM), polymethacrylamid or a combination thereof.

The hydrophilic and neutral block B of the triblock copolymer preferably has a molecular weight between 2,500 and 100,000, more preferably between 5,000 and 50,000. The component C is a polyionic compound, comprising at least 2 charges, more preferably at least 6, even more preferably at least 10 or 15 charges. Examples of component C are polymers (polyelectrolytes), salts containing multiple charges, polyionic surfactants, solid particles and materials of biological nature like proteins.

In a preferred embodiment of the invention the component C is a poly ionic polymer, hereinafter defined as polymer C.

The polymer C according to the invention can be for example a homopolymer, a random copolymer, a block polymer, a natural polymer, or a derivative thereof. In case the polymer C is a homopolymer, or a random copolymer it is a polyelectrolyte. If the polymer C is a block polymer, it comprises at least an ionic block. The polyelectrolyte or the ionic block can be either cationically or anionically chargeable, wherein it is charged oppositely to the ionic blocks A of the triblock copolymer. If the ionic blocks A of the triblock copolymer are a polycation, than the polymer C has an overall anionic character, and if the ionic blocks of the triblock copolymer are a polyanion, than the polymer C has an overall cationic character. If the polymer C is a random copolymer, it preferably comprises a combination of anionic units, or a combination of cationic units, or a combination of anionic units and neutral units, or a combination of cationic units and neutral units. The polymer C according to the invention can be a homopolymer or a random copolymer, a block polymer, a natural polymer, or a derivative thereof. It can be chosen from the same group of polyanions and polycations as the ionic block of the triblock copolymer, but is not limited to this list. In other words, the polymer C, or block thereof, can comprise units and/or derive from monomers, that have been listed above, provided that it is cationic where the triblock copolymer has an anionic block, or that it is anionic where the triblock copolymer has a cationic block. In principle, any ionic block can be used in the preparation of the complex coacervate gels according to the invention, the only restraint being that it is oppositely chargeable to the ionic block of the triblock copolymer. Most preferably, the polymer C is selected from the group consisting of polyacrylic acid (PAA), polymethacrylic acid (PMA), poly (dimethylamino ethyl methacrylate) (PAMA) and poly (N-alkyl-4-vinylpyridinium) (PVP). It can be also a homopolymer or a random copolymer comprising units deriving from the monomers listed above. In case the polymer C is a homopolymer, it preferably comprises at least 5, more preferably at least 10, and most preferably between 15 and 200 monomelic units. The homopolymer has a molecular weight of typically between 500-40,000, preferably between 1 ,000- 20,000. In case the polymer C is a block polymer, the ionic block preferably consists of at least 20, more preferably at least 40, and most preferably at least 50 monomelic units. The ionic block of the polymer C has a molecular weight of preferably less than 100,000, more preferably less than 50,000, most preferably less than 25,000.

In case the polymer C is a block polymer, the second block can be a neutral block that is the same or different than the second block of the triblock copolymer. In principle any monomer can be applied, the only restrictions being that a block of these monomers is water-soluble, can be connected to the ionic block. Most preferably, the hydrophilic and neutral block is a polyethylene glycol, a polyglyceryl methacrylate or a polyacrylamide, or a combination thereof.

The blockcopolymers of the present invention can be prepared in different ways. For example blocks A and B can be directly coupled together, wherein block B has functional groups at both ends of the molecule that can react with a functional group at the end of each A block. This can be done with for example click-chemistry.

A preferred way of making the ABA triblock polymers according to the invention is to start with the middle B-block, which contains two functional groups at both ends of the molecule. From both ends the two blocks A are polymerised from with controlled chain growth chemistry, like for example controlled radical polymerization, anionic or cationic polymerization and the like. Alternatively it is also possible to start with a bifunctional molecule (like for example a bisphenol A) or bifunctional initiator, start making block B with a controlled chain growth mechanism, followed by a controlled chain growth of the two A blocks.

The compositions of the present invention can have numerous applications, for example as thickeners. Other examples of applications are: drug delivery (controlled release agents), rheology modifiers in for example coating formulations, food, cosmetics and the like.

The invention will now be exemplified in detail with reference to the appended Figures:

Figure 1 : Molecular structure of the synthesized triblock copolymer with negatively charged end-blocks.

Figure 2: Results of dynamic light scattering experiments. The scattered lightintensity is given as function of F⁺ . Figure 3: Results of dynamic light scattering dilution experiment. The filled dots represent the scattered light intensity, given on the left y-axis, and the open squares represent the hydrodynamic radius, given on the right y-axis.

Figure 4: Storage modulus (C¹ ) and loss modulus ( G" ) for different ionic strengths. Storage moduli data is represented by closed symbols, the loss moduli data is represented by open symbols.

Figure 5: Relaxation times as function of the ionic strength of the gel.

Figure 6: Flow curves of the gels at two ionic strengths. The line has a slope of unity and is added to guide the eye.

Figure 7: Viscosity as function of the temperature for gels at two ionic strengths.

Figure 8: Results of dynamic light scattering composition titrations. The scattered light intensity is given as function of F⁺ (see equation 1). Titration started at F⁺ = O is represented by the symbol o. Titration started at F⁺ = 1 is represented by the symbol • .

Figure 9: Average scattered light intensity (• , left axis) and hydrodynamic radius (W , right axis) as function of the ionic strength.

Figure 10: Vial with two polyelectrolyte phases separated by a ^'skin' in the middle of vial.

Figure 11: Zero-shear viscosity (η_Q ) of the PSPMA ₂₇— PEO(IOk)-PSPMA₂₇ / PAH ₁₆₀ gels at 400 mM KCI as function of the total polymer concentration. The polyelectrolytes are mixed at stoichiometric charge ratio.

Figure 12: Frequency sweep for a 12% gel at 20» C. The storage modulus is depicted by • ; the loss modulus is depicted by o. Both moduli are equal at an angular frequency of 13.8 s-' .

Figure 13: High frequency modulus of different gels measured at 20 » C.

Figure 14: Intensity of scattered light of mixtures of the cationic ABA triblock copolymer of example 2 and anionic polymer polyacrylic acid (DP = 150), versus the mixing ratio.

Figure 15: example of a hydrogel prepared in example 4 Examples

Experiment 1. Preparation of polyethylene oxide based bifunctional macroinitator

30.0 grams of hydroxy-termiπated polyethylene oxide (PEO) of nominal moiecuiar weight 10,000 g/mol (FLUKA), was dissolved in 290.5 grams toluene. 100 ml of the solvent was removed through azeotropic distillation under ambient pressure and temperature of 155 deg C. The solution was brought to 30 deg C and 3 ml of triethylamine was added. 3 ml of 2-bromoisobutyryl bromide was added drop wise over 30 minutes to the mixture under constant stirring. The reaction was left to take place for 7 days at 30 deg C. The dark brown mixture was treated with 30 grams of decolorizing charcoal. After removal of the charcoal by filtration, the polymer was precipitated into a 10-fold excess of petroleum ether. The pale yellow powder was now dissolved in absolute ethanol, and recrystalized at 4 deg C. The filtered product (white powder) was again dissolved in tetrahydrofuran and precipitated in a 5-fold excess of petroleum ether (repeat once). The remaining solvent was removed from the final product under reduced pressure at ambient temperature. Yield: 27.8 gram = 93 wt%, Degree of conversion (¹H NMR) > 95%, Structure of the product is:

Example 2. Preparation of an ABA triblock polymer

Preparation of A_n-B_1n-A_n triblock copolymer, where B = polyethylene oxide of 10,000 g/mol (i.e. 228 repeat units) according to experiment 1 and polytrimethylamino ethylmethacrylate (PTMAEMA) with a chloride counterion.

7.5 grams of the macroinitiator prepared in example 1 , 0.30 grams of 2,2- dipyridyl and 8,76 grams of a 75 wt% aqueous solution of the monomer (trimethylamiπo ethylmethacrylate) with chloride counterions are dissolved in a mixture of 15.0 grams of isopropanol and 15.0 grams of demineralized water. The mixture is degassed by bubbling with N₂ while stirring for 45 mins. The mixture is subsequently brought to a temperature of 40 deg C, placed under reflux and kept under a N₂ atmosphere. 0.075 grams of Cu(I)CI is added under nitrogen overpressure. Reaction is proceeded for 2.5h at 40 deg C. The reaction in the dark brown liquid is stopped by exposing the mixture to oxygen, turning the reaction mixture blue. The mixture is diluted with 50ml of demineralized water. Purification of the product is performed by dialysis (in 1,000 g/mol cut-off dialysis tubing) against demineralized water. The product (a white powder) is obtained through freeze drying. Yield: 11.7 grams = 83 wt%, ¹H NMR on the A_n-B_m-A_n block copolymer showed that n = 20 with m = 228 (from the supplier). The structure of the product is:

Example 3. Test of the association properties of the synthesized triblock copolymer in example 2 with polyacrylic acid.

10ml of a 1 gram/liter solution of the cationic ABA polymer of example 2 in water was placed in a glass cell, that was placed in a light scattering set-up. With a computerized titration set-up, a 2 gram/liter of the anionic polymer polyacrylic acid

(PAA) with a degree of polymerization of 150, was added stepwise to the solution in the cell. When the intensity of the light scattered by the polymer solution is plotted versus the charge stoichiometry (Figure 14), expressed as the ratio of the number of negative charges over the total number of charged groups in the system, we see that around 0.7 there is a large increase in scattered intensity, which is indicative of the formation of micelles, as is well established in literature. For the system investigated here we find a hydrodynamic radius for the micelles of 17nm, again in correspondence to what is described in literature for similar systems of diblock copolymers. The position of the peak in scattered intensity, known as the preferred micellar composition, represents the mixing ratio of the two components where the associative interactions are at a maximum. This experiment confirms that association between the cationic triblock copolymer and the anionic homopolymer takes place as expected.

Example 4. Formation of hydrogels from the ABA triblock copolymer from example 2 and polyacrylic acid (DP = 150).

Stock solutions of 100 gram/liter of the ABA triblock copolymer of example 2 and 100 gram/liter polyacrylic acid (degree of polymerization = 150) are mixed to yield a solution in which the charge mixing ratio is equal to 0.7, corresponding to the preferred micellar composition described in example 3. The charge mixing ratio is defined here as the number of negative charges (from the PAA) divided by the total number of charged groups (from the ABA triblock + the PAA). For an overall polymer concentration of 100 grams/liter, the mixtures instantly forms a hydrogel (90 wt% water) that can support its own weight (see left vial in figure 15). Upon diluting with water to give a polymer concentration of 10 g/L the mixtures again becomes liquid like (right vial in figure 15). This experiment confirms that at high enough concentrations, the association of the ABA triblock and an oppositely charged polyelectrolyte, leads to the formation of a hydrogel with significantly increased viscosity.

Example 5

5. Synthesis

A triblock copolymer was synthesized consisting of a PEO-IOk middle block and two negatively charged end-blocks. The triblock copolymer was prepared based on the works of Jankova et al.[macromolecules 31 (2): 538-541 , 1998], and Masci et al.fmacromolecules 37 (12) 4473, 2004], but will also be described here.

5.1 Double macro-initiator synthesis; Ml-batch 1

A bifunctional macro-initiator (MMOk) was prepared by dissolving 29.9 g of polyethylene glycol) (PEG) with AZ_n 10.000 g/mol (Fluka) in 300 ml toluene (Sigma

Aldrich). After azeotropic distillation of 100 ml toluene, a ten-times molar excess, with respect to the amount of PEG, of triethylamine (Sigma Aldrich) was added. In this example that corresponds to 3 ml triethylamine. Subsequently, a ten-times molar excess, with respect to the amount of PEG, of 2-bromoisobutyryl bromide (Sigma Aldrich) was added dropwise. In this example that corresponds to 2.74 ml of 2- bromoisobutyrylbromide. The reaction mixture was stirred for five days at 30⁰C.

Purification of the double macro-initiator was started by treatment of the reaction mixture with decolourising charcoal at 40⁰C for 30 min. Subsequently, the solids were removed by Bϋchner filtration. The solvent was partly removed by rotary evaporation before precipitation of the product in a ten-fold excess of petroleum ether. After filtration, the product was redissolved in THF before precipitation in a ten-fold excess of petroleum ether (twice). The product was obtained by filtration and dried under vacuum overnight. Yield was determined to be 87.6%. The degree of esterification was determined by ¹H NMR to be 99%. This batch of macro-initiator will be referred to as ^" Ml-batch 1'.

5.2 Double macro-initiator synthesis; Ml-batch 2

A second batch of MI-IOk was prepared, which will be referred to as ^% Ml-batch 2'. The synthesis was performed according to the procedure described in section 5.1. However, the second batch was scaled up five times compared to the quantities described in section 5.1. Yield was 88%, with a degree of esterification of 100%, as determined by ¹H NMR.

5.3 Triblock copolymer synthesis; TB-batch 1

The first batch of triblock copolymers, hereafter denoted by TB-batch 1\ was synthesized according to the following procedure: Degassing of the solid mixture of 2.02 g of MI-IOk (Ml-batch 1) and 4.04 g of 3-sulfopropylmethacrylate potassium salt (KSPMA) (Sigma Aldrich), which is a 110-fold excess of reactive monomer, aiming for an average degree of polymerization of 110. The solid mixture was dissolved in 4 ml of a degassed mixture of water/DMF (1 :1 ) at 60⁰C. The reaction mixture was kept under argon flow until completion. An ATRP catalyst mixture was prepared by dissolving an equal molar amount, with respect to the amount of MI-IOk, of Cu(I)CI (Sigma Aldrich), a double molar amount, with respect to the amount of MI-IOk₁ of Cu(II)CI (Sigma Aldrich) and a 7.5-times molar excess, with respect to the amount of MI-IOk, of 2,2-bipyridine (Sigma Aldrich) in 2 ml of a water/DMF mixture (1 :1). The ATRP catalyst mixture was added to the MMOk/KSPMA solution to start the polymerization The reaction was quenched after 2.5 hours by bubbling oxygen through the sample. Purification of the product was achieved by dilution with water and subsequent filtration over a silica-gel column. Traces of silica-gel were removed by filtration through a 0.45 μm filter. Further purification was achieved by extensive dialysis against 0.1 M KCI solution, followed by dialysis against pure water. The triblock copolymer was obtained by freeze-drying overnight. Yield was determined to be 52%, with an average degree of polymerization of 110, as determined by ¹H NMR.

The structure of the resulting triblock copolymer is shown in figure 1 , and will be abbreviated as PSPMA_n,- PEO_n- PSPMA_n, throughout this work. In this formula, m is the amount of KSPMA groups on each side of the middle-block and n is the amount of monomers in the middle-block. Hence, for TB-batch 1 the average number of charged groups per side of the triblock (m ) was found to be 55.

5.4 Triblock copolymer synthesis; TB-batch 2

Another batch of triblock copolymer, with negatively charged end-blocks based on the 3-sulfopropylmethacrylate monomer, was synthesized, according to the procedure described in section 5.3. In this synthesis Ml-batch 1 was used as MI-IOk source. This second triblock copolymer batch will be denoted as TB-batch 2'. The synthesis of TB-batch 2 aimed for shorter end-blocks. Yield after the ATRP reaction was approximately 43% by weight. ¹H NMR spectra analysis indicated an average DP of 35 groups per end-block: PSPMA₃₅ -PEO(IOk)-PSPMA₃₅ .

5.5 Triblock copolymer synthesis; TB-batch 3

A third batch of PSPMA_w— PEO(lOfc)— PSPMA_m triblock copolymer was synthesized, to be referred to as TB-batch 3'. The synthesis was performed according to the method described in section 5.3. Ml-batch 2 was used as macro-initiator source in the the synthesis of TB-batch 3. This third batch of triblock copolymer aimed at approximately the same amount of end-groups as in TB-batch 2, but now in higher quantities. 15,3 grams of triblock was obtained. The product was characterized by ■ H NMR and GPC. From the GPC chromatogram it was concluded that the polymerization reaction proceeded well; there were no traces of the MM Ok in the triblock copolymer product and a polydispersity index of 1.12. From ¹H NMR spectra it was concluded that TB-batch 3 has on average 27 groups at each side: PSPMA₂₇ --PEO(IOk)- PSPMA ' 2-7 '

Example 6

6.1 Physical gel formation by mixing PSPMA_n, --PEO(IOk)- PSPMA_1n with

PDMAEMA₁₅₀

6.1.1 Co-assembly behaviour TB-batch 1

Dynamic light scattering experiments at different salt concentrations were performed, using the weak polyelectrolyte poly(dimethyl-aminoethyl methacrylate)_l50

(PDMAEMA) ₁₅₀ at pH w 2.5 as cationic homopolymer. It was assumed that all amine groups in the PDMAEMA were protonated, since the pK_a of PDMAEMA is approximately 6.5. The DLS results are summarized in figure 2. To take into account the amount of charges in the system, a composition variable F⁺ is defined, which is the fraction of positive charges in the system:

W+Η

Here, [+] is the concentration of positive charges and [-] is the concentration of negative charges.

As can be seen in figure 2, the scattered light intensity is a strong function of both the composition in the system as well as the ionic strength. The scattered light intensity has a peak around the stoichiometric charge ratio, F⁺ = 0.5 . This indicates the formation of multimolecular nano-assemblies (presumably flowerlike micelles) in solution. The scattered light intensity at F+ = 0.5 decreases with increasing salt concentration. Above 400 rtiM of KCI no complexes are formed anymore. Analysis of the correlation function shows that the size of the objects formed decreases with increasing ionic strength, hence the scattered light intensity decreases.

The dependence on the ionic strength was further investigated by a dilution experiment. A triblock copolymer/PDMAEMA mixture at F+ = 0.5 was prepared at 500 mM KCI. Water was added to dilute the mixture while measuring the scattered light intensity. The result is shown in figure 3.

The scattered light intensity increases around 450 mM of KCI. This increase is caused by the formation of complexes and this value can therefore be regarded as the 'critical' ionic strength for this particular system. With the increase in scattered light intensity, also the hydrodynamic radius increases. At the onset of co-assembly, relatively big complexes are formed. It is assumed that at this critical point, very large but dilute complexes are formed. Upon increasing the attractive interaction, by lowering the salt concentration, the complexes become smaller again, until an equilibrium value of R_h « 20 nm is reached. The average scattered light intensity keeps increasing with decreasing salt concentration, indicating that more and more micelles are formed.

6.1.2 Co-assembly behaviour TB-batch 2

A concentrated sample with a PEO middle-block concentration of 100 g/l was prepared. PDMAEMA ₁₅₀ was added up to stoichiometric charge ratio. Upon acidifying the solution to pH « 3 , the sample became transparent and thickened. This observation led to a new series of measurements.

Mixtures of PSPMA₃₅ -PEO(IOk)-PSPMA₃₅ and PDMAEMA₁₅₀ at pH » 2.5 and 500 mM KCI, above the critical ionic strength, were prepared. These liquid mixtures were then dialysed against different, lower, salt concentrations using dialysis cassettes (Pierce). Gelation occurred and the transparent gels were investigated by rheometry, using a cone-plate geometry. The results of a frequency sweep at two salt concentrations are shown in figure 4.

From figure 4 it shows that the relaxation time (the crossover between G' and G" ) of the gels is dependent on the ionic strength; the relaxation time increases with decreasing salt concentration. For four different ionic strengths the relaxation time dependence on the ionic strength is shown in figure 5. Remarkable is the fact that the relaxation time is in the order of milliseconds. This is of the same order as the relaxation times in the classical associative thickeners based on hydrophobic interactions. To investigate the flow behaviour of the PSPMA₃₅ -PEO(IOk)- PSPMA₃₅ /PDMAEMA ₁₅₀ gels, flow curves were measured up to the shear rates accessible by cone-plate geometry. The results are shown in figure 6.

Figure 6 shows that all gels behave as Newtonian fluids in this range of shear rates. The viscosity at low shear rates (zero-shear viscosity) differs for the different samples.

The effect of temperature on the viscosity of the PSPMA₃₅ — PEO(I Ok)-- PSPMA₃₅ /PDMAEMA _|50 gels was investigated. Results are shown in figure 7.

The viscosity decreases with increasing temperature, which corresponds to a

lowering of the relaxation time at higher temperatures.

Example 7

7.1 Physical gel formation by mixing PSPMA_n, - PEO(IOk)- PSPMA _m with PAH

The co-assembly behaviour of TB-batch 3 with the weakly charged polyelectrolyte poly(allyl amine hydrochlorid)₁₆₀ (PAH₁₆₀ ) was investigated. PAH is a weakly charged polymer with p K_Λ « 9.5. Upon dissolving PAH in water the p H of the solution is approximately 4.2. Therefore it is assumed that all amine groups are charged upon dissolving the polyelectrolyte in water. To investigate the co-assembly behaviour dynamic light scattering titrations were performed. The results are shown in figure 8.

From figure 8 it can be seen that co-assembly of PSPMA₂₇ — PEO(IOk) — PSPMA₂₇ with PAH₁₆₀ takes place irrespective of the titration starting point, i.e. the scattered light intensity increases with increasing addition of one of the two components. Co-assembly is strongest at stoichiometric charge ratio (F+ = 0.5 ), as expected. The complexes formed are presumably flowerlike micelles that have an average hydrodynamic radius of « 20 nm, with becomes slightly higher around the stoichiometric charge ratio (data not shown). To determine the 'critical ionic strength' of this system, above which no co- assembly occurs, three DLS dilution experiments were performed. Solutions of PSPMA₂₇ — PEO(IOk)-PSPMA₂₇ and PAH ₁₆₀ at stoichiometric charge ratio were prepared at a certain salt concentration. In the measurement water was added to dilute the system. The results are shown in figure 9. Note that the scattered light intensity is πormaiized with respect to the weight concentration of polymer in the system, hereby assuming that the scattered light intensity decreases linearly with the total polymer concentration.

From figure 9 the critical ionic strength is determined to be 1.7 M KCI. Above this ionic strength the scattered light intensity is very low, i.e. no co-assembly occurs due to the screening of the electrostatic interactions. Below the 1.7 M the scattered light intensity increases, up to 0 M KCI. This increase is partly caused by the increase in hydrodynamic radius of the complexes. However, the contrast as well as the number of micelles might also increase upon diluting the system.

Physical gels were prepared based on the DLS experiments. Two separate solutions of either polyelectrolyte were prepared in such a way that upon mixing the system would be at stoichiometric charge ratio and at an ionic strength of 400 mM KCI. Both polymer solutions behave as low viscosity fluids. Upon mixing the two solutions a physical gel is formed instantly. If one of the polyelectrolyte solutions is added carefully on top of the other polyelectrolyte solution it is possible to create a 'skin' between the two polymer phases, see figure 10. This skin disappears upon mixing the two phases.

A concentration series of the PSPMA₂₇ -PEO(IOk)-PSPMA₂₇ / PAH₁₆₀ physical gels was prepared and the mechanical properties were investigated using rheometry. The zero-shear viscosity (η₀ ) as function of concentration is given in figure 11. From this figure it can be seen that the zero-shear viscosity is an extremely strong function of the total polymer concentration above a concentration of 60 g/L.

Oscillatory measurements were performed to probe the viscoelastic properties of the gels. A typical frequency sweep at 20° C is shown in figure 12. From the crossover point between the storage modulus (G' ) and the loss modulus (G" ) in frequency sweep measurements, the relaxation time of the gel can be derived. The relaxation time ( T ) is given as the inverse of the cross-over frequency. In this particular example

the relaxation time of the gel is τ = = 0.07 s.

13.8 The high frequency storage modulus represents the elastic modulus (G ) of the system. The modulus as function of the concentration is given in figure 13.

Claims

1 A composition comprising water, a triblock copolymer and polyionic component C, wherein the triblock copolymer comprises an ABA composition, having two charged blocks A and a water soluble neutral block B, and the polyionic component C has a charge opposite to the charge of block A of the copolymer.

2 The composition according to claim 1 , wherein each charged block A comprises independently from 6 to 100 ionic groups.

3 The composition according to claim 1 , wherein each charged block A comprises independently from 10 to 50 ionic groups.

4 The composition according to anyone of claims 1-3, wherein the A block is a cationic block, chosen from the group consisting of dimethylaminoethyl (meth) acrylate, dimethylaminopropyl (meth) acrylate, ditertiobutylaminoethyl (meth) acrylate, dimethylaminomethyl (meth) acrylamide, dimethylaminopropyl (meth) acrylamide, or blocks of poly(dimethylaminoethyl) methacrylate (PDMAEMA), poly(trimethylaminoethyl) methacrylate (PTMAEMA), or polypotassium vinylsulfonate (PKVS).

5 The composition according to anyone of claims 1-3, wherein the A block is an anionic block, chosen from the group consisting of blocks comprising units deriving from at least one anionic monomer selected from acrylic acid; methacrylic acid; vinyl sulphonic acid, salts of vinyl sulfonic acid; vinylbenzene sulphonic acid, salts of vinylbenzene sulphonic acid; alpha-acrylamidomethylpropanesulphonic acid, salts of alpha-acrylamidomethylpropanesulphonic acid; 2-sulphoethyl methacrylate, salts of 2- sulphoethyl methacrylate; acrylamido-2-methylpropanesulphonic acid (AMPS), salts of acrylamido-2- methylpropanesulphonic acid; and styrenesulfonate (SS).

6 The composition according to anyone of the preceding claims, wherein block B is chosen from polyethylene glycol (PEG), polyglyceryl methacrylate (PGMA), polyvinylalcohol, polyacrylamide (PAM), polymethacrylamid.

7 The composition according to anyone of the preceding claims, wherein block B has an average molecular weight between 2,500 and 100,000.

8 The composition according to anyone of the preceding claims, wherein block B has an average molecular weight between 5,000 and 50,000. 9 The composition according to anyone of the preceding claims, wherein component C comprises at least 6 charges.

10 The composition according to anyone of the preceding claims, wherein component C is a polyelectrolyte. 11 The composition according to claim 10, wherein component C is selected from the group consisting of polyacrylic acid (PAA)₁ polymethacrylic acid (PMA), poly (dimethylamino ethyl methacrylate) (PAMA) and poly (N-alkyl-4-vinylpyridinium) (PVP).

12 The composition according to claim 10 or 11 , wherein component C is a homopolymer, having a molecular weight of between 1,000-20,000.

13 Use of the composition according to anyone of the preceding claims in drug delivery (controlled release agents), rheology modifiers in for example coating formulations, food, cosmetics.