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Polymers and polymerization processes Number:6,780,930 from the United States Patent and Trademark Office (PTO) owispatent

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Title: Polymers and polymerization processes

Abstract: Emulsion polymerizations are described in which the monomers include an ethylenically unsaturated ammonium phosphate ester monomer. The processes may be conducted with high total solids, to produce a polymer latex having a solids content in the range 20 to 60%, for instance in the range 25 to 50% by weight. Preferably comonomers include lower alkyl and higher alkyl methacrylate selected to give desirable glass transition temperatures and coalescing films, zwitterionic comonomers, polyethoxylated comonomers to confer desired biocompatibility and latex stability as well as good wetting for a film formed of the polymer and may contain crosslinking monomers, reactive monomers, anionic monomers and/or cationic monomers. The latexes are stable, even when the process is carried out in the substantial absence of non-polymerisable emmulsifier. Coatings formed from the latexes containing zwitterionic comonomer have good biocompatibilising properties.

Patent Number: 6,780,930 Issued on 08/24/2004 to Lewis,   et al.


Inventors: Lewis; Andrew Lennard (Surrey, GB), Hughes; Laurence Gerald (Surrey, GB)
Assignee: Biocompatibles UK Limited (Farnham, GB)
Appl. No.: 09/987,721
Filed: November 15, 2001


Foreign Application Priority Data

Nov 16, 2000 [EP] 00310178

Current U.S. Class: 524/800 ; 524/801; 524/832
Current International Class: C08F 246/00 (20060101)
Field of Search: 524/800,801,832


References Cited [Referenced By]

U.S. Patent Documents
3497482 February 1970 Hwa
5648442 July 1997 Bowers et al.
5705583 January 1998 Bowers et al.
5739236 April 1998 Bowers et al.
5783650 July 1998 Bowers et al.
6087462 July 2000 Bowers et al.
6090901 July 2000 Bowers et al.
6225431 May 2001 Bowers et al.
Foreign Patent Documents
2 717 818 Sep., 1995 FR
WO 93/012221 Jan., 1993 WO
WO 94/14897 Jul., 1994 WO
WO 01/09208 Feb., 2001 WO
WO 01/27209 Apr., 2001 WO

Other References

Yamaguchi et al., "Emulsion polymerization of styrene using phospholipid as emulsifier. Immobilization of phospholipids on the latex surface," Makromol. Chem., vol. 190 (1989) pp. 1195-1205. .
Sugiyama et al., "Synthesis of Poly(methyl methacrylate) Microspheres Bearing Phosphatidylcholine Analogous and Azobenzene Moieties," Polymer Journal, vol. 25, No. 5 (1993), pp. 521-527. .
Sugiyama et al., "Adsorption of Protein on the Surface of Thermosensitive Poly(Methyl Methacrylate) Microspheres Modified with the N-(2-Hydroxypropyl) methacrylamide and 2-(Methacryloyloxy) ethyl Phosphorylcholine Moieties," Journal of Polymer Science, vol. 35, (1997), pp. 3349-3357. .
Zimehl et al., "Some aspects of polymer colloids I. Preparation and properties of different types of latex particles," Colloid Polymer Sci., vol. 268, (1990), pp. 924-933..

Primary Examiner: Cheung; William
Attorney, Agent or Firm: Sughrue Mion, PLLC

Claims



What is claimed is:

1. An emulsion polymerization process comprising the following steps: a) providing a mixture of ethylenically unsaturated monomers including water insoluble monomer; b) dispersing the mixture of ethylenically unsaturated monomers into an aqueous liquid to form an oil-in-water emulsion; c) adding to the oil-in-water emulsion an ammonium phosphate ester zwitterionic monomer; d) adding a water-soluble radical initiator to the oil-in water emulsion; e) polymerizing the monomers to form a product latex of polymer having a polymer solids concentration in the product of at least 20% by weight.

2. An emulsion polymerization process according to claim 1 in which the solids concentration of the product is up to 60%.

3. An emulsion polymerization process according to claim 2 in which the solids concentration of the product is in the range 25 to 50%.

4. An emulsion polymerization process according to claim 1 in which the oil-in-water emulsion is substantially free of non-polymerisable surfactants.

5. An emulsion polymerization process according to claim 1 in which the ammonium phosphate ester zwitterionic monomer is included in the process in an amount in the range 0.01 to 5% by weight based on the total weight of monomers.

6. An emulsion polymerization process according to claim 5 in which the said amount is in the range 0.05 to 2% by weight.

7. An emulsion polymerization process according to any preceding claim in which the ammonium phosphate ester zwitterionic monomer has the general formula I

in which X is said ammonium phosphate ester zwitterionic group; B is selected from the group consisting of a bond, and straight and branched alkanediyl, alkylene oxaalkylene, and alkylene (oligooxalkylene) groups, optionally containing one or more fluorine substituents; and Y is an ethylenically unsaturated group selected from the group consisting of H.sub.2 C.dbd.CR--CO--A--, H.sub.2 C.dbd.CR--C.sub.6 H.sub.4 --A.sup.1 --, H.sub.2 C.dbd.CR--CH.sub.2 A.sup.2 --, R.sup.2 O--CO--CR.dbd.CR--CO--O--, RCH.dbd.CH--CO--O--, RCH.dbd.C(COOR.sup.2)CH.sub.2 --CO--O--, ##STR10## A is --O-- or NR.sup.1 ; A.sup.1 is selected from the group consisting of a bond, (CH.sub.2).sub.n A.sup.2 and (CH.sub.2).sub.n SO.sub.3 -- in which n is 1 to 12; A.sup.2 is selected from the group consisting of a bond, --O--, O--CO--, --CO--O, --CO--NR.sup.1 --, --NR.sup.1 --CO, --O--CO--NR.sup.1 --, and --NR.sup.1 --CO--O--; R is hydrogen or C.sub.1-4 alkyl; R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-4 alkyl and BX; and R.sup.2 is hydrogen or C.sub.1-4 alkyl.

8. An emulsion polymerization process according to claim 1 in which the monomers include at least 50% by weight based on total ethyleneically unsaturated monomers of a hydrophobic ethylenically unsaturated polymerisable compound.

9. An emulsion polymerization process according to claim 8 in which the said hydrophobic compound is selected from the group consisting of C.sub.1-12 alkyl(alk)acrylates and C.sub.2-12 -alkyl and -dialkyl(alk)acrylamides, styrene, and mixtures thereof.

10. An emulsion polymerization process according to claim 1 comprising further adding to the oil-in-water emulsion a sulpho- or carboxy-betaine monomer.

11. An emulsion polymerization process according to claim 10 in which the weight ratio of betaine monomer to ammonium phosphate ester zwitterionic monomer is in the range (1-50):1.

12. An emulsion polymerization process according to claim 11 in which the said ratio is in the range (5-20):1.

13. An emulsion polymerization process according to claim 1 comprising adding to the oil-in-water emulsion a hydrophilic monomer.

14. An emulsion polymerization process according to claim 13 in which the ydrophilic monomer is selected from the group consisting of C.sub.2-4 -hydroxyalkyl(meth)acrylates, C.sub.1-4 -hydroxyalkyl(meth)acrylamides, C.sub.1-3 -alkoxy-C.sub.2-4 -alkyl(meth)acrylates, C.sub.1-3 -alkoxy-C.sub.2-4 -alkyl(meth)acrylamides, C.sub.1-3 -alkoxy-oligoethoxy(meth)acrylates C.sub.1-4 -dihydroxyalkyl(meth)acrylates, N-mono- and N,N- di- C.sub.1-2 alkyl (meth)acrylamides, N-vinylactams and C.sub.2-4 hydroxyalkyl oligoethoxy(meth)acrylates, and mixtures thereof.

15. An emulsion polymerization process according to claim 13 in which the said hydrophilic monomer is added in an amount in the range 0.1 to 50% by weight, based on the total weight of monomer.

16. A process according to claim 15 in which the said range is 5 to 20% by weight.

17. An emulsion polymerization process according to claim 1 comprising adding to the oil-in-water emulsion an acidic monomer in an amount to confer an acidic pH on the oil-in-water emulsion.

18. An emulsion polymerization process according to claim 17 in which the acidic monomer is acylic acid or methacrylic acid, and it is present in an amount in the range 0.1 to 5% by weight based on the total weight of monomers.

19. An emulsion polymerization process according to claim 1 comprising adding to the oil-in-water emulsion a cationic monomer, of the general formula VIII

in which Y.sup.2 is an ethylenically unsaturated group selected from the group consisting of H.sub.2 C.dbd.CR.sup.19 --CO--A.sup.8 --, H.sub.2 C.dbd.CR.sup.19 --C.sub.6 H.sub.4 --A.sup.9 --, H.sub.2 C.dbd.CR.sup.19 --CH.sub.2 A.sup.10, R.sup.21 O--CO--CR.sup.19.dbd.CR.sup.19 --CO--O--, R.sup.19 CH.dbd.CH--CO--O--, R.sup.19 CH.dbd.C(COOR.sup.21)CH.sub.2 --CO--O--, ##STR11## A.sup.8 is --O-- or --NR.sup.20 --; A.sup.9 is selected from the group consisting of a bond, (CH.sub.2).sub.q A.sup.10 and (CH.sub.2).sub.q SO.sub.3 -- in which q is 1 to 12; A.sup.10 is selected from the group consisting of a bond, --O--, O--CO--, --CO--O, --CO--NR.sup.20 --, --NR.sup.20 --CO, O--CO--NR.sup.20 --, and NR.sup.20 --CO--O--; R.sup.19 is hydrogen or C.sub.1-4 alkyl; R.sup.20 is selected from the group consisting of hydrogen, C.sub.1-4 -alkyl and BX; R.sup.21 is hydrogen or C.sub.1-4 alkyl; B.sup.2 is selected from the group consisting of a bond, and straight and branched alkanediyl, alkylene oxaalkylene, and alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and Q is selected from the group consisting of --N.sup..sym. R.sup.22.sup.3, --P.sup..sym. R.sup.23.sub.3 and --S.sup..sym. R.sup.23.sub.2.sub.2 in which the groups R.sup.22 are the same or different and each is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, C.sub.1-6 hydroxyalkyl, aryl, and C.sub.7-12 aralkyl, or two of the groups R.sup.22 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R.sup.22 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R.sup.22 is substituted by a hydrophilic functional group, and the groups R.sup.23 are the same or different and each is R.sup.22 or a group OR.sup.22, where R.sup.22 is as defined above mutatis mutandis.

20. An emulsion polymerization process according to claim 19 in which Y.sup.2 is H.sub.2 C.dbd.CR.sup.19 COA--, in which R.sup.12 is hydrogen or methyl and A is --O-- or --NH--, B.sup.2 is straight chain C.sub.2-6 alkanediyl group and Q is --N.sup..sym. R.sup.33.sub.3 where each R.sup.22 group is a C.sub.1-4 alkyl group.

21. An emulsion polymerization process according to claim 1 comprising further adding to the oil-in-water emulsion a reactive monomer having the general formula IX

in which Y.sup.3 is an ethylenically unsaturated group selected from the group consisting of H.sub.2 C.dbd.CR.sup.24 --CO--A.sup.11 --, H.sub.2 C.dbd.CR.sup.24 --C.sub.6 H.sub.4 --A.sup.12 --, H.sub.2 C.dbd.CR.sup.19 --CH.sub.2 A.sup.13, R.sup.26 O--CO--CR.sup.24.dbd.CR--CO--O--, R.sup.24 CH.dbd.CH--CO--O--, R.sup.24 CH.dbd.C(COOR.sup.26)CH.sub.2 --CO--O--, ##STR12## A.sup.11 is --O-- or --NR.sup.25 ; A.sup.12 is selected from the group consisting of a bond, (CH.sub.2).sub.r A.sup.13 and (CH.sub.2).sub.r SO.sub.3 -- in which r is 1 to 12; A.sup.13 is selected from the group consisting of a bond, --O--, O--CO--, CO--O, --CO--NR.sup.25 --, --NR.sup.25 --CO, --O--CO--NR.sup.25 --, and NR.sup.25 --CO--O--; R.sup.24 is hydrogen or C.sub.1-4 alkyl; R.sup.25 is selected from the group consisting of hydrogen, C.sub.1-4- alkyl and B.sup.3 Q.sup.1. R.sup.26 is hydrogen or C.sub.1-4 alkyl; B.sup.3 is selected from the group consisting of a bond, straight and branched alkanediyl, alkylene oxaalkylene, and alkylene (oligooxalkylene) groups, optionally containing one or more fluorine substituents. Q.sup.1 is a reactive group selected from the group consisting of aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C.sub.1-4 -alkoxy groups; hydroxyl; amino; carboxyl; epoxy; --CHOHCH.sub.2 Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; cinnamyl; ethylenically and acetylenically unsaturated groups; acetoacetoxy; methylol; and chloroalkylsulphone groups; acetoxy; mesylate; carbonyl di(cycloalkyl carbodiimidoyl; and oximino.

22. An emulsion polymerization process according to claim 21 in which Y.sup.3 is H.sub.2 C.dbd.CR.sup.24 COA"-- in which R.sup.24 is hydrogen or methyl and A" is --O-- or NH--, B.sup.3 is a straight chain C.sub.2-6 -alkanediyl group; and Q.sup.1 is a trimethoxysilyl group.

23. An emulsion polymerization process according to claim 22 in which the monomers include a hydrophilic monomer selected from the group consisting of C.sub.2-4 hydroxyalkyl(alk)acrylates and mono- or di- C.sub.2-4 hydroxyalkyl(alk)acrylamides.

24. An emulsion polymerization process comprising the following steps: i) adding an ethylenically unsaturated ammonium phosphate ester zwitterionic monomer and a water-soluble radical initiator in a first stage to an aqueous liquid to form an aqueous continuous phase; ii) forming a monomer seed mixture comprising water-insoluble ethylenically unsaturated monomer, and water-soluble ethylenically unsaturated monomer; iii) before, simultaneously or after step i) adding the monomer seed mixture to the aqueous continuous phase to form a water-in-oil emulsion; iv) after both steps i) and iii) adding water-soluble initiator and initiating polymerization to form an oil-in-water dispersion of emulsion-polymerised polymer seeds; v) forming a seed growth monomer mixture comprising water-insoluble ethylenically unsaturated monomer; vi) dispersing the seed growth monomer to the dispersion of emulsion-polymerised seeds to form an oil-in-water seed growth emulsion; vii) adding seed growth initiator to the seed growth emulsion and initiating seed growth polymerization in the seed growth emulsion to form a product latex.

25. An emulsion polymerization process according to claim 24 in which the composition of the combination of monomer seed mixture and zwitterionic monomer is different to the composition of the seed growth monomer mixture.

26. An emulsion polymerization process according to claim 25 in which the monomer seed mixture consists substantially only of hydrophobic ethylenically unsaturated monomer.

27. An emulsion polymerization process according to claim 26 in which the hydrophobic monomer is selected from the group consisting of C.sub.1-12 alkyl(alk)acrylates and C.sub.2-12 -alkyl and di-alkyl(ak)acrylamides, styrene, and mixtures thereof.

28. An emulsion polymerization process according to claim 25 in which the seed growth monomer mixture comprises ethylenically unsaturated ammonium phosphate ester zwitterionic monomer.

29. An emulsion polymerization process according to claim 28 in which seed growth monomer mixture comprises water-soluble ethylenically unsaturated monomers.

30. An emulsion polymerization process according to claim 29 in which the said water-soluble monomers comprise a hydrophilic monomer.

31. A process according to claim 29 in which the said water soluble monomers include acrylic or methacrylic acid.

32. An emulsion polymerization process according to claim 29 in which the said water-soluble monomers include a cationic monomer, of the general formula VIII

in which Y.sup.2 is an ethylenically unsaturated group selected from the group consisting of H.sub.2 C.dbd.CR.sup.19 --CO--A.sup.8 --, H.sub.2 C.dbd.CR.sup.19 --C.sub.6 H.sub.4 --A.sup.9 --, H.sub.2 C.dbd.CR.sup.19 --CH.sub.2 A.sup.10, R.sup.21 O--CO--CR.sup.19.dbd.CR.sup.19 --CO--O--, R.sup.19 CH.dbd.CH--CO--O--, R.sup.19 CH.dbd.C(COOR.sup.21)CH.sub.2 --CO--O--, ##STR13## A.sup.8 is --O-- or --NR.sup.20 --; A.sup.9 is selected from the group consisting of a bond, (CH.sub.2).sub.q A.sup.10 and (CH.sub.2).sub.q SO.sub.3 -- in which q is 1 to 12; A.sup.10 is selected from the group consisting of a bond, --O--, O--CO--, --CO--O, --CO--NR.sup.20 --, --NR.sup.20 --CO, O--CO--NR.sup.20 --, and NR.sup.20 --CO--O--; R.sup.19 is hydrogen or C.sub.1-4 alkyl; R.sup.20 is selected from the group consisting of hydrogen, C.sub.1-4- alkyl and BX; R.sup.21 is hydrogen or C.sub.1-4 alkyl; B.sup.2 is selected from the group consisting of a bond, and straight and branched alkanediyl, alkylene oxaalkylene, and alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and Q is selected from the group consisting of --N.sup..sym. R.sub.3.sup.22,--P.sup..sym. R.sup.23.sub.3 and --S.sup..sym. R.sup.23 in which the groups R.sup.22 are the same or different and each is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, C.sub.1-6 hydroxyalkyl, aryl, and C.sub.7-12 aralkyl, or two of the groups R.sup.22 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R.sup.22 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R.sup.22 is substituted by a hydrophilic functional group, and the groups R.sup.23 are the same or different and each is R.sup.22 or a group OR.sup.22, where R.sup.22 is as defined above mutatis mutandis.

33. An emulsion polymerization process according to claim 32 in which Y.sup.2 is H.sub.2 C.dbd.CR.sup.19 COA--, in which R.sup.12 is hydrogen or methyl and A is --O-- or --NH--, B.sup.2 is straight chain C.sub.2-6 alkanediyl gruop and Q is --N.sup..sym. R.sub.3.sup.22 where each R.sup.22 group is a C.sub.1-4 alkyl group.

34. An emulsion polymerization process according to claim 24 in which at least a portion of seed growth monomers are premixed before being added to the continuous phase in step iv.

35. An emulsion polymerization process according to claim 34 in which the seed growth monomer mixture is continuously fed into the oil-in-water dispersion compositions of emulsion-polymerised seeds over a monomer feed period during which polymerization continues.

36. An emulsion polymerization process according to claim 35 comprising providing an initiator feed comprising the seed growth initiator and continuously feeding the initiator feed, into the oil-in-water dispersion comprising emulsion polymerised seeds throughout the monomer feed period.

37. An emulsion polymerization process according to claim 35 in which a portion of initiator feed is added to the polymerised growth polymerization mixture after all the premixed seed growth monomer mixture has been added under conditions such that radicals are formed from the initiator.

38. An emulsion polymerization process according to claim 36 in which the initiator feed comprises water-soluble monomer.

39. An emulsion polymerization process according to claim 38 in which the water-soluble monomer comprises a sulpho- or carboxy-betaine monomer.

40. An emulsion polymerization process according to claim 24 in which the latex product comprises a stable dispersion of polymer particles, having a polymer concentration in the range 20 to 60% by weight.

41. An emulsion polymerization process according to claim 24 in which the latex product comprises a dispersed phase having a particle diameter less then 1 .mu.m.

42. An emulsion polymerization according to claim 41 in which the particle diameter is in the range 100 to 400 .mu.m.
Description



The present invention relates to polymers formed from radical polymerization of ethylenically unsaturated monomers including an ammonium phosphate ester zwitterionic monomer, and processes for producing them. In particular, the invention relates to emulsion polymerization processes for forming high solids emulsions without the incorporation of non-polymerisable emulsifier, and to the use of these emulsions to biocompatibilise substrates.

Yamaguchi et al in Makromol. Chem. (1989), 190, 1195-1205, describe an oil-in-water emulsion polymerization of styrene in the presence of polymerisable and non-polymerisable phosphoryl choline compounds as emulsifier. The latex product is stable, the non-polymerisable emulsifiers giving more regular shaped and sized spherical particles than the polymerisable emulsifiers. The polymerizations were conducted to form latexes having around 10 wt % solids. The mole percent of polymerisable emulsifier based on total monomer is around 10%. The base monomer on which the polymerizations were based was styrene.

Sugiyama et al in Polym. J. (1993) 25(5), 521-527, describe an emulsifier free radical polymerization of ethylenically unsaturated monomers comprising methylmethacrylate, in the presence of an ethylenically unsaturated ammonium phosphate ester zwitterionic monomer, using a water-soluble initiator. The latex product had a concentration of around 10% by weight polymer. Increasing the amount of zwitterionic monomer resulted in reduced stability of the latex. Whilst low levels of zwitterionic monomer reduced the particle size of microspheres in the latex product as compared to a process containing no such monomer, increasing the level from a mole % of 0.01, based on total monomer, to 0.5 resulted in an increase in the diameter of the microsphere of the product. The microspheres themselves were found to have low levels of adsorption of albumin as compared to polymethylmethacrylate polymerised in the absence of the ammonium phosphate ester zwitterionic monomer.

Sugiyama et al, in J. Polym. Sci., Part A (1997) 35, 3349-3357, describe oil-in-water emulsion polymerization of methylmethacrylate, optionally with a comonomer of hydroxypropyl methacrylamide, in the presence of 2-methacryloyloxyethyl-2'-trimethylammoniumethyl phosphate inner salt (MPC). The MPC is present at a level of about 1% based on total ethylenically unsaturated monomer. The latex product had a polymer solids concentration of around 10% by weight. Again the presence of MPC resulted in a decrease in the stability of the latex product with more aggregates being formed. The process was dependent on the choice of initiator, between potassium peroxodisulphate, and 2,2'-azobis[2-(imidazolin-2-yl)propane]dihydrochloride (ABIP). The ABIP initiated products were more influenced by the presence of the MPC monomer in terms of particle size and level of aggregates. In both Sugiyama papers, the reaction mixture was agitated at high speed, with all monomers being included in the reaction vessel at the commencement of the polymerization. It is not clear how the methylmethacrylate dispersed phase is maintained in suspension during the process for example with no MPC monomer.

Zimehl et al, in Colloid Polym. Sci. (1990) 268, 924-933 describe emulsion polymerization of polystyrene using potassium peroxodisulphate in the presence of N-(3-sulphopropyl)-N-methacrylomidyl propyl (N,N-dimethylammonium betaine) (SPP) at SPP concentrations in the range 5 to 70% by weight based on total monomer. The particle size of the latex product was dependent upon the initiator and the level of betaine comonomer. Again, all of the monomers were dispersed into the aqueous continuous phase before polymerization was initiated. The solids concentration of product latex was around 10% by weight.

In U.S. Pat. No. 3,497,482 Hwa et al describe a copolymerization of N,N-dimethyl-N-(2-methacryloyloxyethyl)-N-(3-sulphopropyl ammonium inner salt) (SPE), with ethyl methacrylate and acrylamide, in an aqueous continuous phase. Hwa produces a metastable oil-in-water product. He does not describe the particle size of the latex.

In WO-A-93/01221 we describe a range of copolymers of zwitterionic monomer with comonomers such as hydrophobic comonomers, ionic comonomers or reactive comonomers. The copolymers are formed by co-dissolving all the monomers into a solvent in which monomers and polymer are soluble and recovered by precipitation techniques. It is suggested that the product might be a micro emulsion but no examples of emulsion polymerization are given. The polymers are used to coat substrates in order to improve their biocompatibility. Whilst improvements in biocompatibility may be achieved by using molar percentages of 1% or lower of zwitterionic monomer, based on total ethylenically unsaturated monomer, it is often found that at least 20 mol % zwitterionic monomer is needed for satisfactory levels of improved biocompatibility. The higher the level of zwitterionic monomers, the greater the expense.

Zwitterionic polymers made by the techniques such as are described in WO-A-93/01221, may be blended with physically or mechanically desirable copolymers to provide blends which have good biocompatibilising properties. The level of zwitterionic monomer in the total blend is reduced, thereby rendering the product more cost effective than single component zwitterionic polymer products. Such blends are described in, for instance, WO-A1-94/14897 and PCT/GB00103985 (unpublished at the priority date of this application). PCT/GB00/03985 describes blends of MPG copolymers with higher alkyl methacrylate comonomers, blended with alkyl(meth)acrylate polymers. Such blends, co-dissolved in a suitable organic solvent may be coated onto a surface to form a coating having micro-domains of relatively hydrophilic and relatively hydrophobic character. The blends may express higher levels of phosphorylcholine groups at the surface than in the bulk of the coating. This should allow the properties of a substrate coated with the polymer to be tailored for particular biocompatibility.

It would be desirable to produce a latex having high solids, in which a zwitterionic monomer is one of the ethylenically unsaturated monomers. It would furthermore be desirable to produce a copolymer of an ammonium phosphate ester zwitterionic monomer including low levels of that monomer. It would be desirable to carry out an emulsion polymerization to produce a stable latex product having a small particle size, and low particle size distribution and which forms coatings having desirable biocompatibilising properties without using high levels of ammonium phosphate ester zwitterionic monomer.

In a new emulsion polymerization process according to the invention, a mixture of ethylenically unsaturated monomers including water-insoluble monomers is polymerised in the dispersed phase of an oil-in-water emulsion in the presence of a water-soluble radical initiator, ethylenically unsaturated monomers including an ammonium phosphate ester zwitterionic monomer the process being characterised by being carried out at component concentrations to give a latex product having a polymer solids concentration of at least 20% by weight.

In the new process, the solids concentration of the product is usually no more than 60%, preferably in the range 25 to 50% by weight.

The process of the invention may be carried out in the presence of non-polymerisable emulsifiers and/or stabilisers. It is found that it is possible for the emulsion and latex product to be adequately stabilised by the presence of the ammonium phosphate ester zwitterionic monomer, optionally in combination with other surface active monomers. The process is preferably carried out therefore in the substantial absence of non-polymerisable surfactant/emulsifier and stabiliser.

The ammonium phosphate ester zwitterionic monomer is preferably included in an amount in the range 0.01 to 5% by weight, based on the total weight of monomers. More preferably the level of the zwitterionic monomer is in the range 0.05 to 2% by weight, for instance 0.1 to 1% by weight.

The zwitterionic monomer preferably has the general formula I

in which X is the ammonium phosphate ester zwitterionic group; B is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and Y is an ethylenically unsaturated group selected from H.sub.2 C.dbd.CR--CO--A--, H.sub.2 C.dbd.CR--C.sub.6 H.sub.4 --A.sup.1 --, H.sub.2 C.dbd.CR--CH.sub.2 A.sup.2 --, R.sup.2 O--CO--CR.dbd.CR--CO--O--, RCH.dbd.CH--CO--O--, RCH.dbd.C(COOR.sup.2)CH.sub.2 --CO--O--, ##STR1## A is --O-- or NR.sup.1 ; A.sup.1 is selected from a bond, (CH.sub.2).sub.n A.sup.2 and (CH.sub.2).sub.n SO.sub.3 -- in which n is 1 to 12; A.sup.2 is selected from a bond, --O--, O--CO--, --CO--O, --CO--NR.sup.1 --, --NR.sup.1 --CO, --O--CO--NR.sup.1 --, and --NR.sup.1 --CO--O--;

R is hydrogen or C.sub.1-4 alkyl;

R.sup.1 is hydrogen, C.sub.1-4 alkyl or BX; and

R.sup.2 is hydrogen or C.sub.1-4 alkyl.

Generally in the zwitterionic group X, the anion is closer to B than the cation. However in some zwitterions, the cation is closer to the group B than is the anion (called hereinafter phosphobetaines).

Preferably X is a group of the general formula II ##STR2##

in which R.sup.3 is alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, and optionally contains one or more fluorine substituents and/or one or more functional groups; and either the groups R.sup.4 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenyl, or two of the groups R.sup.4 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R.sup.4 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R.sup.4 is substituted by a hydrophilic functional group.

Alternatively X may be a group of the general formula III ##STR3##

in which the group R.sup.5 are the same or different and each is hydrogen, C.sub.1-4 alkyl, such as methyl, or aryl, such as phenyl; R.sup.6 alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, optionally contains one or more fluorine substituents and/or one or more functional groups; R.sup.7 is hydrogen, or an optionally substituted C.sub.1-18 alkyl, C.sub.2-18 alkenyl, C.sub.2-18 alkynyl, C.sub.6-24 aryl or C.sub.7-24 aralkyl group.

In a group of the general formula III, R.sup.7 is preferably other than hydrogen and is more preferably an unsubstituted C.sub.1-6 alkyl, C.sub.6-12 aryl or C.sub.7-12 aralkyl group. Any substituents in a substituted group R.sup.7 are usually fluorine atoms, or hydroxyl or C.sub.1-4 alkoxy groups.

In the new emulsion polymerization process the monomers preferably include at least 50% by weight of ethylenically unsaturated polymerisable monomers. Examples of suitable monomers are compounds selected from the group consisting of C.sub.1-12 -alkyl(alk)acrylates, C.sub.2-12 -alkyl- and -dialkyl-(alk)acrylamides, water insoluble vinyl esters or ethers, allylic compounds, maleic or fumaric esters or imides, aconitic compounds, styrenic compounds, e.g. styrene, and mixtures thereof.

As is known in emulsion polymerization techniques, the choice of monomers affects the physical properties of the mixture, in particular whether the polymer particles of the product are able to coalesce after removal of water, for instance to form stable film coatings. It is preferred that the hydrophobic compounds are selected for their ability to form films at suitable temperatures for coating processes.

It is found that particularly desirable characteristics are achieved by using a blend of hydrophobic compounds, which would tend to confer different properties of hardness on the resultant polymer. Monomers which tend to produce hard polymers are lower alkyl(meth)acrylate especially methylmethacrylate. Compounds which tend to produce softer copolymers are alkylacrylates and methacrylates having straight or branched alkyl groups with at least 4 carbon atoms, such as butyl, hexyl, 2-ethylhexyl or n-octyl groups. Preferably the hydrophobic compound comprises a mixture of methylmethacrylate with a C.sub.4-8 alkyl acrylate.

The emulsion polymerization itself and the properties of the product, especially the biocompatibility of films produced from the emulsion, are beneficially affected by incorporating a zwitterionic comonomer. The zwitterionic comonomer preferably comprises as cation a quaternary ammonium or phosphonium group but may comprise a tertiary sulphonium group. The anion may be a sulphonate, sulphate, phosphonate, or carboxylate anion, most preferably a sulphonate or carboxylate anion. Most preferably the comonomer is a sulpho- or carboxy-betaine monomer. The zwitterionic comonomer is suitably a compound of the general formula IV

in which Y.sup.1 is an ethylenically unsaturated group selected from H.sub.2 C.dbd.CR.sup.8 --CO--A.sup.6 --, H.sub.2 C.dbd.CR.sup.8 --C.sub.6 H.sub.4 --A.sup.3 --, H.sub.2 C.dbd.CR.sup.8 --CH.sub.2 A.sup.4 --, R.sup.9 O--CO--CR.sup.8.dbd.CR.sup.8 --CO--O--, R.sup.8 CH.dbd.CH--CO--O--, R.sup.8 CH.dbd.C(COOR.sup.9)CH.sub.2 --CO--O, ##STR4## A.sup.6 is --O-- or NR.sup.10 ; A.sup.3 is selected from a bond, (CH.sub.2).sub.m A.sup.4 and (CH.sub.2).sub.m SO.sub.3 -- in which m is 1 to 12; A.sup.4 is selected from a bond, --O--, O--CO--, CO--O, --CO--NR.sup.10 --, --NR.sup.10 --CO, --O--CO--NR.sup.10 --, and NR.sup.10 --CO--O--; R.sup.8 is hydrogen or C.sub.1-4 alkyl; R.sup.10 is hydrogen, C.sub.1-4 -alkyl or B.sup.1 X.sup.1 ;

R.sup.9 is hydrogen or C.sub.1-4 alkyl; B.sup.1 is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and X.sup.1 is a zwitterionic group other than an ammonium phosphate ester.

The zwitterionic group X.sup.1 may have, as anion a carboxylate group, a sulphate group, a sulphonate group or a phosphonate group, preferably carboxylate or, more preferably a sulphonate group. The zwitterionic group X.sup.1 may have as cationic group an ammonium, phosphonium or sulphonium group, preferably an ammonium group.

A preferred zwitterionic group X.sup.1 has the general formula V ##STR5##

where the groups R.sup.11 are the same or different and each is hydrogen or C.sub.1-4 alkyl and s is from 2 to 4. Preferably the groups R.sup.11 are the same. It is also preferable that at least one of the groups R.sup.11 is methyl, and more preferable that the groups R.sup.11 are both methyl. Preferably s is 2 or 3, more preferably 3.

Alternatively the zwitterionic group may be an amino acid moiety in which the alpha carbon atom (to which an amine group and the carboxylic acid group are attached) is joined through a linker group to the backbone of the biocompatible polymer. Such groups may be represented by the general formula VI ##STR6##

in which A.sup.5 is a valence bond, --O--, --S--or --NH--, preferably --O--, R.sup.12 is a valence bond (optionally together with A.sup.5) or alkanediyl, --C(O)alkylene-, NHCOalkylene or --C(O)NHalkylene, preferably alkanediyl and preferably containing from 1 to 6 carbon atoms; and the groups R.sup.13 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or two or three of the groups R.sup.13, together with the nitrogen to which they are attached, form a heterocyclic ring of from 5 to 7 atoms, or the three group R.sup.13 together with the nitrogen atom to which they are attached form a fused ring heterocyclic structure containing from 5 to 7 atoms in each ring.

Alternatively the zwitterion may be a carboxy betaine --N.sup..sym. (R.sup.14).sub.2 (CH.sub.2).sub.r COO.sup..crclbar. in which the R.sup.14 groups are the same or different and each is hydrogen or C.sub.14 alkyl and r is 2 to 6, preferably 2 or 3.

In another embodiment, the zwitterionic group X.sup.1 has the general formula VII ##STR7## W is S, PR.sup.16 or NR.sup.16 ; the or each groups R.sup.16 is hydrogen or alkyl of 1 to 4 carbon atoms or the two groups R.sup.16 together with the heteroatom to which they are attached form a heterocyclic ring of 5 to 7 atoms; R.sup.17 is alkanediyl of 1 to 20, preferably 1 to 10, more preferably 1 to 6 carbon atoms; A.sup.7 is a bond, NH, S or O, preferably O; and

R.sup.18 is a C.sub.1-12 alkyl, C.sub.7-18 aralkyl or C.sub.6-18 aryl group or, where A.sup.7 is other than a bond, is a C.sub.1-12 -alkoxy, C.sub.6-18 -aryloxy or C.sub.7-18 -aralkoxy group.

In compounds comprising a group of the general formula VII, it is preferred that W is NR.sup.16 ; each R.sup.16 is C.sub.1-4 alkyl; and R.sup.17 is C.sub.2-6 alkanediyl.

In all embodiments, in the zwitterionic comonomer of the general formula IV Y.sup.1 is preferably H.sub.2 C.dbd.CR.sup.8 --CO--A.sup.3 --. Such acrylic moieties are preferably methacrylic, that is in which R.sup.8 is methyl, or acrylic, in which R.sup.8 is hydrogen. Whilst the compounds may be acrylamido compounds (in which A is NR.sup.10), in which case R.sup.10 is preferably hydrogen, or less preferably, methyl, most preferably the compounds are esters, that is in which A.sup.3 is O. Suitable examples of comonomer of the general formula IV are SPP and SPE.

In monomers of the general formula IV, especially where Y is the preferred acrylic group, B.sup.1 is most preferably an alkanediyl group. Whilst some of the hydrogen atoms of such group may be substituted by fluorine atoms, preferably B.sup.1 is an unsubstituted alkanediyl group, most preferably a straight chain group having 2 to 6 carbon atoms.

Where a zwitterionic comonomer is included, the ratio of that comonomer to ammonium phosphate ester zwitterionic monomer is preferably in the range (1 to 50):1, more preferably in the range (5 to 20):1.

The ethylenically unsaturated monomers may further comprise hydrophilic monomer, for instance relatively water-soluble monomers.

Hydrophilic monomers are preferably selected from the group consisting of C.sub.1-4 -hydroxyalkyl(meth)acrylates, C.sub.1-4 -hydroxyalkyl(meth)acrylamides, C.sub.1-3 -alkoxy-C.sub.2-4 -alkyl(meth)acrylates, C.sub.1-3 -alkoxy-C.sub.2-4 -alkyl(meth)acrylamides, C.sub.1-3 -alkoxy-oligoethoxy(meth)acrylates, C.sub.1-4 -dihydroxyalkyl(meth)acrylates, N-mono- or N,N- di- C.sub.1-2 alkyl (meth)acrylamides, N-vinylactams, and C.sub.2-4 -hydroxyalkyl-oligoethoxy(meth)acrylates and mixtures thereof.

It has been found to be particularly useful to include, as a hydrophilic monomer, a monomer comprising an oligoethoxy moiety, that is selected from C.sub.1-3 -alkoxy-oligoethoxy(meth)acrylates and C.sub.2-4 -hydroxyalkyl-oligoethoxy(meth)acrylates, more preferably the alkoxy terminated compounds. Preferably an alkoxy group is methoxy or ethoxy. Such compounds preferably have 5 to 50 ethoxy groups, for instance in the range 10 to 20 methoxy groups. Oligoethoxylated polymerisable compounds improve the stability of the emulsion during the process, as well as the latex product, and may confer desirable wetting characteristics on a product polymer as well as useful biocompatibility.

A hydrophilic monomer is preferably included in an amount in the range 0.1 to 50% by weight of total monomers, more preferably an amount in the range 1 to 25% by weight, for instance an amount in the range 5 to 20% by weight. An oligo ethoxylated comonomer is preferably included in an amount in the range 1 to 20% by weight, more preferably in the range 5 to 10% by weight. It is often used in conjunction with one or more other hydrophilic monomers, such that the total amount of hydrophilic monomer is in the range 5 to 50% by weight.

The stability of the emulsion during polymerization is found to be improved if the pH of the emulsion is maintained slightly acidic, that is has a pH less than 7, more preferably in the range 4 to 6.8, for instance about 5. Whilst the acidity may be achieved by adding a non-polymerisable acid for instance a mineral acid, to the emulsion, it is preferable to include a polymerisable acid as one of the ethylenically unsaturated monomers. Preferably an ethylenically unsaturated acid is selected from fumaric acid, maleic acid, vinyl sulphonic acid and styrene sulphonic acid, more preferably selected from acrylic and methacrylic acids, and is most preferably methacrylic acid.

Where acidic monomer is included, it is present in an amount in the range 0.1 to 5% by weight, more preferably in the range 0.2 to 2% by weight, based on the total weight of monomers.

Other compounds, especially other monomers may be included in the polymerization mixture, for instance to achieve desired product characteristics.

It may also be desirable to include non-polymerisable components in the polymerization mixture, for instance in the continuous aqueous phase or in the dispersed oil phase, or at the interface. Non-polymerisable emulsifiers and suspending agents may be included, but are preferably not included. Drugs, especially water-insoluble, oil-soluble drugs may be added whereby they may become absorbed in the latex particles of the product.

It may be desirable to include cationic monomer, in order to provide a product polymer having an overall cationic charge.

As described in our application number WO-A-93/01221 and WO-A-98/22516, the presence of cationic groups in a polymer may confer desirable binding properties either to underlying counterionically charged surfaces, or to anionic compounds which may be contacted with a surface coated with the polymer to achieve desirable results.

A cationic monomer is preferably a compound of the general formula VIII

in which Y.sup.2 is an ethylenically unsaturated group selected from H.sub.2 C.dbd.CR.sup.19 --CO--A.sup.8 --, H.sub.2 C.dbd.CR.sup.19 --C.sub.6 H.sub.4 --A.sup.9 --, H.sub.2 C.dbd.CR.sup.19 --CH.sub.2 A.sup.10, R.sup.21 O--CO--CR.sup.19.dbd.CR.sup.19 --CO--O--, R.sup.19 CH.dbd.CH--CO--O--, R.sup.19 CH.dbd.C(COOR.sup.21)CH.sub.2 --CO--O--, ##STR8## A.sup.8 is --O-- or --NR.sup.20 --; A.sup.9 is selected from a bond, (CH.sub.2).sub.q A.sup.10 and (CH.sub.2).sub.q SO.sub.3 -- in which q is 1 to 12; A.sup.10 is selected from a bond, --O--, O--CO--, --CO--O, --CO--NR.sup.20 --, --NR.sup.20 --CO, O--CO--NR.sup.20 --, and NR.sup.20 --CO--O--; R.sup.19 is hydrogen or C.sub.1-4 alkyl; R.sup.20 is hydrogen, C.sub.1-4 alkyl or BX. R.sup.21 is hydrogen or C.sub.1-4 alkyl; B.sup.2 is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and Q is --N.sup..sym. R.sup.22.sub.3, --P.sup..sym. R.sup.23.sub.3 or --S.sup..sym. R.sub.23.sub.2 in which either the groups R.sup.22 are the same or different and each is hydrogen, alkyl of 1 to 6 carbon atoms, preferably methyl, C.sub.1-6 hydroxyalkyl, aryl, such as phenyl, or C.sub.7-12 aralkyl, or two of the groups R.sup.22 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R.sup.22 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R.sup.3 is substituted by a hydrophilic functional group, and the groups R.sup.23 are the same or different and each is R.sup.22 or a group OR.sup.22, where R.sup.22 is as defined above mutatis mutandis.

In the cationic monomer of the general formula VIII Q is preferably --N.sup..sym. R.sup.22.sub.3, in which each R.sup.22 is a C.sub.1-4 alkyl group, preferably each R.sup.22 being methyl. The group Y.sup.2 is preferably an acrylic group, that is of the formula H.sub.2 C.dbd.CR.sup.19 COA.sup.8. In such groups R.sup.19 is either hydrogen or methyl, preferably methyl, and A.sup.8 is preferably --O--. B.sup.2 is preferably a C.sub.2-618 alkanediyl group, more preferably a C.sub.2-6 alkanediyl. Examples of suitable cationic monomers are 2-(N,N-dimethylamino)ethyl methacrylate methyl chloride or methyl sulphate salt, and 2-(N,N-dimethyl amino) ethyl acrylate methyl chloride or methyl sulphate salt.

A cationic monomer may be included in an amount in the range 0.1 to 25% by weight, more preferably an amount in the range 1 to 20% by weight, most preferably in an amount in the range 2 to 15% by weight.

Other monomers which may useful be included in the mixture include functional monomers, comprising reactive groups which are useful to provide attachment points for ligands or for underlying substrate surfaces having co-reactive functional groups, or to provide inter- or intra-molecular crosslinkability. Such functional groups may react with co-reactive groups derived from other functional monomers such as hydroxyl or amine group containing monomers.

Preferably a reactive monomer has the general formula IX

in which Y.sup.3 is an ethylenically unsaturated group selected from H.sub.2 C.dbd.CR.sup.24 --CO--A.sup.11 --, H.sub.2 C.dbd.CR.sup.24 --C.sub.6 H.sub.4 --A.sup.12, H.sub.2 C.dbd.CR.sup.19 --CH.sub.2 A.sup.13, R.sup.26 O--CO--CR.sup.24.dbd.CR--CO--O--, R.sup.24 CH.dbd.CH--CO--O--, R.sup.24 CH.dbd.C(COOR.sup.26)CH.sub.2 --CO--O--, ##STR9## A.sup.11 is --O-- or --NR.sup.25 ; A.sup.12 is selected from a bond, (CH.sub.2).sub.r A.sup.13 and (CH.sub.2).sub.r SO.sub.3 -- in which r is 1 to 12; A.sup.13 is selected from a bond, --O--, O--CO--, CO--O, --CO--NR.sup.25 --, --NR.sup.25 --CO, --O--CO--NR.sup.25, and NR.sup.25 --CO--O--; R.sup.24 is hydrogen or C.sub.1-4 alkyl; R.sup.25 is hydrogen, C.sub.1-4 -alkyl or B.sup.3 Q.sup.1 ; R.sup.26 is hydrogen or C.sub.1-4 alkyl; B.sup.3 is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents.

Q.sup.1 is a reactive group selected from the group consisting of aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C.sub.1-4 -alkoxy groups; hydroxyl; amino; carboxyl; epoxy; --CHOHCH.sub.2 Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; cinnamyl; ethylenically and acetylenically unsaturated groups; acetoacetoxy; methylol; and chloroalkylsulphone groups; acetoxy; mesylate; carbonyl di(cycloalkyl carbodiimidoyl; and oximino.

Preferred groups Q.sup.1 are aldehyde, reactive silane and siloxane, amino, epoxy, CHOHCH.sub.2 Hal (in which Hal is halogen), succimimido, tosylate, triflate, imidazolecarbonyl amino and optionally substituted triazine groups. Most preferably Q.sup.1 is a trialkoxy silyl group, such as a trimethoxysilyl group.

In the reactive monomer of the general formula IX the ethylenically unsaturated group Y.sup.3 is preferably and acrylic type group, that is a group H.sub.2 C.dbd.CR.sup.24 A.sup.11 --, R.sup.24 preferably being hydrogen or, most preferably, methyl and A.sup.11 preferably being --O--. Preferred groups B.sup.3 are C.sub.2-18 alkanediyl, most preferably C.sub.2-6 -alkanediyl.

The emulsion polymerization of the invention may be carried out in a single step, in which all of the monomers are dispersed into an aqueous continuous phase and agitation applied to form an emulsion having suitable sized droplets followed by initiation of polymerization. However, optimum particle size distribution is achieved if a two-step process is used, in a first step of which a seed polymer is formed, and in the second step the seeds are grown. In such a process, the seed monomers are dispersed into the aqueous phase and polymerization is initiated. To the seed polymer latex, the remaining monomers and additional initiator are added, so that polymerization is initiated at the seeds. Monomer travels from monomer droplets to the polymer seeds.

Preferably in a process involving a seed polymerization step, the monomers from which the seed polymer is formed comprise at least a portion of the ammonium phosphate ester zwitterionic monomer which is preferably added to the polymerization mixture in the form of an aqueous solution. The seed monomers must include at least a portion of the water-insoluble monomers. These monomers are dispersed into the aqueous continuous phase in the presence of the ammonium phosphate ester zwitterionic monomer whereby an emulsion of seed monomer is formed. Polymerization is initiated by radical initiator by a water-soluble initiator.

After seed polymerization has continued until the yield of polymer is at least 1% based on solids, seed growth emulsion polymerization step is then carried out by adding further monomer including at least a portion of the remaining water-insoluble monomer to the emulsion, along with further water-soluble initiator. It may be desirable for the polymer formed after the initial seed polymerization step to have a substantially constant composition. In this case, it is desirable for a water-immiscible liquid containing the water-insoluble monomers and other compatible comonomers and for this mixture to be added in a single addition step or continuously over an extended period to the aqueous reaction mixture. If any of the monomers selected components for the ethylenically unsaturated monomers are immiscible with the water-insoluble monomer blend, it may be desirable for the or all of the monomers of that type to be added separately to the polymerization mixture, for instance in the form of an aqueous solution.

It is preferred that the monomer blend be added over a period during which polymerization continues to the reaction mixture, and that polymerization be continued after all of the monomer has been added. During the monomer feed period, it is preferred for initiator to be continuously added to the reaction mixture. Preferably a portion of initiator is retained until after all of the monomer has been added to the mixture and is then included to minimise the level of residual unpolymerised monomer in the product.

It may be desirable for the polymerization to form a core-shell morphology. Such morphologies are generally achieved by carrying out the polymerization, generally after a seed polymerization step, in two or more phases. Generally the polymer formed in the two or more phases differs in terms of the monomers used and/or their ratios. Using such techniques it is possible to form a product latex in which the polymer particles have tailored characteristics with cores and shells of desired hardness, desired hydrophilicity or desired porosity. Such characteristics are achieved by selecting monomers according to their glass transition temperatures, hydrophilicities, or crosslinkability. To achieve a low porosity product, for instance, it may be desirable to incorporate di-, tri- or higher-functional ethylenically unsaturated monomers, or to include functional monomers which may be reacted with the same or different functional monomers during or after polymerization to provide intermolecular crosslinks.

Core/shell morphology may be achieved by changing the composition of monomers added to the polymerization mixture during the polymerization process. Thus monomers for forming the core should be added and polymerised in the mixture before addition of monomers for forming the shell.

In one particular embodiment of the process of the invention, a zwitterionic comonomer is included as part of the ethylenically unsaturated monomer and is added to the polymerization mixture as a component of the aqueous initiator composition, and is preferably added continuously over a monomer feed period during which water-insoluble monomer blend is separately added to the polymerization mixture. Preferably a monomer feed period is conducted for a period in the range 5 to 1200 minutes, most preferably in the range 30 to 240 minutes.

By the use of the ammonium phosphate ester zwitterionic monomer it has been found possible to conduct the emulsion polymerization under conditions such that high solid content latex products are formed. Thus the level of polymer in the latex product may be higher than 20% by weight, for instance up to 6%, preferably in the range 20 to 60% by weight, without adversely affecting the stability nor viscosity. Such latexes are convenient to handle. Whilst water may be evaporated from the product latex to achieve such high solids materials, or the polymer particles may be recovered by agglomeration or coagulation techniques and redissolved into water, preferably no such steps are carried out to achieve the 20 to 50% by weight solids latex. Alternatively the latex may be diluted before use or compounded with other ingredients compatible with its end use, such as water, other latices or coalescing aids. Coalescing aids may assist in the film formation of the final product, especially where the polymer is film forming at a higher temperature than room temperature. One suitable component is a latex preservative, for instance which inhibits bacterial growth or is a biocide or fungicide, suitably an alcohol such as benzyl alcohol.

It is believed that this is the first time that ammonium phosphate ester zwitterionic monomers have been used in emulsion polymerization processes including a seed polymer formation phase. According to a further aspect of the invention there is provided a seeded emulsion polymerization process in which a mixture of ethylenically unsaturated monomers including water-insoluble monomers and an ammonium phosphate ester zwitterionic monomer is copolymerised in the dispersed phase of an oil-in-water emulsion in the presence of a water-soluble radical initiator comprising the steps i) providing an aqueous solution comprising at least a portion of the ammonium phosphate ester zwitterionic monomer and a portion of the initiator; ii) forming a dispersed phase comprising a monomer seed composition comprising at least a portion of the water-insoluble monomers to form a seed emulsion; iii) initiating polymerization of the seed emulsion whereby a seed latex is formed; iv) providing a seed growth monomer mixture comprising the remaining water-insoluble monomers; and v) adding the monomer cell mixture to the seed polymer latex and initiating polymerization of the monomers of the seed growth mixture in the dispersed seeds, to form a product polymer latex.

In the seeded emulsion polymerization process it is preferred that all of the ammonium phosphate ester zwitterionic monomer is present in the seed polymerization mixture.

Whilst the novel seeded polymerization process may be carried out to provide a relatively low solid product polymer latex of less than 20%, for instance in the range 2 to 20%, it is possible to carry out the process under conditions such that the product latex has a solid concentration in the range 20 to 60% by weight.

The seeded polymerization process allows formation of a product polymer latex having very low distribution of product particle size. The particle size may be controlled by the levels of seed monomer, initiator and seed growth monomer, as well as the choice of the type and amount of ammonium phosphate ester zwitterionic monomer, as well as other monomer components. Preferably the product latex has dispersed phase with average particle diameter of less than 1 .mu.m, more preferably less than 500 nm, most preferably in the range 100 to 400 nm. Preferably the polydispersity of particle size (number average over weight average diameter) is in the range 1.0 to 2.0.

It is preferred that the level of initiator for these low particle size distributions is in the range 0.001 to 0.5 weight % based on solids, preferably in the range 0.01 to 0.1 weight % . Preferably the ratio of weight of combined seed monomer to seed growth polymer is in the range 1:99 to 99:1, preferably in the range 1:50 to 1:10.

The seeded emulsion polymerization technique may be used to form a core-shell polymer product, using the techniques described above in connection with the first aspect of the invention. In such a process the seed growth monomers comprise two or more mixtures including a core mixture and a shell mixture, usually differing in terms of composition.

The seeded emulsion polymerization process has preferred components as described above in connection with the first aspect of the invention.

The polymer latex product of the first aspect of the invention forms a further aspect of the invention. A novel stable latex comprises a dispersion of polymer particles in aqueous continuous phase, having a polymer concentration in the range 20 to 60% by weight based on the total weight of the latex, an average particle diameter of less than 1 .mu.m, the polymer being formed from radical polymerised ethylenically unsaturated monomers comprising water-insoluble monomer and ammonium phosphate ester zwitterionic monomer.

The novel latex may further comprise additional components. For instance it may be desirable to add to the latex suspended particulate solids selected from organic and inorganic water-insoluble materials. Particularly preferred are suspended inorganic solids such as pigments, preferably having particle sizes less than 1 .mu.m. The latex may additionally comprise dissolved or miscible components for instance to improve the storage stability of the latex, or to provide additional properties for the product of the final dried film. For instance, drugs may be incorporated into the latex, either by adding a suspension or an aqueous or organic solvent-based solution to the latex. Colouring agents may also be included.

The novel latex, or the product of one of the novel polymerization processes, may be used as a coating composition.

According to a further aspect of the invention there is provided a novel coating process in which such a dispersion is coated onto a substrate to form a liquid coating on a surface thereof, and water is removed from the liquid coating to form a stable solid polymer coating on the said surface. Generally water is removed by evaporation although contact with precipitating solvents may also be utilised. Evaporation may be conducted at raised temperature and/or reduced pressure, and coalescing acids, such as alcohols, esters, glycols or other ethers, may be used to provide added control over film formation.

Preferably water removal is conducted under conditions of raised temperature under which the polymer particles coalesce to form a coherent and substantially void-free, preferably clear film.

The dried film may be subjected to additional steps such as curing, for instance by heating, especially where the monomers include a cross-linking monomer such as monomers of the general formula IX above. Gamma or other e.m. radiation or ethyleneoxide treatment may also be carried out to cure and/or sterilise the film.

The product films have particularly desirable biocompatibilising properties. They are generally used in environments in which the coated surface is contacted with aqueous liquids, generally biological liquids, for instance containing dissolved protein or suspended cells, such as bacterial or, preferably, blood cells. Preferably such liquids are selected from blood and serum.

According to a further aspect of the invention there is provided a novel biocompatibilising process in which a subs


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