Monodisperse submicron polymer particles

Abstract

This invention relates to monodisperse cross-linked polymer particles, comprising particles with a substantially smooth outer surface and an average diameter of less than 1 μm, wherein the particles are solid or porous, and wherein the coefficient of variation (CV) % of the particles, when measured by CPS disk centrifugation analysis, is less than 15%. These monodisperse cross-linked polymer particles may comprise magnetic material and are useful in various application. This invention also relates to monodisperse polymer particles for use as seed particles in the Ugelstad process.

1 . Monodisperse cross-linked polymer particles having the following characteristics:
 a substantially smooth outer surface;   a z-average diameter of less than 1 μm;   the particles are porous; and   a coefficient of variation (CV) %, when measured by CPS disk centrifugation analysis, of less than 15%.   
     
     
         2 . The polymer particles of  claim 1 , wherein the polymer particles have a z-average diameter of no more than 700 nm. 
     
     
         3 . The polymer particles of  claim 1 , wherein the polymer particles have a z-average diameter of at least 300 nm. 
     
     
         4 . The polymer particles of  claim 1 , wherein the coefficient of variation (CV) % of the particles, when measured by CPS disc centrifugation analysis, is less than 10. 
     
     
         5 . The polymer particles of  claim 1 , wherein the polymer particles constitute a first population of particles and have a swellability of not more than the swellability of a second population of polymer particles, wherein the second population of particles are reference particles produced by a known Ugelstad process and made of a comparable polymer to the first population, wherein the amount of cross-linker monomer used in the suspension polymerisation stage of the known Ugelstand process is >25% by weight of the total weight of monomers used in the suspension polymerisation stage. 
     
     
         6 . The polymer particles of  claim 5 , wherein the amount of the cross-linker monomer used in said suspension polymerisation stage is 30-60%. 
     
     
         7 . The polymer particles of  claim 1 , wherein the particles have a specific surface area of from 300 to 700 m 2 /g when measured by gas adsorption analysis. 
     
     
         8 . The polymer particles of  claim 7  wherein the measured specific surface area is from 400 to 600 m 2 /g. 
     
     
         9 . The polymer particles of  claim 1 , further comprising a magnetic material substantially located in pores of the polymeric material. 
     
     
         10 . The polymer particles of  claim 1 , further comprising a superparamagnetic material substantially located in pores of the polymeric material. 
     
     
         11 . The polymer particles of  claim 10 , wherein the superparamagnetic material comprises ferrite or coated iron based or iron-nickel alloy nanoparticles. 
     
     
         12 . The polymer particles of  claim 1 , wherein the outer surface further comprises a coating and/or a functional group, wherein the functional group is selected from carboxylic acid, amine, tosyl, epoxy and hydroxyl. 
     
     
         13 . The polymer particles of  claim 1 , wherein the polymer comprises a cross-linked polymer selected from polymers and copolymers of one or more of the following monomeric materials: methacrylate or another acrylic monomer and/or a styrenic monomer. 
     
     
         14 . The polymer particles of  claim 2  which comprise:
 a matrix polymer which is selected from polymers of styrenic monomers and polymers of acrylic monomers;   magnetic crystals; and   a polymer coating.   
     
     
         15 . Monodisperse cross-linked polymer particles being a first population of polymer particles and having the following characteristics
 a substantially smooth outer surface;   a z-average diameter of less than 1 μm;   a coefficient of variation (CV) %, when measured by CPS disk centrifugation analysis, of less than 15%; and   the swellability of a second population of polymer particles, wherein the second population of particles are reference particles produced by a known Ugelstad process and made of a comparable polymer to the first population, wherein the amount of cross-linker monomer used in the suspension polymerisation stage of the known Ugelstand process is >25% by weight of the total weight of monomers used in the suspension polymerisation stage.   
     
     
         16 . The polymer particles of  claim 15 , wherein the polymer particles have a z-average diameter of no more than 700 nm. 
     
     
         17 . The polymer particles of  claim 15 , wherein the polymer particles have a z-average diameter of at least 200 nm. 
     
     
         18 . The polymer particles of  claim 15 , wherein the coefficient of variation (CV) % of the particles, when measured by CPS disc centrifugation analysis, is less than 10%. 
     
     
         19 . The polymer particles of  claim 15 , wherein the amount of the cross-linker monomer used in said suspension polymerisation stage is 25-70% wt cross-linker. 
     
     
         20 . The polymer particles of  claim 15 , wherein the particles are non-porous and have a specific surface area of from 5 to 30 m 2 /g when measured by gas adsorption analysis. 
     
     
         21 . The polymer particles of  claim 15 , wherein the outer surface further comprises a coating and/or a functional group selected from carboxylic acid, amine, tosyl, epoxy and hydroxyl. 
     
     
         22 . The polymer particles of  claim 15 , wherein the polymer comprises a cross-linked polymer selected from polymers and copolymers of one or more of the following monomeric materials: methacrylate or another acrylic monomer and/or a styrenic monomer. 
     
     
         23 . Monodisperse cross-linked polymer particles, having the following characteristics:
 a z-average diameter of less than 1 μm,   a coefficient of variation (CV) %, when measured by CPS disk centrifugation analysis, of less than 15%   a specific surface area of from 300 to 700 m 2 /g when measured by gas adsorption analysis.   
     
     
         24 . Monodisperse particles of  claim 1  which have a silica coating. 
     
     
         25 . Monodisperse polymer particles for use as seed particles in the Ugelstad process, wherein the particles have a z-average diameter of from 50 nm to 200 nm and the polymer has a mean weight average molecular weight of more than 1,000 and less than 70,000, when measured by gel permeation chromatography. 
     
     
         26 . The polymer particles of  claim 25 , wherein the mean weight average molecular weight is less than 40,000. 
     
     
         27 . The polymer particles of  claim 25 , wherein the mean weight average molecular weight is more than 6,000. 
     
     
         28 . The polymer particles of  claim 25 , wherein the CV of the particles, when measured by CPS disc centrifugation analysis, is less than 10%. 
     
     
         29 . The polymer particles of  claim 25 , wherein the polymer comprises a polymer selected from polymers and copolymers of one or more of the following monomeric materials: acrylic monomers and styrenic monomers. 
     
     
         30 . A process for the preparation of monodisperse particles for use as Ugelstad seed particles, the process comprising an emulsion polymerisation process comprising:
 forming an aqueous dispersion comprising a vinylic monomer and a water soluble polymerisation initiator; and   agitating until the commencement of particle nucleation;   
       characterised in that:
 the aqueous dispersion comprises a surfactant and a chain transfer agent is added after the commencement of particle nucleation, such that the polymerisation forms monodisperse seed particles having a z-average diameter of from 50 nm to 200 nm and, when measured by gel permeation chromatography, the polymer has a mean weight average molecular weight of more than 1,000 and less than 70,000. 
 
     
     
         31 . The process of  claim 30 , wherein the surfactant is present below its critical micelle concentration. 
     
     
         32 . The process of  claim 30 , wherein the surfactant is present in a concentration of not more than 2.5 g/L. 
     
     
         33 . The process of  claim 30 , wherein the surfactant is present in a concentration of at least 0.5 g/L. 
     
     
         34 . The process of  claim 30 , wherein the surfactant is sodium dodecyl sulfate. 
     
     
         35 . The process of  claim 30 , wherein the surfactant is provided at a purity of at least 95%. 
     
     
         36 . The process of  claim 30 , wherein the vinylic monomer is methacrylate or another acrylic monomer, or a styrene monomer. 
     
     
         37 . The process of  claim 30 , wherein the chain transfer agent comprises a haloalkane. 
     
     
         38 . The process of  claim 30 , wherein the chain transfer agent comprises an alkylmercaptan. 
     
     
         39 . The process of  claim 30 , wherein the addition of chain transfer agent starts about 5 to 15 minutes after the commencement of visible particle nucleation, optionally about 10 minutes after the commencement of visible particle nucleation. 
     
     
         40 . The process of  claim 30 , wherein the chain transfer agent is added at a single timepoint. 
     
     
         41 . The process of  claim 30 , wherein the chain transfer agent is added at a constant rate for a period of from 20 minutes to 4 hours. 
     
     
         42 . The process of  claim 30 , wherein the initiator is a persulfate. 
     
     
         43 . The process of  claim 30 , wherein the aqueous dispersion further comprises a buffer, optionally wherein the buffer is borax. 
     
     
         44 . The process of  claim 30 , further comprising subjecting the monodisperse seed particles to an Ugelstad process wherein the percentage by weight of cross-linker monomer included in the total monomer used in the suspension polymerisation stage of the Ugelstad process (the final polymerisation stage where there are plural polymerisation stages) is >25% wt cross-linker, to form submicron monodisperse particles and a z-average diameter of less than 1 μm. 
     
     
         45 . The process of  claim 44 , wherein the Ugelstad process comprises:
 (i) forming an aqueous dispersion comprising
 the monodisperse seed particles, 
 finely divided droplets comprising an organic compound of molecular weight below 5,000 and water solubility at 25° C. of less than 10 −2  g/L, and 
 an organic solvent in which the organic compound is soluble, the organic solvent being optional when the polymer forming the seed particles has an average molecular weight which corresponds to up to 50 monomer units; 
   (ii) allowing the organic compound to diffuse into the monodisperse seed particles, causing the seed particles to become activated;   (iii) removing the organic solvent, where present from inside the seed particles, and contacting the activated seed particle with an aqueous vehicle containing a monomer that is at least 10 times more soluble in water than the organic compound, and a crosslinker;   (iv) allowing the monomer to diffuse into the activated seed particles to form an aqueous dispersion of swollen seed particles; and   (v) initiating polymerisation of the monomer in the swollen seed particles.   
     
     
         46 . A process for the preparation of monodisperse particles comprising an Ugelstad process, wherein the Ugelstad process comprises:
 (i) forming an aqueous dispersion comprising
 monodisperse seed particles which are the monodisperse polymer particles of  claim 25 , 
 finely divided droplets comprising an organic compound of molecular weight below 5,000 and water solubility at 25° C. of less than 10 −2  g/L, and 
 an organic solvent in which the organic compound is soluble, the organic solvent being optional when the polymer forming the seed particles has an average molecular weight which corresponds to up to 50 monomer units; 
   (ii) allowing the organic compound to diffuse into the monodisperse seed particles, causing the seed particles to become activated;   (iii) removing the organic solvent, where present, from inside the seed particles, and contacting the activated seed particle with an aqueous vehicle containing a monomer that is at least 10 times more soluble in water than is the organic compound, and a crosslinker;   (iv) allowing the monomer to diffuse into the activated seed particles to form an aqueous dispersion of swollen seed particles; and   (v) initiating polymerisation of the monomer in the swollen seed particles.   
     
     
         47 . The process of  claim 46 , wherein the organic compound is a polymerisation initiator. 
     
     
         48 . The process of  claim 46 , further comprising contacting the seed particles with toluene or another porogen in step (iii). 
     
     
         49 . The process of  claim 46 , wherein the organic solvent is removed from inside the seed particles by selecting a water-miscible organic solvent and contacting the seed particles with an excess of the aqueous vehicle, whereby the organic solvent diffuses into the aqueous vehicle. 
     
     
         50 . The process of  claim 46 , wherein the percentage by weight of cross-linker is greater than 25% wt of the total amount of monomer plus cross-linker. 
     
     
         51 . The process of  claim 46 , wherein after the Ugelstad process the monodisperse particles have the following characteristics:
 a substantially smooth outer surface;   a z-average diameter of less than 1 μm;   the particles are porous; and   a coefficient of variation (CV) %, when measured by CPS disk centrifugation analysis, of less than 15%.   
     
     
         52 . The process of  claim 46 , wherein the aqueous dispersion further includes a porogen whereby the monodisperse particles made using the Ugelstad process are porous, and the process further comprises depositing magnetic material in the pores. 
     
     
         53 . The process of  claim 54 , wherein the magnetic material is a superparamagnetic material which comprises a ferrite or coated iron based or iron-nickel alloy nanoparticles. 
     
     
         54 . The process of  claim 46 , further comprising adding a coating and/or functional groups to the outer surface of the submicron monodisperse particles made using the Ugelstad process. 
     
     
         55 . Monodisperse magnetic polymer particles comprising a matrix polymer and magnetic crystals, the particles having a z-average diameter of less than 1 μm, and having a CV, when measured by disc centrifugation analysis, of less than 15%. 
     
     
         56 . Monodisperse particles of  claim 55  having a smooth outer surface. 
     
     
         57 . Monodisperse particles of  claim 55  wherein the matrix polymer is polystyrene. 
     
     
         58 . Monodisperse particles of  claim 55  which have a z-average diameter of between 400 and 800 nm. 
     
     
         59 . Monodisperse particles of  claim 55  wherein the paramagnetic crystals are superparamagnetic crystals. 
     
     
         60 . Monodisperse particles of  claim 55  wherein the paramagnetic crystals are iron oxide crystals. 
     
     
         61 . Monodisperse particles of  claim 55  which further comprise a coating polymer formed from one or more epoxides. 
     
     
         62 . A process for the preparation of monodisperse particles comprising an Ugelstad process with more than one swelling and polymerisation stage, the Ugelstad process comprising a first pass and a final pass of the following steps (i) to (vi):
 (i) forming an aqueous dispersion comprising
 the monodisperse seed particles (first pass) or intermediate particles (final pass and optional intermediate pass), 
 finely divided droplets comprising an organic compound of molecular weight below 5,000 and water solubility at 25° C. of less than 10 −2  g/L, and 
 an organic solvent in which the organic compound is soluble, the organic solvent being optional when the polymer forming the seed particles has an average molecular weight which corresponds to up to 50 monomer units; 
   (ii) allowing the organic compound to diffuse into the monodisperse seed particles, causing the seed particles to become activated;   (iii) removing the organic solvent, where present, from inside the seed particles, and contacting the activated seed particles or intermediate particles with an aqueous vehicle containing a monomer having a solubility in water at least 10 times that of the organic compound and, in the final pass only, a cross-linker;   (iv) allowing the monomer and, in the final pass only, the cross-linker to diffuse into the activated seed particles or intermediate particles to form an aqueous dispersion of swollen seed particles or intermediate particles; and   (v) initiating polymerisation of the monomer and, in the final pass only, the cross-linker in the swollen seed particles.   
     
     
         63 - 64 . (canceled) 
     
     
         65 . Monodisperse particles of  claim 1 , wherein the polymer particles do not comprise methylene bridged phenyl groups. 
     
     
         66 . Monodisperse particles of  claim 15 , wherein the polymer particles do not comprise methylene bridged phenyl groups. 
     
     
         67 . (canceled) 
     
     
         68 . The polymer particles of  claim 5 , wherein the first population of polymer particles are polystyrenic particles and the monomers used in the suspension polymerisation stage in the preparation of the reference particles were styrene and, as a crosslinker monomer, divinylbenzene, the divinylbenzene being in an amount of >25% by weight of the total of styrene plus divinylbenzene. 
     
     
         69 . The polymer particles of  claim 15 , wherein the first population of polymer particles are polystyrenic particles and the monomers used in the suspension polymerisation stage in the preparation of the reference particles are styrene and, as a crosslinker monomer, divinylbenzene, the divinylbenzene being in an amount of >25% by weight of the total of styrene plus divinylbenzene. 
     
     
         70 . The process of  claim 44 , wherein the submicron monodisperse particles are porous particles having a smooth outer surface. 
     
     
         71 . Particles obtained by the process of  claim 30 . 
     
     
         72 . Particles obtained by the process of  claim 44 . 
     
     
         73 . Particles obtained by the process of  claim 62 . 
     
     
         74 . Particles having the characteristics of particles obtained by the process of  claim 30 . 
     
     
         75 . Particles having the characteristics of particles obtained by the process of  claim 44 . 
     
     
         76 . Particles having the characteristics of particles obtained by the process of  claim 62 . 
     
     
         77 . A method of forming a product, comprising coupling monodisperse submicron particles of  claim 1  to a nucleic acid. 
     
     
         78 . The method of  claim 77 , further comprising immobilising the resultant nucleic acid-laden particles on a surface. 
     
     
         79 . A method of forming a product, comprising coupling monodisperse submicron particles of  claim 55  to a nucleic acid. 
     
     
         80 . A method of  claim 79 , further comprising immobilising the resultant nucleic acid-laden particles on a surface.