WO2022192963A1

WO2022192963A1 - Core-shell polymer inclusion microbeads and processes for their preparation

Info

Publication number: WO2022192963A1
Application number: PCT/AU2022/050242
Authority: WO
Inventors: Spas Dimitrov KOLEV; Yanlin Zhang; Robert Walter CATTRALL
Original assignee: The University Of Melbourne
Priority date: 2021-03-18
Filing date: 2022-03-18
Publication date: 2022-09-22

Abstract

The present invention provides a method of producing core-shell polymer microbeads, the method comprising: (a) providing a core solution containing one or more water insoluble polymers in a water-soluble solvent; (b) providing a shell solution containing one or more water insoluble polymers in a water-soluble solvent; (c) providing a first aqueous solution; (d) injecting the core solution, the shell solution and the first aqueous solution into a mixing zone through an injector, wherein the injector is configured such that the core solution is injected through substantially the center of the injector, the shell solution is injected adjacent to the core solution and the first aqueous solution is injected adjacent to the shell solution, wherein the solutions form a mixture containing droplets of the core solution surrounded by the shell solution in the first aqueous solution; (e) passing the mixture into a de-solvation column containing a second aqueous solution.

Description

Core-Shell Polymer Inclusion Microbeads and Processes for their Preparation Technical Field

[0001] The present invention relates to an improved method for making core-shell polymer microbeads such as core-shell polymer inclusion microbeads which may contain organic functional agent(s) in their shell. In particular, the present invention provides for the fast fabrication of core-shell polymer microbeads using microfluidics. The core-shell polymer microbeads that can be manufactured efficiently using the method of the present invention may be used in a diverse range of areas meaning that the method can be used for the fabrication of specialty materials for use in a wide range of industries. The present invention also provides novel core-shell polymer inclusion microbeads that may be made using the process of the present invention.

Background of Invention

[0002] Microbeads can be used in a wide range of industrial applications and their synthesis is therefore of significant interest due to their flexibility in use. For example, one application that microbeads have been utilised is in the area of purification/separation technology.

[0003] Accordingly, one method utilised for the removal of impurities such as metals from solution is to incorporate metal extractants (metal sequestering agents or metal chelating agents) in a polymer solution and then create polymer microbeads containing the metal extractant dispersed through the polymer. The microbeads can then be used to remove metal ions from a solution by contacting the solution with the microbeads either in a batch wise fashion or by passing the solution through a column containing the microbeads. As the solution containing the metal ions passes the microbeads the metal ions are extracted into these microbeads and the solution is purified. [0004] Whilst this technique works reasonably well, and polymer microbeads of this type are relatively easy to fabricate the microbeads produced have some down sides in terms of extraction efficiency and regeneration after use. Specifically, as the metal extractant is relatively uniformly dispersed throughout the polymer the speed of extraction can be relatively slow because the extractant binds the metal at the microbead/solution interface and there is time required for the metal ion-extractant adduct to diffuse into the microbead core and for unreacted extractant to diffuse from the interior of the microbead towards its surface. Accordingly, the extraction process using microbeads of this type can be relatively slow making it less desirable for industrial scale up.

[0005] In addition, once the metal ions to be extracted have been bound into the microbeads and the microbeads isolated, they are then treated to recover the metal ions and regenerate the microbeads for use in further extractions. The stripping (back- extraction) of the metal ions from the microbeads occurs at their interface with the stripping solution. As will be appreciated by a skilled worker in the field as the metal ion-extractant adducts diffuse completely through a microbead the recovery of the metal ions from the microbead can be slow. This is because in order for metal ions to be recovered from the interior of the microbead it is necessary for the metal ion- extractant adducts to diffuse all the way from the interior of the microbead to its surface. Depending upon the size of the microbead this can be quite a tedious process meaning that it is unsuitable for industrial scale up.

[0006] Accordingly, it would be desirable to provide alternative polymer microbeads and methods for the manufacture of materials of this type. It would also be desirable to provide polymer microbeads of core shell morphology with high entrapment efficiency of metal extractants used. As will be appreciated by a skilled worker in the field whilst the discussion above focusses on the incorporation of a metal extractant into core-shell microbeads for ease of explanation the process of the present invention provides an improved method of fabrication of core-shell microbeads and is not limited to the incorporation of an active agent into the shell layer. Nevertheless, it should also be appreciated that the process is flexible enough to accommodate the incorporation of a wide range of potential functional agents into the shell of the core-shell microbeads with high entrapment efficiency. Summary of Invention

[0007] As a result of the desire to provide an improved process to produce core shell microbeads, the applicants have identified a relatively straightforward process that overcomes a number of the issues identified and is readily scalable.

[0008] Accordingly, the present invention provides a method of producing core-shell polymer microbeads, the method comprising (a) providing a core solution containing one or more water insoluble polymers in a water-soluble solvent; (b) providing a shell solution containing one or more water insoluble polymers in a water-soluble solvent; (c) providing a first aqueous solution; (d) injecting the core solution, the shell solution and the first aqueous solution into a mixing zone through an injector, wherein the injector is configured such that the core solution is injected through substantially the center of the injector, the shell solution is injected adjacent to the core solution and the first aqueous solution is injected adjacent to the shell solution, wherein the solutions form a mixture containing droplets of the core solution surrounded by the shell solution in the first aqueous solution; and (e) passing the mixture into a de-solvation column containing a second aqueous solution.

[0009] The applicants have found that control of the parameters of the process allow for the fabrication of core-shell microbeads in which the ratio of the core to the coating (shell) can be controlled leading to process control which in turn makes it possible to provide core-shell microbeads suitable for a wide range of applications.

[0010] The bead fabrication process of the present invention allows for the fabrication of a wide range of core-shell polymer microbeads and, in particular, provides a facile technique for the production of core-shell polymer inclusion microbeads where the shell contains an organic functional agent.

[0011] Accordingly, in yet an even further aspect the present invention provides a core-shell polymer inclusion microbead comprising; (a) a core containing one or more water insoluble polymers and (b) a shell containing one or more water insoluble polymers and one or more organic functional agents. Description of the Drawings

[0012] Figure 1. Shows a schematic of one fabrication setup for core-shell structured microbeads.

[0013] Figure 2. Shows the fluorescent microscopic image of a core-shell microbead with a poly(vinyl chloride) (PVC) core and a PVC shell containing Aliquat 336 and 1-tetradecanol.

[0014] Figure 3. Shows the diameter distribution of core-shell microbeads using fabrication conditions of core solution flow rate - 160 pL min ¹, shell solution flow rate - 40 mI_ min^-1, and first aqueous solution containing NaCI flow rate - 1 ,800 mI_ min^-1. [0015] Figure 4. Shows the microscopic image of core-shell microbeads with a PVC core and a PVC shell containing Aliquat 336 and 1-tetradecanol.

Detailed Description

[0016] In this specification, a number of terms are used that are well known to a skilled addressee. Nevertheless, for the purposes of clarity, a number of these terms will be defined.

[0017] Throughout the description and the claims of this specification the word “comprise”, and variations of the word, such as “comprising” and “comprises” is not intended to exclude other additives, components, integers or steps.

[0018] As discussed above the present invention relates to an improved method for the manufacture of core-shell microbeads. As used herein a core-shell microbead refers to a microbead containing a core wherein the core is covered by a shell or coating layer. Whilst in general the core and shell have different properties it is to be noted that the different properties may be created by formation of the core and the shell from different base materials or it may be created by incorporation of an additive to either of the core or the shell. If an additive is used it is typically added to the shell layer. A core shell polymer microbead containing an additive in the shell layer is typically called a core-shell polymer inclusion microbead. [0019] As discussed above the present invention provides a method of producing core-shell polymer microbeads, the method comprising (a) providing a core solution containing one or more water insoluble polymers in a water-soluble solvent; (b) providing a shell solution containing one or more water insoluble polymers in a water-soluble solvent; (c) providing a first aqueous solution; (d) injecting the core solution, the shell solution and the first aqueous solution into a mixing zone through an injector, wherein the injector is configured such that the core solution is injected through substantially the centre of the injector, the shell solution is injected adjacent to the core solution and the first aqueous solution is injected adjacent to the shell solution, wherein the solutions form a mixture containing droplets of the core solution surrounded by the shell solution in the first aqueous solution; and (e) passing the mixture into a de solvation column containing a second aqueous solution. It is thought that during injection of the solutions, the coaxial laminar flow of the core solution and the surrounding shell solution is hydrodynamically focused at an orifice by the surrounding flow of the first aqueous solution to form droplets of the core solution surrounded by the shell solution in the first aqueous solution.

[0020] Without wishing to be bound by theory it is understood by the applicants that control of the injection of the core solution, shell solution and first aqueous solution into the mixing zone leads to formation of a solution containing droplets of the core solution surrounded by the shell solution in the first aqueous solution in the mixing zone. Once these droplets have been formed as the core solution and the shell solution both contain water insoluble polymer(s) and water-soluble solvents as they pass into the de solvation column the solvent(s) migrates to the surface of the droplets and passes into the second aqueous solution. This leads to the droplets shrinking as they lose solvent(s) and the formation of a solid core surrounded by a shell coating relatively uniformly the core.

[0021] The first steps in the process are therefore the provision of a core solution, a shell solution and a first aqueous solution. The Core Solution

[0022] The core solution used in the process of the present invention is a solution containing one or more water insoluble polymers in a water-soluble solvent.

[0023] In principle any water insoluble polymer or mixture of polymers may be used in forming the core solution with the only real limitations being placed on the polymer or mixture of polymers being that (1 ) they are water insoluble and (2) that they dissolve in a water-soluble solvent.

[0024] In one embodiment the water insoluble polymer used in the core solution is selected from the group consisting of poly(vinyl chloride), poly(vinylidene fluoride-co- hexafluoropropylene), polystyrene, polylactic acid, poly(vinylidene fluoride), poly(lactic- co-glycolic acid), poly(vinyl chloride-co-vinyl acetate), poly(methyl methacrylate), polysulfone, and mixtures thereof.

[0025] In one embodiment the water insoluble polymer used in the core solution is poly(vinyl chloride). In one embodiment the water insoluble polymer used in the core solution is poly(vinylidene fluoride-co-hexafluoropropylene). In one embodiment the water insoluble polymer used in the core solution is polystyrene. In one embodiment the water insoluble polymer used in the core solution is polylactic acid. In one embodiment the water insoluble polymer used in the core solution is poly(vinylidene fluoride). In one embodiment the water insoluble polymer used in the core solution is poly(lactic-co-glycolic acid). In one embodiment the water insoluble polymer used in the core solution is poly(vinyl chloride-co-vinyl acetate). In one embodiment the water insoluble polymer used in the core solution is poly(methyl methacrylate.

[0026] As with the water insoluble polymer in principle any water-soluble solvent can be used in the formation of the core solution with the limitations being that (1 ) the solvent or mixture of solvents must be water soluble and (2) the water insoluble polymer must be soluble in the water-soluble solvent. As will be appreciated by a skilled worker in the field not all water insoluble polymers are soluble in all water-soluble solvents and so a skilled worker is required to make judicious choices based on the water insoluble polymer(s) chosen as the basis of the core solution. [0027] In one embodiment the water soluble solvent used in the core solution is selected from the group consisting of tetrahydrofuran, ethyl acetate, Cyrene, acetone, N,N-dimethyl formamide, N,N-diethyl formamide, N, N-dimethyl acetamide, N-methyl pyrrolidone, dimethyl sulfoxide, and mixtures thereof.

[0028] In one embodiment, the water-soluble solvent used in the core solution is tetrahydrofuran. In one embodiment the water-soluble solvent used in the core solution is ethyl acetate. In one embodiment the water-soluble solvent used in the core solution is Cyrene. In one embodiment the water-soluble solvent used in the core solution is acetone. In one embodiment the water soluble solvent used in the core solution is N,N- dimethyl formamide. In one embodiment the water-soluble solvent used in the core solution is N,N-diethyl formamide. In one embodiment the water-soluble solvent used in the core solution is N-methyl pyrrolidone. In one embodiment the water-soluble solvent used in the core solution is dimethyl sulfoxide.

[0029] In formation of the core solution a wide range of concentrations of water insoluble polymers in water soluble solvents is contemplated in the process of the present invention. In general, however, the concentration of the water insoluble polymer(s) in the water soluble solvent needs to be low so that the solution has the required flow properties whilst at the same time being sufficiently high enough such that the process is efficient. In general, therefore, in the core solution the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.01% to 20%.

[0030] In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.05% to 10%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.06% to 9%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.07% to 8%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.08% to 7%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.09% to 6%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.1% to 5%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.2% to 4.5%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.5% to 4%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 1.0% to 3%.

The Shell Solution [0031] The shell solution used in the process of the present invention is a solution containing one or more water insoluble polymers in a water-soluble solvent.

[0032] In principle any water insoluble polymer or mixture of polymers may be used in forming the shell solution with the only real limitations being placed on the polymer or mixture of polymers being that (1 ) they are water insoluble and (2) that they dissolve in a water-soluble solvent.

[0033] In one embodiment the water insoluble polymer(s) used in the shell solution is selected from the group consisting of poly(vinyl chloride), poly(vinylidene fluoride-co- hexafluoropropylene), polystyrene, polylactic acid, poly(vinylidene fluoride), poly(lactic- co-glycolic acid), poly(vinyl chloride-co-vinyl acetate), poly(methyl methacrylate), polysulfone, and mixtures thereof.

[0034] In one embodiment the water insoluble polymer used in the core solution is poly(vinyl chloride). In one embodiment the water insoluble polymer used in the shell solution is poly(vinylidene fluoride-co-hexafluoropropylene). In one embodiment the water insoluble polymer used in the shell solution is polystyrene. In one embodiment the water insoluble polymer used in the shell solution is polylactic acid. In one embodiment the water insoluble polymer used in the shell solution is poly(vinylidene fluoride). In one embodiment the water insoluble polymer used in the shell solution is poly(lactic-co-glycolic acid). In one embodiment the water insoluble polymer used in the shell solution is poly(vinyl chloride-co-vinyl acetate). In one embodiment the water insoluble polymer used in the shell solution is poly(methyl methacrylate).

[0035] As with the water insoluble polymer(s) in principle any water-soluble solvent can be used in the formation of the shell solution with the limitations being that (1) the solvent or mixture of solvents must be water soluble and (2) the water insoluble polymer(s) must be soluble in the water-soluble solvent. As will be appreciated by a skilled worker in the field not all water insoluble polymers are soluble in all water-soluble solvents and so a skilled worker is required to make judicious choices based on the water insoluble polymer chosen as the basis of the shell solution.

[0036] In one embodiment the water soluble solvent used in the shell solution is selected from the group consisting of tetrahydrofuran, ethyl acetate, Cyrene, acetone, N,N-dimethyl formamide, N,N-diethyl formamide, N-methyl pyrrolidone, dimethyl sulfoxide, and mixtures thereof.

[0037] In one embodiment, the water-soluble solvent used in the shell solution is tetrahydrofuran. In one embodiment the water-soluble solvent used in the shell solution is ethyl acetate. In one embodiment the water-soluble solvent used in the shell solution is Cyrene. In one embodiment the water-soluble solvent used in the shell solution is acetone. In one embodiment the water soluble solvent used in the shell solution is N,N- dimethyl formamide. In one embodiment the water soluble solvent used in the shell solution is N,N-diethyl formamide. In one embodiment the water-soluble solvent used in the shell solution is N-methyl pyrrolidone. In one embodiment the water-soluble solvent used in the shell solution is dimethyl sulfoxide.

[0038] In formation of the shell solution a wide range of concentrations of water insoluble polymer(s) in water soluble solvents is contemplated in the process of the present invention. In general, however, the concentration of water insoluble polymer(s) in the water soluble solvent needs to be low so that the solution has the required flow properties whilst at the same time being sufficiently high enough such that the process is efficient. In general, therefore, in the shell solution the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.01% to 20%.

[0039] In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.05% to 10%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.06% to 9%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.07% to 8%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.08% to 7%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.09% to 6%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.1% to 5%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.2% to 4.5%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 0.5% to 4%. In one embodiment the concentration of polymer(s) on a mass per volume percentage basis (m/v%) is from 1 .0% to 3%.

[0040] The shell solution may also contain an organic functional agent that remains in the shell of the core-shell microbeads produced by the process of the present invention. A number of organic functional agents may be used with the only real limitation being that the organic functional agent(s) needs to be soluble in the water- soluble solvent and insoluble in water. An example of a suitable organic functional agents is a metal extractant. Suitable metal extractants include Aliquat 336 (a mixture of quaternary alkylammonium chlorides with the dominant species being trioctylmethylammonium chloride), trihexyl(tetradecyl)phosphonium chloride (Cyphos IL 101 ), trihexyl(tetradecyl)-phosphonium bromide (Cyphos IL 102), tetradecyl(trihexyl)phosphonium decanoate (Cyphos IL 103), (trihexyl(tetradecyl)phosphonium bis-2,4,4-(trimethylpentyl) phosphinate (Cyphos 104), trihexyl(tetradecyl)phosphonium dicyanamide (Cyphos IL 105), trihexyl(tetradecyl)phosphonium bis(trifluoromethanesulfonyl)amide (Cyphos IL 109), trihexyl(tetradecyl)phosphonium hexafluorophosphate (Cyphos IL 110), tributyl(tetradecyl)phosphonium dodecylbenzenesulfonate (Cyphos IL 201 ), tributyl(tetradecyl)phosphonium methanesulfonate (Cyphos IL 203), tetraoctylphosphonium bromide, tributyl(ethyl)phosphonium diethylphosphate, tributyl(methyl)phosphonium methylsulfate, tri-i-butyl(methyl)phosphonium tosylate, 1 - hexadecyl-3-methylimidazolium chloride, bis/2,4,4-trimethylpentyl/ phosphinic acid) (Cyanex 272), Cyanex 600, Cyanex 923, bis(2,4,4-trimethylpentyl)dithiophosphinic acid (HR) (Cyanex 301), Cyanex 302, and di-(2-ethylhexyl)phosphoric acid (D2EHPA).

The First Aqueous Solution

[0041] In the process of the present invention the role of the first aqueous solution is to flow around the core and shell fluid to maintain them in relative contact and to provide an aqueous solution in the mixing zone such that at a certain point droplets of the core solution surrounded by the shell solution are formed due to the large difference in surface tension between the two organic solutions and the first aqueous solution. Once the droplets are formed the first aqueous solution serves as a carrier for the droplets into the de-solvation column.

[0042] The first aqueous solution may be water per se, however it has been found that it preferably contains a salt additive which serves the purpose of controlling the solubility of the water-soluble solvents in the core solution and the shell solution in the first aqueous solution. Any suitable salt may be used with sodium chloride being found to be particularly suitable.

[0043] If a salt is present it may be present in a wide range of concentrations and the exact concentration chosen will depend upon the nature of the water-soluble solvents and the respective volumes of the core solution, shell solution and first aqueous solution used. In general, however, the salt is present in a range of from 0.1% (w/v) to 50% (w/v). In one embodiment the salt is present in a range of from 0.5% (w/v) to 45% (w/v). In one embodiment the salt is present in a range of from 1.0% (w/v) to 40% (w/v). In one embodiment the salt is present in a range of from 1 .5% (w/v) to 37.5% (w/v). In one embodiment the salt is present in a range of from 2.0% (w/v) to 35% (w/v). In one embodiment the salt is present in a range of from 5% (w/v) to 25% (w/v).

Mixing the Solutions in a Mixing Zone

[0044] Once the core solution, shell solution and first aqueous solution have been prepared they are ready to be injected into a mixing zone to form a mixture containing droplets of the core solution surrounded by the shell solution in the first aqueous solution.

[0045] This process involves injecting the core solution, the shell solution and the first aqueous solution into a mixing zone through an injector, wherein the injector is configured such that the core solution is injected through substantially the center of the injector, the shell solution is injected adjacent to the core solution and the first aqueous solution is injected adjacent to the shell solution, wherein the coaxial laminar flow of the core solution and shell solution is focused at an orifice by the surrounding first aqueous solution and segmented by it to form droplets of the core solution surrounded by the shell solution in the first aqueous solution.

[0046] As will be appreciated, there are any number of potential configurations that may be used to achieve this result with the requirements that the solutions be injected such that the shell solution is injected adjacent to the core solution and the first aqueous solution is injected adjacent to the shell solution. Whilst there are preferred ways of doing this as discussed below almost any configuration of microfluidic mixing that achieves this result will be suitable for use in the present invention.

[0047] In one embodiment the injector comprises an inner capillary, an intermediate capillary and an outer capillary, wherein the intermediate capillary surrounds the inner capillary and the outer capillary surrounds the intermediate capillary and further wherein the core solution is injected through the inner capillary, the shell solution is injected through the intermediate capillary and the first aqueous solution is injected through the outer capillary. In general, in this form the capillaries will be coaxial capillaries although this is not strictly speaking required.

[0048] An example of one form of this embodiment is provided in Figure 1 . The system was composed of three syringe pumps (NE-1000, New Era Pump Systems Inc., Farmingdale, NY, USA), a flow focusing droplet generation component and a de solvation column. Two of the syringe pumps (P1 and P2) were each equipped with a 5 ml_ gas-tight glass syringe for the delivery of the core fluid and shell fluid, respectively, and the third syringe pump (P3) was furnished with a 35 ml_ polypropylene syringe for the transport of the first aqueous solution containing 20% (w/v) NaCI. The droplet generation component was composed of three co-axial capillaries. The inner stainless steel (SS) capillary with an inner diameter of 250 pm and outer diameter of 500 pm was for the delivery of the core fluid and the intermediate SS capillary had an inner diameter of 570 pm and an outer diameter of 1 ,000 pm for the delivery of the shell fluid. Outside of them was a glass capillary with an inner diameter of 1 .5 mm and 8 cm in length. The SS orifice at the top of the glass capillary has an inner diameter of 500 pm and a length of 7 mm. As will be appreciated the geometry of each capillary may vary greatly in size and configuration and the numbers provided above merely represent one form. [0049] As shown in the figure (Figure 1 ), a core solution (i.e., a polymer solution containing a polymer or a mixture of polymers dissolved in an organic solvent) is propelled through the inner capillary of the coaxial capillary droplet generator at a constant flow rate. A shell solution, (i.e., a solution containing a polymer or a mixture of polymers, dissolved in an organic solvent) is propelled through the intermediate capillary of the droplet generator at a constant flow rate. At the same time, the first aqueous solution (typically a NaCI solution with a NaCI concentration of 20% (w/v)) is propelled through the outer capillary of the droplet generator. In the droplet generator, the coaxial core solution flow and the shell flow, with the former surrounded by the latter, are focused at the orifice by the flow of the first aqueous solution surrounding them and segmented into uniform bands and then transformed into spherical droplets due to the large difference in surface tension between the organic solutions and the first aqueous solution and the droplets are carried by the first aqueous solution into the de-solvation column.

[0050] In formation of the core-shell microbeads it is desirable that the shell is a thin layer covering the core although this is not always the case. Accordingly, in the process of the present invention the ratio of core solution to shell solution may vary widely in order to control the final configuration or the core-shell microbeads ultimately produced. In the process of the present invention the ratio of core solution to shell solution used is from 40:1 to 1 :1. In one embodiment the ratio of core solution to shell solution used is from 35:1 to 2:1 . In one embodiment the ratio of core solution to shell solution used is from 30:1 to 5:1 . In one embodiment the ratio of core solution to shell solution used is from 20:1 to 10:1 .

[0051] In addition, in the process of the present invention the ratio of core solution to first aqueous solution may also vary widely with the amount of first aqueous solution typically being used in a far greater amount to ensure droplet integrity in the droplet generator. Whilst in principle the ratio of core solution to first aqueous solution may be very low in practice, the ratio of core solution to first aqueous solution is typically 1 :20 to 1 : 5. In one embodiment the ratio of core solution to first aqueous solution is from 1 :18 to 1 : 6. In one embodiment the ratio of core solution to first aqueous solution is from 1 :16 to 1 : 7. In one embodiment the ratio of core solution to first aqueous solution is from 1 :14 to 1 : 8. In one embodiment the ratio of core solution to first aqueous solution is from 1 :12 to 1 : 9.

The De-solvation Column

[0052] Once the droplets have been produced as discussed above, they are then passed into a de-solvation column containing a second aqueous solution.

[0053] The second aqueous solution may be the same as the first aqueous solution or it may be different. Accordingly, whilst it may be water per se, it has been found that it preferably contains a salt additive which serves the purpose of controlling the solubility of the water-soluble solvents in the core solution and the shell solution in the second aqueous solution which in turns provides some control of the de-solvation process. Any suitable salt may be used with sodium chloride being found to be particularly suitable.

[0054] If a salt is present it may be present in a wide range of concentrations and the exact concentration chosen will depend upon the nature of the water-soluble solvents and the respective volumes of the core solution, shell solution and first aqueous solution used. In general, however, the salt is present in a range of from 0.1% (w/v) to 50% (w/v). In one embodiment the salt is present in a range of from 0.5% (w/v) to 45% (w/v). In one embodiment the salt is present in a range of from 1.0% (w/v) to 40% (w/v). In one embodiment the salt is present in a range of from 1 .5% (w/v) to 37.5% (w/v). In one embodiment the salt is present in a range of from 2.0% (w/v) to 35% (w/v). In one embodiment the salt is present in a range of from 5% (w/v) to 25% (w/v). In one embodiment the salt is present in a range of from 1% (w/v) to 20% (w/v).

[0055] In the de-solvation column, the droplets initially rise due to the lower density of the droplets in comparison to that of the second aqueous solution. As the solvents contained in both the core solution and the shell solution are both water soluble the solvent molecules migrate to the surface of the droplets and then pass into the second aqueous solution. As there is a loss of solvent from both the core and the shell the droplets shrink leading over time to the formation of a polymer core being formed with a polymer shell coating. Once sufficient amounts of the water-soluble solvent have passed into the second aqueous solution the density of the droplets (now in the form of microbeads) increases such that it becomes greater than the density of the second aqueous solution. The microbeads thus tend to descend back down into the column and may be collected at the bottom of the column.

Core-Shell Polymer Inclusion Microbeads [0056] As discussed above the process of the present invention allows for the facile formation of core-shell polymer microbeads. The flexibility of the process allows for the ready incorporation of an additive into the shell but not the core, or vice-versa, or the incorporation of the same or different additives in both the shell and the core, and therefore allows for the facile preparation of core-shell polymer inclusion microbeads. Accordingly, the present invention provides a core-shell polymer inclusion microbead comprising (a) a core containing one or more water insoluble polymers and (b) a shell containing one or more water insoluble polymers and one or more organic functional agents.

[0057] In the core-shell polymer inclusion microbeads the respective amounts of the core and the shell may vary widely depending upon the desired end use application. In general, however, the core comprises from 60 wt% to 99.9 wt% of the total weight of the microbead. In one embodiment the core comprises from 70 wt% to 99.9 wt% of the total weight of the microbead. In yet an even further embodiment the core comprises from 80 wt% to 99.5 wt% of the total weight of the microbead. In yet an even further embodiment the core comprises from 85 wt% to 99.0 wt% of the total weight of the microbead. In yet an even further embodiment the core comprises from 90 wt% to 97.5 wt% of the total weight of the microbead. In yet an even further embodiment the core comprises from 95 wt% to 97.5 wt% of the total weight of the microbead.

[0058] The core comprises one or more water insoluble polymers. In one embodiment the water insoluble polymer in the core is selected from the group consisting of poly(vinyl chloride), poly(vinylidene fluoride-co-hexafluoropropylene), polystyrene, polylactic acid, poly(vinylidene fluoride), poly(lactic-co-glycolic acid), poly(vinyl chloride-co-vinyl acetate), poly(methyl methacrylate), polysulfone, and mixtures thereof. [0059] In one embodiment the water insoluble polymer in the core is poly(vinyl chloride). In one embodiment the water insoluble polymer in the core is poly(vinylidene fluoride-co-hexafluoropropylene). In one embodiment the water insoluble polymer in the core is polystyrene. In one embodiment the water insoluble polymer in the core is polylactic acid. In one embodiment the water insoluble polymer in the core is poly(vinylidene fluoride). In one embodiment the water insoluble polymer in the core is poly(lactic-co-glycolic acid). In one embodiment the water insoluble polymer in the core is poly(vinyl chloride-co-vinyl acetate). In one embodiment the water insoluble polymer in the core is poly(methyl methacrylate. In one embodiment the water insoluble polymer in the core is polysulfone.

[0060] The core-shell polymer inclusion microbeads may take a variety of shapes but are typically substantially spherical. The beads vary in size with the core typically having a diameter of from 30 to 200 pm. In one embodiment the core has a diameter of from 50 to 150 pm. In one embodiment the core has a diameter of from 75 to 125 pm. [0061] As with the core there may also be significant variation in the shell. In general, however, the shell comprises from 0.1 wt% to 40.0 wt% of the total weight of the microbead. In one embodiment the shell comprises from 0.1 wt% to 30.0 wt% of the total weight of the microbead. In yet an even further embodiment the shell comprises from 0.5 wt% to 20.0 wt% of the total weight of the microbead. In yet an even further embodiment the shell comprises from 1.0 wt% to 15.0 wt% of the total weight of the microbead. In yet an even further embodiment the shell comprises from 2.5 wt% to 10.0 wt% of the total weight of the microbead. In yet an even further embodiment the shell comprises from 2.5 wt% to 5 wt% of the total weight of the microbead.

[0062] In addition, the thickness of the shell may vary significantly but is typically from 0.1 to 5.0 pm. In one embodiment the shell has a thickness of from 0.5 to 4.5 pm.

In one embodiment the shell has a thickness of from 0.5 to 4.5 pm. In one embodiment the shell has a thickness of from 1.0 to 4.0 pm. In one embodiment the shell has a thickness of from 1.5 to 3.5 pm. In one embodiment the shell has a thickness of from 2.0 to 3.0 pm. [0063] The shell comprises one or more water insoluble polymers. In one embodiment the water insoluble polymer(s) in the shell is selected from the group consisting of poly(vinyl chloride), poly(vinylidene fluoride-co-hexafluoropropylene), polystyrene, polylactic acid, poly(vinylidene fluoride), poly(lactic-co-glycolic acid), poly(vinyl chloride-co-vinyl acetate), poly(methyl methacrylate), polysulfone, and mixtures thereof.

[0064] In one embodiment the water insoluble polymer in the shell is poly(vinyl chloride). In one embodiment the water insoluble polymer in the shell is poly(vinylidene fluoride-co-hexafluoropropylene). In one embodiment the water insoluble polymer in the shell is polystyrene. In one embodiment the water insoluble polymer in the shell is polylactic acid. In one embodiment the water insoluble polymer in the shell is poly(vinylidene fluoride). In one embodiment the water insoluble polymer in the shell is poly(lactic-co-glycolic acid). In one embodiment the water insoluble polymer in the shell is poly(vinyl chloride-co-vinyl acetate). In one embodiment the water insoluble polymer in the shell is poly(methyl methacrylate. In one embodiment the water insoluble polymer in the shell is polysulfone.

[0065] The shell of the core-shell polymer inclusion microbeads contains a water insoluble polymer(s) and a functional agent(s). The concentration of water insoluble polymer(s) is typically from 30 wt% to 90 wt% of the total weight of the shell. In one embodiment the concentration of water insoluble polymer(s) is from 40 wt% to 80 wt% of the total weight of the shell. In one embodiment the concentration of water insoluble polymer is from 50 wt% to 70 wt% of the total weight of the shell.

[0066] The concentration of functional agent(s) is typically from 10 wt% to 70 wt% of the total weight of the shell. In one embodiment the concentration of functional agent(s) is from 20 wt% to 60 wt% of the total weight of the shell. In one embodiment the amount of functional agent(s) is from 30 wt% to 50 wt% of the total weight of the shell.

[0067] A number of organic functional agents may be used in the shell. An example of a suitable organic functional agent is a metal extractant. Suitable metal extractants include trioctylmethylammonium chloride (Aliquat 336), trihexyl(tetradecyl)phosphonium chloride (Cyphos IL 101 ), trihexyl(tetradecyl)- phosphonium bromide (Cyphos IL 102), tetradecyl(trihexyl)phosphonium decanoate (Cyphos IL 103), (trihexyl(tetradecyl)phosphonium bis-2,4,4-(trimethylpentyl) phosphinate (Cyphos 104), trihexyl(tetradecyl)phosphonium dicyanamide (Cyphos IL 105), trihexyl(tetradecyl)phosphonium bis(trifluoromethanesulfonyl)amide (Cyphos IL 109), trihexyl(tetradecyl)phosphonium hexafluorophosphate (Cyphos IL 110), tributyl(tetradecyl)phosphonium dodecylbenzenesulfonate (Cyphos IL 201), tributyl(tetradecyl)phosphonium methanesulfonate (Cyphos IL 203), tetraoctylphosphonium bromide, tributyl(ethyl)phosphonium diethylphosphate, tributyl(methyl)phosphonium methylsulfate, tri-i-butyl(methyl)phosphonium tosylate, 1 - hexadecyl-3-methylimidazolium chloride, bis/2,4,4-trimethylpentyl/ phosphinic acid) (Cyanex 272), Cyanex 600, Cyanex 923, bis(2,4,4-trimethylpentyl)dithiophosphinic acid (HR) (Cyanex 301), Cyanex 302, and di-(2-ethylhexyl)phosphoric acid (D2EHPA).

[0068] An advantage of the process of the present invention is that it provides core shell microbeads with the metal extractant dispersed through the shell and with no extractant located in the core. Such core-shell materials are found to be typically more efficient in both extraction and regeneration as both the metal extractant and its adduct with the extracted metal are located in the relatively thin shell of the core-shell microbeads meaning that the distance that these two chemical species are required to diffuse in both the extraction and recovery steps is significantly smaller leading to an overall separation process that is significantly faster. As such extractions using core shell materials of this type have superseded extractions where the metal extractant is located uniformly dispersed through polymer microbeads.

[0069] The above process will now be described with reference to the following examples.

Examples

Example 1

[0070] All chemicals are of analytical reagent grade. For the fabrication of core-shell polymer inclusion microbeads, 3 g of poly(vinyl chloride) (PVC, M_w=43 kDa, Sigma- Aldrich) were dissolved in 97 mL of tetrahydrofuran (THF, Sigma-Aldrich) as the core solution, while 0.2 g of PVC, 0.1 g of Aliquat 336 (Sigma-Aldrich) and 0.05 g of 1 - tetradodecanol (Sigma-Aldrich) were dissolved in 99.7 ml_ of THF as the shell fluid. To ascertain the core-shell structure, a core-shell microbead sample was fabricated in which 20 mg L ¹ Rhodamine B (Sigma-Aldrich) was added in the shell fluid and the core-shell microbeads were observed with fluorescent microscopy as illustrated in Figure 2 and detailed below. For comparison, homogeneous polymer inclusion microbeads were fabricated using a solution containing 2 g of PVC, 1 g of Aliquat 336, and 0.5 g of 1 -tetradecanol in 96.5 ml_ of THF. A 20% (w/v) NaCI (Merck) solution and a 10% (w/v) NaCI solution were prepared as the first aqueous solution for the polymer solution droplet generation and the second aqueous solution for the subsequent de solvation of the droplets, respectively.

[0071] Core-shell microbeads were fabricated using the apparatus as depicted in Figure 1 . The system was composed of three syringe pumps (NE-1000, New Era Pump Systems Inc., Farmingdale, NY, USA), a flow focusing droplet generation component and a de-solvation column. Two of the syringe pumps (P1 and P2) were each equipped with a 5 ml_ gas-tight glass syringe for the delivery of the core fluid and shell fluid, respectively, and the third syringe pump (P3) was furnished with a 35 ml_ polypropylene syringe for the transport of the 20% (w/v) NaCI first aqueous solution. The droplet generation component was composed of three coaxial capillaries. The inner stainless steel (SS) capillary with an inner diameter of 250 pm and outer diameter of 500 pm was used for the delivery of the core fluid, and the intermediate SS capillary with an inner diameter of 570 pm and an outer diameter of 1 ,000 pm was used for the delivery of the shell fluid. Outside of them was a glass capillary with an inner diameter of 1 .5 mm and 8 cm in length which was used for the delivery of the first aqueous solution. The SS orifice at the top of the glass capillary had an inner diameter of 500 pm and a length of 7 mm.

[0072] By injecting the core solution, the shell solution and the first aqueous solution at flow rates of 160 pL min ¹, 40 pL min ¹ and 1 ,800 pL min ¹ through the inner SS capillary, the intermediate SS capillary and the glass capillary of the droplet generation unit of the microfluidic system, respectively, concentric laminar flow of the core and shell fluids were hydrodynamically focused at the entrance of the orifice and segmented by the first aqueous solution to form polymer solution microdroplets in the orifice which were propelled into the de-solvation column by the first aqueous solution. The de solvation column contained 300 ml_ of the second aqueous solution (10% (w/v) NaCI solution) and the droplets in this aqueous solution moved upwards due to their lower density than that of the aqueous solution. In this ascending process, the droplets were de-solvated due to the high solubility of TFIF in the aqueous solution and solid microbeads were formed in the column.

[0073] After separation from the second aqueous solution by filtration and thorough washing with water to remove the residual NaCI on their surface, the core-shell microbeads were left for air-drying overnight to remove the moisture on the surface and then were applied to Au(lll) separation from other metal ions.

[0074] With a NaCI solution flow rate of 1 ,800 mI_ min^-1, ideal particle size for microbeads, i.e., 50 to 100 pm in diameter, was obtained. Under such conditions, the effect of the ratio between the core fluid flow rate and the shell fluid flow rate on the shell thickness is illustrated in Table 1 below.

Table 1 Theoretical shell thickness with different fabrication parameters

Core flow rate (pL s ¹) Shell flow rate (pL s ¹) Shell thickness (pm)**

160 40 035

140 60 0.58

120 80 0.85

100 100 1.18

^* 20% (w/v) NaCI solution: 1.8 imL min ¹, ^** calculated according to the average particle size.

[0075] It can be seen that the increase of the shell solution flow rate and decrease of the core solution flow rate, the shell thickness was increased. By using flow rates of 160 mI_ min ¹ and 40 mI_ min ¹ for the core and shell solutions, respectively, the particle size distribution is illustrated in Figure 3 and an average diameter calculated with 200 microbeads (Figure 4) was 74.3 pm with a dispersity index of 9.7%. The microbeads were successfully applied to the separation of Au(lll) from other metal ions with thiourea as the stripping reagent and complete separation of Au(lll) was achieved.

Example 2

[0076] Fabrication of the core-shell microbeads for Cu(ll) separation from other metal ions was carried out by following the general procedure outlined in Example 1 and using 3% (w/v) of PVC solution in THF as the core solution, a shell TFIF solution containing PVDF-FIFP (Sigma-Aldrich), 2-hydroxy-5-nonylacetophenone oxime (LIX 84I, BASF) and 2-nitrophenyl octyl ether (NPOE, Sigma-Aldrich)), and a 20% (w/v) NaCI solution as the first aqueous solution.

[0077] The droplet generation component was composed of three coaxial capillaries. The inner stainless steel (SS) capillary with an inner diameter of 250 pm and outer diameter of 500 pm was used for the delivery of the core fluid, and the intermediate SS capillary with an inner diameter of 570 pm and an outer diameter of 1 ,000 pm was used for the delivery of the shell fluid. Outside of them was a glass capillary with an inner diameter of 1 .5 mm and 8 cm in length which was used for the delivery of the first aqueous solution. The SS orifice at the top of the glass capillary had an inner diameter of 500 pm and a length of 7 mm.

[0078] By injecting the core solution, the shell solution and the first aqueous solution at flow rates of 160 pL min ¹, 40 pL min ¹ and 1 ,800 pL min ¹ through the inner SS capillary, the intermediate SS capillary and the glass capillary of the droplet generation unit, respectively, concentric laminar flow of the core and shell fluids were hydrodynamically focused at the entrance of the orifice and segmented by the first aqueous solution to form polymer solution microdroplets in the orifice which were propelled into the de-solvation column by the first aqueous solution. The de-solvation column contained 300 ml_ of the second aqueous solution (10% (w/v) NaCI solution) and the droplets in this solution moved upwards due to their lower density than that of the solution. In this ascending process, the droplets were de-solvated due to the high solubility of TFIF in the second aqueous solution and solid microbeads were formed in the column. [0079] After separation from the saline water by filtration and thorough washing with water to remove the residual NaCI on their surface, the core-shell microbeads were left for air-drying overnight to remove the moisture on their surface and were applied to Cu(ll) separation from other metal ions including Fe(lll), Co(ll), Ni(ll), Zn(ll), and Cd(ll). [0080] Finally, it will be appreciated that various modifications and variations of the methods and compositions of the invention described herein would be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood, that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are apparent to those skilled in the art are intended to be within the scope of the present invention.

Claims

The claims defining the invention are as follows:

1 . A method of producing core-shell polymer microbeads, the method comprising:

(a) providing a core solution containing one or more water insoluble polymers in a water-soluble solvent;

(b) providing a shell solution containing one or more water insoluble polymers in a water-soluble solvent;

(c) providing a first aqueous solution;

(d) injecting the core solution, the shell solution and the first aqueous solution into a mixing zone through an injector, wherein the injector is configured such that the core solution is injected through substantially the center of the injector, the shell solution is injected adjacent to the core solution and the first aqueous solution is injected adjacent to the shell solution, wherein the solutions form a mixture containing droplets of the core solution surrounded by the shell solution in the first aqueous solution;

(e) passing the mixture into a de-solvation column containing a second aqueous solution.

2. A method according to claim 1 wherein the injector comprises an inner capillary, an intermediate capillary and an outer capillary, wherein the intermediate capillary surrounds the inner capillary and the outer capillary surrounds the intermediate capillary and further wherein the core solution is injected through the inner capillary, the shell solution is injected through the intermediate capillary and the first aqueous solution is injected through the outer capillary.

3. A method according to any one of claims 1 to 2 wherein in the core solution the water soluble solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, Cyrene, acetone, N,N-dimethyl formamide, N,N-diethyl formamide, N-methyl pyrrolidone, dimethyl sulfoxide, and mixtures thereof.

4. A method according to any one of claims 1 to 3 wherein in the core solution the water-soluble solvent is tetrahydrofuran.

5. A method according to any one of claims 1 to 4 wherein in the core solution the water insoluble polymer is selected from the group consisting of poly(vinyl chloride), poly(vinylidene fluoride-co-hexafluoropropylene), polystyrene, polylactic acid, poly(vinylidene fluoride), poly(lactic-co-glycolic acid), poly(vinyl chloride-co-vinyl acetate), poly(methyl methacrylate), polysulfone, and mixtures thereof.

6. A method according to any one of claims 1 to 5 wherein in the core solution the water insoluble polymer is poly(vinyl chloride).

7. A method according to any one of claims 1 to 6 wherein in the shell solution the water soluble solvent is selected from the group consisting of tetrahydrofuran, ethyl acetate, Cyrene, acetone, N,N-dimethyl formamide, N,N-diethyl formamide, N-methyl pyrrolidone, dimethyl sulfoxide, and mixtures thereof.

8. A method according to any one of claims 1 to 7 wherein in the shell solution the water-soluble solvent is tetrahydrofuran.

9. A method according to any one of claims 1 to 8 wherein in the shell solution the water insoluble polymer is selected from the group consisting of poly(vinyl chloride), poly(vinylidene fluoride-co-hexafluoropropylene), polystyrene, polylactic acid, poly(vinylidene fluoride), poly(lactic-co-glycolic acid), poly(vinyl chloride-co-vinyl acetate), poly(methyl methacrylate), polysulfone, and mixtures thereof.

10. A method according to any one of claims 1 to 9 wherein in the shell solution the water insoluble polymer is poly(vinyl chloride).

11. A method according to any one of claims 1 to 10 wherein the shell solution contains an organic functional agent.

12. A method according to claim 11 wherein the organic functional agent is a metal extractant.

13. A method according to any one of claims 1 to 12 wherein the first aqueous solution is a sodium chloride solution.

14. A method according to claims 1 to 13 wherein the sodium chloride solution has a concentration from 2% (w/v) to 35% (w/v).

15. A method according to any one of claims 1 to 14 wherein the ratio of the core solution to the shell solution is from 40:1 to 1 :1.

16. A method according to any one of claims 1 to 15 wherein the ratio of core solution to first aqueous solution is 1 :20 to 1 :5.

17. A method according to any one of claims 1 to 16 wherein the second aqueous solution is a sodium chloride solution.

18. A method according to claim 17 wherein the sodium chloride solution has a concentration from 1% (w/v) to 20% (w/v).

19. A core-shell polymer inclusion microbead comprising:

(a) a core containing one or more water insoluble polymers;

(b) a shell containing one or more water insoluble polymers and one or more organic functional agents.

20. A core-shell polymer inclusion microbead according to claim 19 wherein the core comprises from 60 wt% to 99.9 wt% of the total weight of the microbead.

21. A core-shell polymer inclusion microbead according to claim 19 wherein the core comprises from 70 wt% to 99.9 wt% of the total weight of the microbead.

22. A core-shell polymer inclusion microbead according to claim 19 wherein the core comprises from 80 wt% to 99.5 wt% of the total weight of the microbead.

23. A core-shell polymer inclusion microbead according to claim 19 wherein the shell comprises from 0.1 wt% to 40 wt% of the total weight of the microbead.

24. A core-shell polymer inclusion microbead according to claim 19 wherein the shell comprises from 0.1 wt% to 30.0 wt% of the total weight of the microbead.

25. A core-shell polymer inclusion microbead according to claim 19 wherein the shell comprises from 0.5 wt% to 20 wt% of the total weight of the microbead.

26. A core-shell polymer inclusion microbead according to claim 19 wherein the core has a diameter of from 30 to 200 pm.

27. A core-shell polymer inclusion microbead according to claim 19 wherein the shell has a thickness of from 0.1 to 5.0 pm.

28. A core-shell polymer inclusion microbead according to claim 19 wherein in the core the water insoluble polymer is selected from the group consisting of poly(vinyl chloride), poly(vinylidene fluoride-co-hexafluoropropylene), polystyrene, polylactic acid, poly(vinylidene fluoride), poly(lactic-co-glycolic acid), poly(vinyl chloride-co-vinyl acetate), poly(methyl methacrylate), polysulfone, and mixtures thereof.

29. A core-shell polymer inclusion microbead according to claim 19 wherein in the core the water insoluble polymer is poly(vinyl chloride).

30. A core-shell polymer inclusion microbead according to claim 19 wherein in the shell the water insoluble polymer is selected from the group consisting of poly(vinyl chloride), poly(vinylidene fluoride-co-hexafluoropropylene), polystyrene, polylactic acid, poly(vinylidene fluoride), poly(lactic-co-glycolic acid), poly(vinyl chloride-co-vinyl acetate), poly(methyl methacrylate), polysulfone, and mixtures thereof.

31. A core-shell polymer inclusion microbead according to claim 19 wherein in the shell the water insoluble polymer is poly(vinyl chloride).

32. A core-shell polymer inclusion microbead according to claim 19 wherein in the shell the organic functional agent is an extractant.

33. A core-shell polymer inclusion microbead according to claim 32 wherein in the shell the organic functional agent is a metal extractant.