Method of producing polymeric particles with selected size, shape, morphology and composition

• US 8,696,952 B2
• Filed: 04/25/2005
• Issued: 04/15/2014
• Est. Priority Date: 04/23/2004
• Status: Active Grant

• Current Assignee: Eugenia Kumacheva, Hong Zhang, Min Seok Seo, Patrick Cameron Lewis, Shengqing Xu, Zhihong Nie
• Original Assignee: Eugenia Kumacheva, Hong Zhang, Min Seok Seo, Patrick Cameron Lewis, Shengqing Xu, Zhihong Nie
• Inventors: Kumacheva, Eugenia, Xu, Shengqing, Nie, Zhihong, Seo, Min Seok, Lewis, Patrick Cameron, Zhang, Hong
• Primary Examiner(s): Seidleck, James J
• Assistant Examiner(s): POURBOHLOUL, SARIRA CAMILLA
• Application Number:
  US11/587,251
• Publication Number:
  US 20110129941A1
• Time in Patent Office: 3,277 Days
• Field of Search: 422/100, 422/130, 422/68.1, 422/103, 422/110, 422/50, 264 4- 47, 436/180, 427/483
• US Class Current: 264/4.1
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5036 Polysaccharides, e.g. gums, alginate; Cyclodextrin
• CPC Class Codes: B01F 23/41 Emulsifying
• CPC Class Codes: B01F 25/4331 Mixers with bended, curved, coiled, wounded mixing tubes or comprising elements for bending the flow
• CPC Class Codes: B01F 33/3011 using a sheathing stream of a fluid surrounding a central stream of a different fluid, e.g. for reducing the cross-section of the central stream or to produce droplets from the central stream
• CPC Class Codes: B01J 19/0093 Microreactors, e.g. miniaturised or microfabricated reactors laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027
• CPC Class Codes: B01J 2219/00783 Laminate assemblies, i.e. the reactor comprising a stack of plates
• CPC Class Codes: B01J 2219/00831 Glass
• CPC Class Codes: B01J 2219/00833 Plastic
• CPC Class Codes: B01J 2219/00835 Comprising catalytically active material
• CPC Class Codes: B01J 2219/0086 Dimensions of the flow channels
• CPC Class Codes: B01J 2219/00873 Heat exchange
• CPC Class Codes: B01J 2219/00889 Mixing micromixers B01F33/30
• CPC Class Codes: B01J 2219/00891 Feeding or evacuation
• CPC Class Codes: B01J 2219/0093 Electric or magnetic energy
• CPC Class Codes: B01J 2219/00936 UV-radiations
• CPC Class Codes: B01J 2219/00984 Residence time
• CPC Class Codes: B82Y 10/00 Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C08J 3/16 : by coagulating dispersions C08J3/122 takes precedence
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

The present invention provides a method and apparatus for producing polymeric particles with pre-designed size, shape, morphology and composition, and more particularly the present invention uses a microfluidic polymerization reactor for producing same. The present invention disclosed herein provides a process for producing polymer particles with pre-selected shapes. The method includes injecting a first fluid comprising a polymerizable constituent with a controlled flow rate into a microfluidic channel and injecting a second fluid with a controlled flow rate into the microfluidic channel in which the second fluid mixes with the first fluid, the second fluid being immiscible with the first fluid so that the first fluid forms into droplets in the microfluidic channel. The microfluidic channel has pre-selected dimensions to give droplets of pre-selected size, morphology and shape. The microfluidic channel is sufficiently long so that the droplets have a sufficiently long residence time in the channel so that they polymerize or otherwise harden into droplets of pre-selected size and shape.

Claims

1. A process for producing core/shell droplets, the process comprising:

providing a microfluidic device comprising

at least five microfluidic inlets, including a central microfluidic channel inlet, two inner microfluidic channel inlets, and two outer microfluidic channel inlets, wherein the inner microfluidic channel inlets are arranged on both sides of the central microfluidic channel inlet, and wherein the outer microfluidic channel inlets are arranged adjacent to the inner microfluidic channel inlets;

an orifice in fluid communication with the at least five microfluidic inlets; and

a microfluidic channel in fluid communication with the orifice;

injecting a first fluid into the central microfluidic channel inlet, a second fluid into the inner microfluidic channel inlets, and a third fluid into the outer microfluidic channel inlets, wherein neighbouring fluids are immiscible;

flowing the first fluid, second fluid, and third fluid through the orifice and into the microfluidic channel, such that the second fluid surrounds the first fluid to form a coaxial stream within the third fluid; and

controlling relative flow rates of each of the first fluid, second fluid, and third fluid, such that during passage of the coaxial stream through the microfluidic channel, the coaxial stream breaks up into segments, thereby forming core/shell fluidic droplets with one or more fluidic cores of the first fluid enveloped by a shell of the second fluid.

2. The process according to claim 1 wherein at least the second fluid comprises a constituent which can harden, and wherein the microfluidic channel is sufficiently long so that at least the shell of each droplet hardens while flowing through the channel, thereby forming core/shell microparticles.

3. The process according to claim 2 wherein the constituent which can harden is hardened by any one of ionic crosslinking, hydrogen bonding, chelation, complexation and combinations thereof.

4. The process according to claim 2 wherein the constituent that can harden comprises a polymerizable constituent, and wherein said shells harden by polymerizing into polymer particles.

5. The process according to claim 1 wherein the microfluidic channel is constructed and configured to produce fluidic droplets having a pre-selected size and or shape.

6. The process according to claim 1 wherein the microfluidic channel has a cross-sectional shape being any one of circular, oval, triangular, irregular, square, and rectangular.

7. The process according to claim 1 wherein the microfluidic channel has an aspect ratio (length to average cross sectional dimension) of at least about 10:

1.

8. The process according to claim 1 wherein a diameter of the fluidic droplets is controlled by controlling one or more of flow rates and flow rate ratios of the fluids, dimensions of said microfluidic channel, properties of the fluids including viscosity and interfacial tension between the fluids, and wherein said microfluidic channel is constructed with pre-selected cross-sectional shape and dimensions to give a desired shape to said fluidic droplets upon transit of said fluidic droplets through said microfluidic channel.

9. The process according to claim 2 wherein said fluidic droplets have a diameter d, and wherein the microfluidic channel is constructed with pre-selected cross-sectional shape and dimensions selected so that d is larger than at least one of the dimensions of the microfluidic channel so that fluidic droplets with non-spherical shapes are formed upon transit through the microfluidic channel with pre-selected cross-sectional shape and dimensions so that microparticles have a non-spherical shape.

10. The process according to claim 9 wherein an aspect ratio for said non-spherical droplets is varied by changing a ratio between fluidic droplet volume and said dimensions of the microfluidic channel.

11. The process according to claim 2 wherein said droplets have a diameter d, and wherein a portion of the microfluidic channel has a width w and a height h, and wherein when said portion of the microfluidic channel is constructed so that w>

d and h>

d, and a flow rate of the droplets through the microfluidic channel is selected to be slow enough so that the microparticles maintain a spherical shape.

12. The process according to claim 2 wherein said fluidic droplets have a diameter d, and wherein a portion of the microfluidic channel has a width w and a height h, and wherein when said portion of the microfluidic channel is constructed so that w>

d and h>

d, and a flow rate of the fluidic droplets through the microfluidic channel is selected to be high enough so that the microparticles acquire an ellipsoidal shape.

13. The process according to claim 2 wherein said fluidic droplets have a diameter d, and wherein a portion of the microfluidic channel has a width w and a height h, and wherein when said portion of the microfluidic channel is constructed with w>

d and h<

d so that the microparticles acquire a discoid shape.

14. The process according to claim 2 wherein said droplets have a diameter d, and wherein a portion of the microfluidic channel has a width w and a height h, and wherein when said portion of the microfluidic channel is constructed with w<

d, h<

d so that the microparticles acquire a rod shape.

15. The process according to claim 1 comprising adjusting a flow rate ratio of each of the first fluid, second fluid, and third fluid to selectively control at least one of size of the cores, a thickness of shells, a size of core-shell fluidic droplets, a number of cores per fluidic droplet.

16. The process according to claim 1 wherein the fluid injected into the two inner microfluidic channel inlets is an oil, and wherein the fluid injected into the two outer microfluidic channel inlets is an aqueous fluid.

17. The process according to claim 1 wherein said coaxial stream is unstable to perturbations with wavelengths larger than a circumference of said coaxial stream which causes the coaxial stream to break up into segments.

18. The process according to claim 1, including controlling a number of cores per fluid droplet by adjusting relative flow rates of the first fluid, second fluid, and third fluid by varying interfacial capillary wavelengths λ

_m and λ

_o, where λ

_m is an interfacial capillary wavelength of said first fluid, and λ

_o is an interfacial capillary wavelength of said second fluid.

19. The process according to claim 2 wherein the constituent which can harden comprises a mixture of two or more monomers, oligomers, liquid polymers or combinations thereof such that said microparticles are copolymer particles.

20. The process according to claim 2 wherein the constituent which can harden comprises a liquid polymer.

21. The process according to claim 1 wherein said microfluidic channel is formed in a microreactor.

22. The process according to claim 21 wherein said microreactor comprises a hydrophilic material.

23. The process according to claim 21 wherein said microreactor comprises a hydrophobic material.

24. The process according to claim 2, wherein said first fluid comprises a constituent selected from the group consisting of organic dyes, chromophores, nonlinear optical compounds, fluorescent dyes, inorganic chemicals, inorganic particles, inorganic pigments, fluorescent inorganic particles, semiconductor nanoparticles, quantum dots, inorganic particles having pre-selected magnetic properties, inorganic particles having pre-selected anti-magnetic properties, inorganic particles having pre-selected electrically conductive and/or semiconducting properties, carbon nanotubes, and liquid crystals, wherein the constituent is incorporated into said microparticles wherein said microparticles are composite hardened particles.

25. The process according to claim 2 wherein said microparticles are monodisperse.

26. The process according to claim 25 wherein no more than approximately 5% of the microparticles have a diameter greater than approximately 5% of the average diameter of all microparticles.

27. The process according to claim 25 wherein no more than approximately 3% of the microparticles have a diameter greater than approximately 10% of the average diameter of all microparticles.

28. The process according to claim 2, wherein the microparticles have an average diameter of less than about 100 micrometers.

29. The process according to claim 2, wherein the microparticles have a shape selected from the group consisting of spherical, disk, rod, oval, ellipsoidal, plates, truncated spheres, hemispheres and bowls.

30. The process according to claim 2, wherein the microparticles are hollow.

31. The process according to claim 2, wherein the microparticles with a core/shell structure have a controlled number of cores.

32. The process according to claim 2, wherein the first fluid further comprises a polymerizable constituent including carbon or carbon-wall nanotubes so that the microparticles are polymer particles having carbon or carbon-wall nanotubes incorporated therein.

33. The process according to claim 2, wherein said first fluid further comprises an unpolymerizable liquid wherein some of said unpolymerizable liquid for producing polymer microparticles having unpolymerizable liquids incorporated into the microparticles.

34. The process according to claim 33, wherein the unpolymerizable liquid is any one of a liquid crystal, a porogen, a dispersion of inorganic or organic particles.

35. The process according to claim 1, wherein said first fluid comprises two or more monomers.

36. The process according to claim 2, wherein said first fluid comprises a biocompatible product including one or more of starch, derivatives, polymers containing 3-hydroxybutyrate and its derivatives, polymers containing 3-hydroxyvalerate and its derivatives, protein, nucleic acids (DNA, RNA), amino acid (peptide), liposomes, agarose and its derivatives, chitosan and its derivatives, alginate and its derivatives, pectin and its derivatives, cellulose derivatives, drugs and their derivatives which are incorporated into said microparticles wherein said microparticles are composite particles.

37. The process according to claim 1 including exposing said fluidic droplets in said microfluidic channel to a polymerizing agent for polymerizing said fluidic droplets.

38. The process according to claim 37 wherein said polymerizing agent is one of heat, ultra-violet light (UV), plasma, irradiation.

39. The process according to claim 1 further comprising exposing said fluidic droplets in said microfluidic channel to an external field selected from the group consisting of a magnetic field, an electric field, light, radiation and combinations thereof.

40. The process according to claim 1 wherein said first fluid includes a gel precursor material that hardens upon chemical or physical crosslinking so that upon hardening the fluidic droplets gel to form microgel particles.

41. The process according to claim 2 wherein said first fluid includes biological cells so that said microparticles contain biological cells.

42. The process according to claim 1 wherein said first fluid comprises two or more monomeric, polymeric or oligomeric constituents, and wherein the fluidic droplets harden in a stepwise manner, the process further comprising exposing said fluidic droplets to polymerizing agents at different positions along said microfluidic channel in a pre-selected sequence to sequentially polymerize the different constituents at different times.

43. The process according to claim 2 wherein production of microparticles is done in a continuous throughput process.

44. The process according to claim 2 wherein the microparticles include cores that are solid.

45. The process according to claim 2 wherein the microparticles include cores are liquids encapsulated by said shell.

46. The process according to claim 1 further comprising forming a two-dimensional lattice of droplets within the microfluidic channel.

47. The process according to claim 2, wherein the microparticles are porous.

48. The process according to claim 1 wherein said microfluidic channel is formed in a microfluidic reactor made of a polyurethane material.