JP4973721B2 - Microparticle structure and method for producing microparticles using the same - Google Patents

Description

The present invention relates to a microchannel structure suitable for producing microparticles such as microdroplets and a method for producing microparticles using the microchannel structure, and more particularly, for a column filler for sorting and separation. The present invention relates to a microchannel structure suitably used for manufacturing gel-like microparticles, microparticles used for microcapsules and the like, and microdroplets, and a method for manufacturing microparticles using the microchannel structure.

In recent years, by using a microchannel structure having a microchannel having a length of about several centimeters on a glass substrate or a resin substrate of several centimeters square and having a width and a depth of sub μm to several hundred μm, Research that produces fine particles by feeding liquids is attracting attention. (For example, see Non-Patent Documents 1 and 2)
As shown in FIGS. 1 (a) and 1 (b), the microchannel of the microchannel structure used for generating the microparticles is formed on the microchannel substrate (1) with the continuous phase inlet (2). T-shaped or Y-shaped having a continuous phase introduction channel (3), a dispersed phase introduction port (4), a dispersed phase introduction channel (5), a discharge channel (16) and a discharge port (18) The shape is used, and the joining portion (6) exists at the portion where the introduced continuous phase and the dispersed phase join together. For example, the depth of the T-shaped micro flow channel shown in FIG. 1A is 100 μm, the width of the introduction flow channel for introducing the dispersed phase is 100 μm, and the width of the introduction flow channel for introducing the continuous phase is 300-500 μm. When liquid is fed using this T-shaped microchannel, the continuous phase fluid shears the dispersed phase fluid at the point where the dispersed phase and the continuous phase merge through the channel, that is, at the junction, Uniform fine particles can be generated, and the particle size can be controlled by changing the flow speed of the dispersed phase and the continuous phase. Further, the depth of the Y-shaped microchannel shown in FIG. 1B is 50 μm, the width of the dispersed phase introduction channel (5), the width of the continuous phase introduction channel (3), and the discharge channel ( The width of 16) is 140 μm. Further, the dispersed phase introduction flow path and the continuous phase introduction flow path merge at an angle of 44 degrees. When liquid feeding is performed using this Y-shaped microchannel, the fluid of the continuous phase shears the fluid of the dispersed phase at the point where the dispersed phase and the continuous phase merge through the introduction channel, that is, at the merged portion. Extremely uniform fine particles can be generated, and the particle size can be changed by changing the flow speed of the dispersed phase and the continuous phase and by changing the merging angle between the dispersed phase introduction channel and the continuous phase introduction channel. Can be controlled.

  However, the minimum value of the particle size of the microparticles that can be controlled by these methods is almost equal to the minimum size of the width or depth of the microchannel. Accordingly, it is theoretically possible to reduce the particle size of the microparticles by reducing the width and depth of the microchannel, but in practice, if the width and depth of the microchannel are reduced, it is usually 1 or less. Since the Reynolds number of the above microchannel having a Reynolds number of smaller is further reduced and a laminar flow is formed more stably, it is very difficult for a continuous phase fluid to shear a dispersed phase fluid, In addition, there is a problem that it is very difficult to produce fine particles having a particle size smaller than about 20 to 30 μm, and further improvement has been demanded.

T.A. NISISAKO et al., “DROPLE FORMATION IN A MICROCHANNEL ON PMMA PLATE”, Micro Total Analysis System 2001, pp. 137-138 A. KAWAI et al., “MASS-PRODUCTION SYSTEM OF NEARLY MONODISPERSE DIAMETER GEL PARTICLES USING DROPLETS FORMATION INA MICROCHANNEL”, Micro Total2

  The present invention has been made in view of the above problems, and uses a microchannel structure that can generate microparticles having a very uniform particle size using a microchannel and smaller than about 20 to 30 μm, and the same. The object is to provide a method for producing fine particles.

In order to solve the above-described problems, the present invention provides a microchannel structure having a microchannel with a microparticle contained in a medium flowing through the microchannel having a cross-sectional area smaller than that of the microchannel. And a method for producing a microparticle, wherein the microparticle is divided into a plurality of microparticles having a volume smaller than that of the microparticles by passing through the microspace branched into a plurality of the microspaces. By providing a microchannel structure, the above-mentioned problems with the conventional technology can be solved, and the present invention has finally been completed.
In the present specification, “microparticles” mean not only microparticles solidified but also liquid microparticles, that is, microdroplets.

  Hereinafter, the present invention will be described in detail.

  The method for producing microparticles in the present invention includes a microchannel for flowing a fluid containing microparticles and a discharge channel communicating with the microchannel, and one or more fluid inlets communicating with the microchannel; A method of producing microparticles using a structure having one or more fluid outlets communicating with the discharge channel, wherein the microparticles in the fluid moving through the microchannels are A microparticle having a cross-sectional area smaller than a cross-sectional area of a road and passing through a plurality of microspaces branched into a plurality of microspaces, the microparticles being divided into the same number as the plurality of microspaces branched into the plurality of microparticles. It is a manufacturing method. In this way, several microparticles having a particle diameter of, for example, about 50 μm or more generated by shearing or the like are passed through a plurality of microspaces having a cross-sectional area smaller than the particle diameter. Can be divided into fine particles. Here, the divided microparticles are smaller than the volume of the microparticles before the division, and smaller microparticles can be generated.

  The method for producing microparticles in the present invention is a method for producing microparticles characterized by repeating the above-described division of microparticles twice or more. By doing so, it is possible to generate smaller particles in a stepwise manner.

  Furthermore, the method for producing microparticles of the present invention has a requirement to form microparticles so that the volume of all the divided microparticles or the particle diameter of the microparticles, or both of them are substantially equal. This is a method for producing fine particles.

  In general, a large number of the above-mentioned divisions can be performed at a time to generate the number of small microparticles divided into one at a time. It is relatively difficult to design the diameter accurately and to manufacture a microchannel, and to generate microparticles with a uniform particle diameter using the design. In order to more accurately and easily control the volume and particle size of the divided microparticles, the number of divisions at one time is most preferably two. Also in this case, by repeating the division into two or more times, it is possible to make the particle size further smaller step by step and to generate fine particles having a uniform particle size.

  Here, the volume of the microparticles or the particle diameter of the microparticles, and both of them being substantially equal means that the degree of dispersion of the microparticles is less than 20%, preferably less than 10%. In addition, the dispersion degree of a microparticle can measure the particle size distribution of the appropriate amount of the obtained microparticle, for example, and can obtain | require as a standard deviation with a statistical method.

  Furthermore, in order to divide the microparticles more accurately, the size of the diameter in the smallest direction of the microparticles to be divided is substantially equal to the smaller one of the width and the depth of the microchannel. More preferably they are equal. This is because if the microparticles before division are smaller than the smaller one of the width and depth of the microchannel, the microparticles move vertically and horizontally in the microchannel, It becomes difficult to accurately divide the microparticles at the branching portion to be divided. That is, the method for producing microparticles of the present invention is characterized in that the size of the diameter of the microparticles in the smallest direction is substantially equal to the smaller one of the width and the depth of the microchannel. This is a method for producing fine particles. Here, the size of the diameter in the smallest direction of the microparticles is substantially equal to the smaller one of the width and the depth of the microchannel. This means that the size is equal to or smaller than the smaller one of the width or depth of the microchannel within a range of 5% or less.

  As described above, as a structure for reducing the space of the microchannel in order to divide the microparticles, a method of installing a porous film in a specific portion of the microchannel can be considered. In order to control the diameter more accurately and uniformly, it is necessary to make the pore size of the porous membrane equal more accurately. However, at the present time, it is very difficult to make all the pore sizes of the porous membrane equal, and even if all the pore sizes of the porous membrane can be made equal, the microparticles have a spherical shape. As described above, depending on the division part of one minute particle, it is divided into different sizes. That is, assuming that the pore sizes of the porous membrane are all equal, the particle size of the microparticle divided at the periphery of the microparticle is smaller than the particle size of the microparticle divided at the center of the microparticle. Therefore, the microchannel structure provided with the porous membrane as described above is not suitable for a method of dividing into fine particles having a more uniform particle diameter.

  Therefore, the microchannel structure according to the present invention includes a microchannel for flowing a fluid containing microparticles and a discharge channel communicating with the microchannel, and introduces one or more fluids communicating with the microchannel. A structure having an outlet and one or more fluid outlets communicating with the outlet passage, wherein the minute passage along the direction in which the fluid flows at a branch portion from the minute passage to the outlet passage The microchannel structure is divided into a plurality of microspaces by a plurality of partition walls having a height substantially equal to the depth. By doing so, the size of dividing the fluid can be accurately controlled by the designed and processed channel structure.

  Further, in the microchannel structure of the present invention, the intervals in the width direction of the microchannels of the plurality of partition walls are arranged such that the plurality of microparticles divided by each partition wall are all divided by an equal volume. A microchannel structure characterized by being designed and processed. That is, by increasing the spacing between the partition walls at the periphery of the microparticles more than the spacing between the partition walls at the center of the microparticles, the volume of the microparticles after splitting, the particle diameter of the microparticles, or both can be made uniform. It becomes possible to divide. Here, the partition wall spacing can be designed by solving a simple integral equation so that the volume of the sphere is divided by the same volume as the number of partition walls.

  FIG. 9 and equation (1) show an example of an integral equation in the case where a microparticle described later is equally divided into four. By solving the equation (1) for the position A that divides the volume of the sphere into four, it is possible to calculate and design the approximate position of the partition wall formed in the microchannel.

  That is, from FIG. 9, the volume of a sphere can be obtained by setting the x-axis passing through the center of the sphere and integrating the area of a circle that intersects the sphere x-axis at right angles. The radius of the circle can be determined by the three square theorem from the x-axis variable x and the sphere radius r. Now, it is assumed that a sphere having a radius r in FIG. 9 passes through a microchannel having a width 2r and a depth 2r. If the coordinate of x that bisects the volume of the hemispherical part is A, the coordinate A can be obtained by equation (1). That is, Expression (1) is an expression indicating that the volume of the sphere having coordinates from the center of the sphere to A is equal to the volume of the sphere from coordinates A to the end r of the sphere. When the sphere radius is normalized by 1 and solved, A is about 0.34 (34%). For example, when the flow path width is 100 μm, the radius of the sphere corresponds to 50 μm. Therefore, if the flow path is partitioned at 34% of 50 μm, that is, 17 μm from the center of the micro flow path, the volume of one half of the sphere Can be divided in half by a partition wall.

  In addition, as described above, it is possible to more accurately and easily divide the microparticles into two by dividing the microparticles into two to reduce the particle size, so that the microfluids flow in the direction in which the fluid flows. More preferably, a plurality of partition walls having a height substantially equal to the depth of the path are present at the center of the microchannel. If this structure is repeated two or more times, it is possible to produce finer particles having a smaller uniform particle size.

  In addition, the thickness of the partition wall described above is more preferably an acute angle in the direction opposite to the fluid traveling direction. By adopting such a structure, it is possible to obtain an effect of cutting fine particles with a knife, and it is possible to divide into fine particles having a more uniform particle diameter.

  As a form of the partition wall (9), as shown in FIG. 2 (a), it may be a wall-like shape formed in a minute flow path, or as shown in FIG. 2 (b). The shape may be such that the microchannel is branched into branches, and there is no particular limitation.

  Further, the microchannel structure of the present invention may have a structure in which the branched microspaces join again without the above-described microparticles divided into a plurality. By doing in this way, it becomes easy to collect | recover the divided | segmented microparticles by one flow path. However, when the microchannel (11) having the structure shown in FIG. 3 (a) is branched at the branching portion (10), the divided microparticles are merged at the joining portion (6). There is a high possibility that the microparticles will collide with each other and coalesce. Therefore, as shown in FIG. 3 (b), the microchannels are joined again at the merging portion (6) by changing the length of the microchannel where the microchannel (11) is branched at the branching portion (10). Even if it makes it, it becomes possible to avoid the collision at the confluence of the fine particles.

  In the microchannel structure of the present invention, the width or depth of the microchannel in the vicinity immediately before the plurality of partition walls are formed is narrower than other portions of the microchannel. This is a microchannel structure. An example of this mode is shown in FIG. By doing in this way, since the vertical and horizontal vibrations of the microparticles immediately before the division can be suppressed as much as possible, it becomes possible to divide the microparticles more accurately and evenly at the partition wall portion.

  In addition, the manufacturing method of the microparticle before the division | segmentation in this invention does not have a restriction | limiting in particular. For example, as described in Non-Patent Document 1 and Non-Patent Document 2, fine particles may be formed by shearing a dispersed phase fluid with a continuous phase fluid at a portion where two phase fluids merge, The two phases may be suspended to form microparticles and then introduced into the microchannel structure of the present invention. Alternatively, the organic phase and the aqueous phase may be alternately sent in a time-sharing manner to one introduction flow path, so that the organic phase or the aqueous phase may be sent in a segment shape. However, if the particle size of the microparticles before the division is uniform, the particles can be divided into more uniform microparticles. If the particles are formed in the microchannel, the microparticles of the present invention are formed downstream of the microchannel. Considering that it is possible to easily further reduce the diameter of the microparticles by adding the structure of the flow channel structure, the method for generating the microparticles before the division is shown in FIGS. 1 (a) and (b). It is more preferable that the method is as described in Non-Patent Document 1 or Non-Patent Document 2. In this case, a mode of a microchannel structure as shown in FIG. 5 can be considered as an example, but it should be understood that the mode is not limited to this mode as long as it does not depart from the gist of the present invention.

  The microchannel structure of the present invention has the structure and performance described above, but as shown in FIG. 6, a substrate in which microchannels partitioned by a partition wall are formed on a microchannel substrate. And at least two or more small holes for communicating the microchannel and the outside of the microchannel structure are disposed at predetermined positions of the microchannel so as to cover the substrate surface on which the microchannel is formed. The cover body may be laminated and integrated. Thereby, the fluid containing particles is introduced from the outside of the microchannel structure into the microchannel, and the liquid containing the particles divided after passing through the microchannel structure can be discharged again to the outside of the microchannel structure. It is possible to allow the liquid containing the particles to pass through the microchannel stably. The liquid containing the particles may be fed using mechanical means such as a plunger pump or a pressure feed pump, and the means is not particularly limited.

  As the material of the substrate and the cover body on which the microchannel is formed, it is desirable that the microchannel can be formed, has excellent chemical resistance, and has an appropriate rigidity. For example, glass, quartz, ceramic, silicon, or metal or resin may be used. The size and shape of the substrate and cover body are not particularly limited, but the thickness is preferably about several mm or less. The small holes arranged in the cover body communicate with the microchannel and the outside of the microchannel structure, and when used as a fluid inlet or outlet, the diameter is preferably, for example, several mm or less. The small holes in the cover body can be processed chemically, mechanically, or by various means such as laser irradiation or ion etching.

  Further, in the microchannel structure of the present invention, the substrate on which the microchannel is formed and the cover body are laminated and integrated by means such as heat treatment bonding or adhesion using an adhesive such as photo-curing resin or thermosetting resin. be able to.

The present invention has the following effects.
According to the method for producing microparticles in the present invention, in a microchannel structure having microchannels, the microparticles contained in the medium flowing through the microchannels have a cross-sectional area smaller than the cross-sectional area of the microchannels. In addition, by passing through a plurality of minute spaces branched, it becomes possible to divide into minute particles having a volume smaller than that of the minute particles by the same number as the number of minute spaces branched into the plurality. By passing fine particles generated by shearing, for example, having a particle size of about 50 μm or more into a plurality of fine spaces having a cross-sectional area smaller than the particle size, one fine particle is divided into several fine particles. The divided microparticles are smaller than the volume of the microparticles before the division, so that smaller microparticles can be generated.

  Further, by the method for producing fine particles according to the present invention, the above-mentioned fine particle division is repeated twice or more, whereby even smaller fine particles can be generated stepwise.

  Further, according to the method for producing fine particles of the present invention, the number of divisions at one time is divided into two, and the two divisions are repeated two or more times, so that the particle size is further reduced stepwise so that all the divided fine particles are obtained. The microparticles can be formed so that the volume and / or the particle diameter of the microparticles are substantially equal.

  Furthermore, by the method for producing microparticles of the present invention, the size of the smallest direction of the microparticles to be divided is made substantially equal to the smaller one of the width and the depth of the microchannel. Thus, it is possible to divide the fine particles more accurately and evenly by suppressing the vertical and horizontal movements of the fine particles before the division.

  A microchannel structure in which a plurality of partition walls having a height substantially equal to the depth of the microchannel are formed by micromachining along the direction of fluid flow, and the interior of the microchannel is divided into a plurality of microspaces By using the body, the size of dividing the fluid can be accurately controlled by the designed and processed channel structure.

  In addition, a plurality of microparticles divided by each partition wall can be divided into substantially equal volumes and / or particle diameters so that the microparticles can be separated from the partition wall spacing at the center of the microparticles. By using a microchannel structure that is designed and processed so that the interval between the partition walls in the periphery is widened, it is possible to divide the volume and / or particle size of the microparticles substantially evenly and uniformly. It becomes.

  In addition, by using a microchannel structure in which the width or depth of the microchannel in the vicinity immediately before a plurality of partition walls is formed is narrower than other parts of the microchannel, Since vibrations in the vertical and horizontal directions can be suppressed as much as possible, it becomes possible to divide the microparticles more accurately and evenly in the partition wall portion.

  In addition, by using the microparticle generation method of the present invention and the microchannel structure therefor, it is possible to generate microparticles having a particle diameter smaller than the channel width of the microchannel in the microchannel. As a ripple effect of the invention, when the microparticle is a droplet, the specific surface area with the medium around the droplet is more than the specific surface area when a two-liquid laminar flow is formed in the microchannel. Therefore, using this micro droplet, the reaction rate between the reaction substrate contained in the droplet and the reaction substrate contained in the surrounding medium can be improved, and the droplet and the surrounding medium can be improved. The effect of improving the extraction speed in solvent extraction can be expected.

  Hereinafter, examples of the present invention will be described, and the embodiments of the invention will be described in more detail. It is needless to say that the present invention is not limited to the following examples and can be arbitrarily changed without departing from the gist of the present invention.

  The microchannel structure used in the first embodiment of the present invention is shown in FIG. The microchannel is formed on a microchannel substrate (1) made of Pyrex (registered trademark) of 70 mm × 38 mm × 1 mm (thickness) by general photolithography and wet etching. A Pyrex (registered trademark) board of the same size provided with a small hole (12) having a diameter of 0.6 mm by a mechanical processing means at a position corresponding to two discharge ports (18) is used as a cover body (17) for heat fusion. The microchannels were sealed by bonding by wearing. The formed microchannel has a depth of 20 μm, the width of the introduction channel (14) communicating from the introduction port is 100 μm, and the discharge channel (16) branched into two at the branching portion (10) from the introduction channel. Each width is 50 μm. Further, as shown in FIG. 6B, the flow path width of the 50 μm portion immediately before the branching portion was narrowed to 90 μm from both sides. As shown in FIG. 4 (b), the discharge channel branching form at the branching portion is a curved shape with a radius of curvature of 20 mm, and is processed so as to gradually and gradually branch from the branching portion. Further, by branching in this way, the tip of the branching portion could be formed in an acute angle like a knife in the direction opposite to the fluid traveling direction.

  A fluid containing microparticles having an average particle diameter of about 100 μm and a dispersion degree of 9.6% was introduced from the introduction port (17) of the microchannel. As a method for introducing a fluid containing microparticles, a microchannel structure (24) is held by a holder (20) or the like so that fluid can be fed as shown in FIG. (Trademark) Tube (22) and fillet joint (21) were fixed to the holder. The other end of the Teflon (registered trademark) tube connected to the introduction port was connected to a microsyringe pump (23), and a fluid containing microparticles was introduced into the microchannel by this microsyringe pump. The fluid containing the fine particles actually used is a fluid of 3% aqueous solution of polyvinyl alcohol containing 100 μm fine particles made of divinylbenzene and butyl acetate. The liquid feeding speed was 10 μl / min. The fine particles are divided into two at the branching portion (10) through the introduction flow path (14) in a stable liquid flow rate state, and are fixed to the two discharge ports (18) via the discharge flow path (16). The beaker (27) was recovered through a fillet joint and a Teflon tube.

  When the divided fine particles were observed, they were almost spherical particles. Further, when 100 fine particles were taken and the particle size was measured, the average particle size was 52 μm and the degree of dispersion was 9.8%, and the particles were very uniform in particle size distribution.

(Comparative Example 1)
The microchannel structure used in the first comparative example for the first embodiment of the present invention is shown in FIG. The microchannel structure was manufactured in the same manner as in Example 1. The formed microchannel has a depth of 20 μm, the width of the introduction channel (14) communicating from the introduction port is 120 μm, and the discharge channel (16) branched into two at the branching portion (10) from the introduction channel. Each width is 50 μm. As shown in FIG. 8B, the form of branching of the discharge flow path in the branching portion was a curved shape having a curvature radius of 20 mm, and was processed so as to gradually and gradually branch from the branching portion. Further, by branching in this way, the tip of the branching portion could be formed in an acute angle like a knife in the direction opposite to the fluid traveling direction.

  A fluid containing microparticles having an average particle diameter of about 100 μm and a dispersion degree of 9.6% was introduced from the introduction port (17) of the microchannel. The components of the fluid containing fine particles and the method for introducing them were the same as in Example 1. The particles were divided into two at the branching portion (10) through the introduction flow path (14) in a stable liquid flow rate state, and fixed to the two discharge ports (18) via the discharge flow path (16). It was collected in a beaker (27) through a fillet joint and a Teflon tube.

  When 100 divided fine particles were taken and the particle size was measured, the average particle size was 51 μm and the degree of dispersion was 30%, and it was not possible to obtain fine particles with a uniform particle size of 20% or less.

  The microchannel structure used in the second embodiment of the present invention is shown in FIG. The microchannel structure was manufactured in the same manner as in Example 1. The depth of the micro channel is 5 μm, the channel width of the introduction channel (14) communicating from the introduction port (17) is about 150 μm, and the first branch part (13) branches from the introduction channel into two. The first branch channel (15) has a channel width of about 75 μm, and the second branch channel (28) is further branched into two at the second branch part (26) from the first branch channel. The third branch flow path A (30), B (31), C (each of which has a flow path width of about 35 μm and is further branched into two at the third branch portion (29) from the second branch flow path. 32), D (33), E (34), F (35), G (36), and H (37) were designed to have a channel width of about 18 μm. As shown in FIG. 6B, the branch form of the discharge flow path in each branch portion is a curved shape having a curvature radius of 20 mm and is processed so as to gradually and gradually branch from the branch portion. The tip of this was formed into a knife-like acute angle in the direction opposite to the fluid traveling direction. Moreover, the flow path width just before a branch part was made into the shape which squeezed about 5% of width | variety from both sides like Example 1. FIG.

  The third branch channel finally divided into eight was joined at one place at the discharge port (18). When merging, in order to avoid collision of fine particles at the merging portion, the flow path length from the third branching portion (29) to the discharge port (18) was changed by 1000 μm and merged with the discharge port. That is, the length of the third branch channel A is the same as that of the third branch channel A (30) in front of FIG. The length of the third branch flow path C (32) adjacent to the length is 249 mm, the length of the third branch flow path D (33) adjacent to the length is 247 mm, and the third branch next to the length is 247 mm. The length of the flow path E (34) is 246 mm, the length of the adjacent third branch flow path F (35) is 245 mm, the length of the adjacent third branch flow path G (36) is 244 mm, The length of the adjacent third branch flow path H (37) was 243 mm. In the same manner as in Example 1, the fluid containing microparticles was a fluid of 3% aqueous solution of polyvinyl alcohol containing 150 μm microparticles composed of divinylbenzene and butyl acetate. It was introduced into the body's microchannel. The liquid feeding speed was 5 μl / min. The microparticles divided into two at the first branch part through the introduction flow path (38) in a stable liquid flow rate state are again divided into two at the second branch part and further divided into two at the third branch part. It was.

  As described above, when the microparticles obtained from the third branch portion (10) branched into eight via the discharge channel (16) and the discharge port (18) were observed, there were. When 100 fine particles were taken and the particle size was measured, the average particle size was about 17 μm, the degree of dispersion was 9.6%, and the particles were extremely uniform in particle size distribution.

The microchannel structure used in the third embodiment of the present invention is shown in FIG. The micro-channel has two inlets and two outlets formed by general photolithography and wet etching on a Pyrex (registered trademark) micro-channel substrate (1) of 70 mm × 38 mm × 1 mm (thickness). A double Y-shaped microchannel was formed. A Pyrex (registered trademark) board of the same size, in which small holes (12) having a diameter of 0.6 mm are provided by mechanical processing means at positions corresponding to the two inlets (17) and the two outlets (18). The microchannel was sealed by joining as a cover body (19) by heat sealing. The formed microchannel has a depth of 20 μm, a width of the introduction channel (14) communicating from the two introduction ports is 120 μm, and the introduction channel is a microchannel (11 having a channel width of 100 μm at the junction (6). ) And the respective introduction flow paths merge at an angle of 22 degrees with respect to the fine flow paths. Moreover, the width of the discharge flow path (16) branched into two in the branch part (10) from the micro flow path is 50 μm. The form of branching of the discharge channel at the branching portion is a curved shape with a curvature radius of 20 mm as shown in FIG. 5B as in the first embodiment, and is processed so as to gradually and gradually branch from the branching portion. The tip of the branching portion was formed in a knife-like acute angle in the direction opposite to the fluid traveling direction. Further, as shown in FIG. 5B, the channel width of the 50 μm portion immediately before the branching portion was narrowed to 90 μm from both sides in the same manner as in Example 1.

  From one of the two inlets (17) of the microchannel, a 3% aqueous solution of polyvinyl alcohol is introduced into the microchannel as a continuous aqueous phase, and a dispersed phase is introduced from the other inlet. A mixed solution of divinylbenzene and butyl acetate was introduced as the organic phase. As in the first and second embodiments, the fluid is introduced by using a holder (20) or the like so that the fluid can be fed through the microchannel structure (24) as shown in FIG. 5 (a). While holding, the Teflon (R) tube (22) and the fillet joint (21) are fixed to the holder, and the other Teflon (R) tube connected to the inlet is connected to the microsyringe pump (23). The fluid was introduced into the microchannel in the microchannel structure by this microsyringe pump. The liquid feeding speed was 20 μl / min for both the dispersed phase and the continuous phase. In a state where the liquid feeding speed is stable, the introduction flow channel introducing the dispersed phase and the introduction flow channel introducing the continuous phase merge at the joining portion of the micro flow channel, and the organic phase in which the continuous aqueous phase is the dispersed phase Formation of liquid fine particles (hereinafter referred to as droplets) was observed by shearing the phases. This droplet flows through the microchannel as it is, and when it reaches the bifurcation, it is divided into two, and is connected to the two discharge ports (18) via the discharge channel (16) and Teflon (registered trademark). ) It was collected into a beaker (27) through a tube.

  Observation of the divided fine particles revealed that the particles were spherical. When 100 fine particles were taken and the particle size thereof was measured, the average particle size was 55 μm, the degree of dispersion was 9.0%, and the particles were extremely uniform in particle size distribution.

  FIG. 7A shows the microchannel structure used in the fourth example of the present invention. The microchannel structure was manufactured in the same manner as in Example 1. The depth of the micro channel is 20 μm, the channel width of the introduction channel (14) communicating from the introduction port (17) is about 100 μm, and the branch channel (10) has four discharge channels ( Branched 16). As shown in FIG. 7 (b), the width of the discharge channel is set such that the width of the two discharge channels on the outside is about 32 μm and the width of the two inner discharge channels is about 18 μm. The path is curved with a radius of curvature of 20 mm and the two outer discharge channels are curved with a radius of curvature of 15 mm, and are processed so as to gradually and gradually branch off from the branch part, and the tip of the branch part is opposite to the fluid traveling direction. A sharp angle was formed in the direction of a knife. Further, as shown in FIG. 7B, the flow path width of the 50 μm portion immediately before the branching portion was narrowed to 90 μm from both sides as in Example 1. Each width of the discharge channel is calculated from the figure shown in FIG. 9 and the formula (1) shown below so that the volume of the sphere when the droplet is a perfect sphere is divided into four equal parts. The value of A was solved and calculated.

  That is, from FIG. 9, the volume of a sphere can be obtained by setting the x-axis passing through the center of the sphere and integrating the area of a circle that intersects the sphere x-axis at right angles. The radius of the circle can be determined by the three square theorem from the x-axis variable x and the sphere radius r. Now, it is assumed that a sphere having a radius r in FIG. 9 passes through a microchannel having a width 2r and a depth 2r. If the coordinate of x that bisects the volume of the hemispherical part is A, the coordinate A can be obtained by equation (1). That is, Expression (1) is an expression indicating that the volume of the sphere having coordinates from the center of the sphere to A is equal to the volume of the sphere from coordinates A to the end r of the sphere. When the sphere radius is normalized by 1 and solved, A is about 0.34 (34%). For example, when the flow path width is 100 μm, the radius of the sphere corresponds to 50 μm. Therefore, if the flow path is partitioned at 34% of 50 μm, that is, 17 μm from the center of the micro flow path, the volume of one half of the sphere Can be divided in half by a partition wall.

  The fluid containing microparticles was a fluid of 3% polyvinyl alcohol solution containing 100 μm microparticles composed of divinylbenzene and butyl acetate as in Example 1, and a microchannel structure by the same method as in Example 1. Introduced into the microchannel. The liquid feeding speed was 10 μl / min. The fine particles were divided into four at the branching portion through the introduction flow path (14) at a stable liquid feeding speed.

  Observation of the obtained fine particles revealed that the particles were spherical. When 100 fine particles were taken and the particle size was measured, the average particle size was about 26 μm, the degree of dispersion was about 9.2%, and the particles were very uniform in particle size distribution.

(Comparative Example 2)
The microchannel structure used in the second comparative example with respect to the fourth embodiment of the present invention is shown in FIG. The flow channel structure was manufactured in the same manner as in Example 1. The depth of the micro channel is 20 μm, the channel width of the introduction channel (14) communicating from the introduction port (17) is about 100 μm, and the branch channel (10) has four discharge channels ( Branched 16). Basically, the microchannel structure is the same as in Example 4, but the widths of the discharge channels are all 25 μm. Further, as shown in FIG. 10B, the inner two discharge channels have a curved shape with a radius of curvature of 20 mm and the outer two discharge channels have a curved shape with a radius of curvature of 15 mm, and gradually and gradually branch from the branching portion. The tip of the branching portion was formed into a knife-like acute angle in the direction opposite to the fluid traveling direction. Further, as shown in FIG. 10B, the flow path width of the 50 μm portion immediately before the branching portion was narrowed to 90 μm from both sides as in Example 1.

  The fluid containing microparticles was a fluid of 3% polyvinyl alcohol solution containing 100 μm microparticles composed of divinylbenzene and butyl acetate as in Example 1, and a microchannel structure by the same method as in Example 1. Introduced into the microchannel. The liquid feeding speed was 10 μl / min. When 100 fine particles divided into four at the branching portion through the introduction channel (14) in a stable liquid flow rate state were taken and measured for the particle size, the average particle size of the fine particles was about 26 μm. The peaks indicating the particle size distribution are present in the vicinity of about 35 μm and about 15 μm, the degree of dispersion is about 38%, and it was impossible to obtain fine particles with a very uniform particle size distribution with a degree of dispersion of 20% or less. .

It is the figure which showed the conceptual diagram of the microparticle production | generation method using the conventional microchannel structure, (a) shows the conceptual diagram of the microparticle production | generation method using a T-shaped microchannel, (b ) Is a conceptual diagram of a microparticle generation method using a Y-shaped microchannel. It is a conceptual diagram of the typical shape of the aspect of the partition wall formed in the microchannel in this invention. (A) is a conceptual diagram of a plate-shaped partition wall, (b) is a conceptual diagram of the partition wall when the discharge flow path is branched into branches. It is the figure which made the mode when the microchannel was merged again after dividing the microparticle in the bifurcation part. (A) The microparticle divided at the junction of the microchannel may collide and be united. FIG. 4B is a conceptual diagram of a highly minute microchannel, in which (b) represents a microparticle that can avoid collision of microparticles at the junction of the microchannel by changing the channel length of each branched microchannel. It is a conceptual diagram of a flow path. It is the schematic which shows the microchannel structure used for the 1st Example of this invention. (A) is the figure which showed the used microchannel structure and the liquid feeding method to a microchannel, (b) is the schematic of the top view in the branch part of a microchannel. It is the schematic which shows the microchannel structure used for the 3rd Example of this invention. (A) is the figure which showed the used microchannel structure and the liquid feeding method to a microchannel, (b) is the schematic of the top view in the branch part of a microchannel. It is the schematic which shows the microchannel structure used for the 2nd Example of this invention. (A) is the figure which showed the used microchannel structure and the liquid feeding method to a microchannel, (b) is the schematic of the top view in the branch part of a microchannel. It is the schematic which shows the microchannel structure used for the 4th Example of this invention. (A) is the figure which showed the used microchannel structure and the liquid feeding method to a microchannel, (b) is the schematic of the top view in the branch part of a microchannel. It is the schematic which shows the microchannel structure used for the 1st comparative example of this invention. (A) is the figure which showed the used microchannel structure and the liquid feeding method to a microchannel, (b) is the schematic of the top view in the branch part of a microchannel. It is a figure for deriving the integral equation for calculating and designing the position in the minute channel of the partition wall for dividing the volume of a sphere by the volume equal to the number of partition walls. It is the schematic which shows the microchannel structure used for the 2nd comparative example of this invention. (A) is the figure which showed the used microchannel structure and the liquid feeding method to a microchannel, (b) is the schematic of the top view in the branch part of a microchannel.

1: Microchannel substrate 2: Continuous phase inlet port 3: Continuous phase inlet channel 4: Dispersed phase inlet port 5: Dispersed phase inlet channel 6: Junction portion 7: Ideal sphere 8 showing the microparticles before division: Ideal Partition wall position for dividing the sphere into four equal volumes in the Y-axis direction 9: Partition wall 10: Branching portion 11: Micro flow channel 12: Small hole 13: First branching portion 14: Introduction flow channel 15: No. 1 branch channel 16: discharge channel 17: introduction port 18: discharge port 19: cover body 20: holder 21: fillet joint 22: Teflon (registered trademark) tube 23: micro syringe pump 24: micro channel structure 25 : Microsyringe pump driver 26: 2nd branch part 27: Beaker 28: 2nd branch flow path 29: 3rd branch part 30: 3rd branch flow path A
31: Third branch flow path B
32: Third branch flow path C
33: Third branch flow path D
34: Third branch flow path E
35: Third branch flow path F
36: Third branch channel G
37: Third branch flow path H

Claims (2)

One or more inlets of one or more fluids that communicate with the microchannels and one or more fluid inlets that communicate with the microchannels, and a microchannel for flowing a fluid containing microparticles A method for producing microparticles using a structure having a fluid discharge port, wherein a liquid small particle in a fluid moving through the microchannel is smaller in cross-sectional area than the microchannel And a fine particle manufacturing method, wherein the fine particles are divided so that the degree of dispersion of the particle size of the liquid fine particles after passing is less than 20%. The method for producing fine particles according to claim 1, wherein the division is repeated twice or more.

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