JP2012139621A - Microchannel structure and method of manufacturing fine particle using the same - Google Patents

Microchannel structure and method of manufacturing fine particle using the same Download PDF

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JP2012139621A
JP2012139621A JP2010292717A JP2010292717A JP2012139621A JP 2012139621 A JP2012139621 A JP 2012139621A JP 2010292717 A JP2010292717 A JP 2010292717A JP 2010292717 A JP2010292717 A JP 2010292717A JP 2012139621 A JP2012139621 A JP 2012139621A
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channel
continuous phase
dispersed phase
fluid
phase introduction
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JP5625900B2 (en
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Hideaki Kiritani
英昭 桐谷
Hiroki Takamiya
裕樹 高宮
Katsuyuki Hara
克幸 原
Koji Katayama
晃治 片山
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Tosoh Corp
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Abstract

PROBLEM TO BE SOLVED: To provide a microchannel structure having a microchannel for stably producing a large amount of fine particles in a uniform size and a method of manufacturing fine particles using the same.SOLUTION: A microchannel structure includes a continuous phase introduction channel for introducing a fluid that becomes a continuous phase, a dispersed phase introduction channel which is provided for introducing a fluid that becomes a dispersed phase, and is merged with the continuous phase introduction channel, and a discharge channel which is formed in a joint part where the dispersed phase introduction channel is merged with the continuous phase introduction channel, for discharging a fluid containing fine particles of the dispersed phase. The microchannel structure is comprised of quartz glass and characterized in that at least surface coarseness Ra of a wall surface of the discharge channel is 10.0 nm or more.

Description

本発明は、相溶しない流体を均一かつ大量に導入させ、分取・分離用カラム充填剤や、医薬品、含酵素カプセル、化粧品、香料、表示・記録材料、接着剤及び農薬等に利用されるマイクロカプセル等の微小粒子を均一な大きさで安定して大量に製造する際に用いられる微小流路構造体に関する。また、本発明は、該微小流路構造体を用いた微小粒子の製造方法に関する。   INDUSTRIAL APPLICABILITY The present invention introduces incompatible fluids uniformly and in large quantities, and is used for column fillers for separation and separation, pharmaceuticals, enzyme-containing capsules, cosmetics, fragrances, display / recording materials, adhesives, agricultural chemicals, and the like The present invention relates to a microchannel structure used when a large amount of microparticles such as microcapsules is stably manufactured in a uniform size. The present invention also relates to a method for producing microparticles using the microchannel structure.

近年、数ｃｍ角のガラス基板上に長さが数ｃｍ程度で、幅と深さがサブμｍから数百μｍの微小流路を有する微小流路構造体を用い、流体を微小流路へ導入することにより、化学反応を行わせる研究あるいは微小粒子の生成を行わせる研究が注目されている。このような微小流路では、微小流路中の微小空間が短い分子間距離および大きな比界面積を有していることにより、効率の良い化学反応を行なわせることができることが知られている（例えば、非特許文献１）。
また、界面張力の異なる２種類の液体を、交差部分が存在する流路に導入することにより粒径が極めて均一な微小粒子を作製できることが知られている（例えば、非特許文献２、特許文献１及び特許文献２）。 In recent years, a fluid is introduced into a microchannel using a microchannel structure having a microchannel having a length of about several centimeters on a glass substrate of several cm square and a width and depth of sub-μm to several hundred μm. By doing so, research that causes chemical reaction or research that produces fine particles has been attracting attention. In such a microchannel, it is known that an efficient chemical reaction can be performed because the microspace in the microchannel has a short intermolecular distance and a large specific interface area ( For example, Non-Patent Document 1).
In addition, it is known that microparticles having extremely uniform particle diameters can be produced by introducing two types of liquids having different interfacial tensions into a channel having an intersecting portion (for example, Non-Patent Document 2, Patent Document). 1 and Patent Document 2).

また、前述した微小流路の空間の特性を生かし、微小流路内での化学処理や微小流路内での微小粒子の生産を工業的に利用しようとする試みも行われている。この場合、微小流路の空間の小ささ故に、単一の微小流路では、単位時間当りの目的の生成物の生成量が少なくならざるを得ないが、多数の微小流路を並列に配置させることで、前記微小流路の特性を生かしたまま単位時間当たりの目的の生成物の生成量を増加させることができる（例えば、非特許文献３及び非特許文献４）。   In addition, attempts have been made to industrially utilize the chemical treatment in the microchannel and the production of microparticles in the microchannel by making use of the characteristics of the space of the microchannel described above. In this case, due to the small space of the microchannels, the amount of target product produced per unit time must be reduced with a single microchannel, but many microchannels are arranged in parallel. By doing so, the production amount of the target product per unit time can be increased while taking advantage of the characteristics of the microchannel (for example, Non-Patent Document 3 and Non-Patent Document 4).

非特許文献３に示されるように、１本の微小流路を有する複数の微小流路基板を、反応溶液の入り口や反応生成物の出口などの共通部分を貫通した縦穴でつないで積層することなどが試みられている。このように、微小流路の空間の特徴を生かし、化学合成や微小粒子の生成を大量に行なうことは、最小単位である微小流路の密度を平面的に高めたり、あるいは基盤を立体的に積層して微小流路の数を増やすことで可能であると言われている。例えば、微小流路構造体を使って化学処理を行う、あるいは、微小粒子を製造するための化学プラントに用いられるマイクロ化学装置としては、多数の微小流路を集積した微小流路構造体が挙げられる。このようなマイクロ化学装置では、原料の供給と生成物の回収がシステム化されている（例えば特許文献３参照）。   As shown in Non-Patent Document 3, a plurality of micro-channel substrates having one micro-channel are stacked by connecting through vertical holes penetrating common parts such as an inlet of a reaction solution and an outlet of a reaction product. Etc. have been tried. In this way, taking advantage of the characteristics of the space of the microchannel, and performing large amounts of chemical synthesis and generation of microparticles, the density of the microchannel, which is the smallest unit, can be increased planarly, or the base can be three-dimensionally It is said that this is possible by stacking and increasing the number of microchannels. For example, as a microchemical apparatus used in a chemical plant for performing chemical treatment using a microchannel structure or manufacturing microparticles, there is a microchannel structure in which a large number of microchannels are integrated. It is done. In such a microchemical apparatus, supply of raw materials and recovery of products are systemized (for example, see Patent Document 3).

しかしながら、このような微小流路構造体を用いて、精密な化学反応や混合を起こさせたり、微粒子を生成させるシステムであっても、各々の微小流路での単位時間当りの目的物の生成量が少ないために微小流路構造体全体としての生成量を増加させることが難しいという課題があり、改善が求められていた。   However, even in a system that uses such a microchannel structure to cause precise chemical reaction and mixing, or to generate fine particles, the production of the target object per unit time in each microchannel Since the amount is small, there is a problem that it is difficult to increase the generation amount of the entire microchannel structure, and improvement has been demanded.

特許第２９７５９４３号公報Japanese Patent No. 2975943 特許第３７４６７６６号公報Japanese Patent No. 3746766 特許第４０３２１２８号公報Japanese Patent No. 4032128

Ｈ．Ｈｉｓａｍｏｔｏ ｅｔ．ａｌ．（Ｈ．ひさもと ら著）「Ｆａｓｔ ａｎｄ ｈｉｇｈ ｃｏｎｖｅｒｓｉｏｎ ｐｈａｓｅ−ｔｒａｎｓｆｅｒ ｓｙｎｔｈｅｓｉｓ ｅｘｐｌｏｉｔｉｎｇ ｔｈｅ ｌｉｑｕｉｄ−ｌｉｑｕｉｄ ｉｎｔｅｒｆａｃｅ ｆｏｒｍｅｄ ｉｎ ａ ｍｉｃｒｏｃｈａｎｎｅｌ ｃｈｉｐ」， Ｃｈｅｍ．Ｃｏｍｍｕｎ．， ２６６２−２６６３頁， ２００１年発行H. Hisamoto et. al. (H. Hisamoto et al.) “Fast and high conversion phase-transfer synthesis exploitation the liquid-liquid interface formed in a microchannel chip”, Chem. Commun. , 2662-2663, published 2001 西迫貴志ら、「マイクロチャネルにおける液中微小液滴生成」、第４回化学とマイクロシステム研究会講演予稿集、５９頁、２００１年発行Takashi Nishisako et al., “Liquid microdroplet generation in microchannels”, Proceedings of the 4th Chemistry and Microsystem Study Group, 59 pages, 2001 菊谷ら、「パイルアップマイクロリアクターによる高収量マイクロチャンネル内合成」、第３回化学とマイクロシステム研究会公演予稿集、９頁、２００１年発行Kikutani et al., “High-yield microchannel synthesis using pile-up microreactors”, Proceedings of the 3rd Chemistry and Microsystem Research Meeting, 9 pages, 2001 Ａ．Ｋａｗａｉ ｅｔ．ａｌ．「ＭＡＳＳ−ＰＲＯＤＵＣＴＩＯＮ ＳＹＳＴＥＭ ＯＦ ＮＥＡＲＬＹ ＭＯＮＯＤＩＳＰＥＲＳＥ ＤＩＡＭＥＴＥＲ ＧＥＬ ＰＡＲＴＩＣＬＥＳ ＵＳＩＮＧ ＤＲＯＰＬＥＴＳ ＦＯＲＭＡＴＩＯＮ ＩＮ Ａ ＭＩＣＲＯＣＨＡＮＮＥＬ」，μ−ＴＡＳ ２００２ ｖｏｌ．１ ３６８−３７０頁、 ２００２年発行A. Kawai et. al. “MASS-PRODUCTION SYSTEM OF NEARLY MONODISPERSE DIAMETER GEL PARTICLES USING DROPLETS FORMATION IN A MICROCHANNEL”, μ-TAS 2002 vol. 1 pp. 368-370, published in 2002

本発明の目的は、かかる従来の実情に鑑みて提案されたものであり、均一な大きさの微小粒子を安定して大量に生成させるための微小流路を有する微小流路構造体およびそれを用いた微小粒子の製造方法を提供することにある。   An object of the present invention has been proposed in view of the conventional situation, and a microchannel structure having a microchannel for stably generating a large amount of microparticles of a uniform size and the same. The object is to provide a method for producing the fine particles used.

本発明者らは、連続相となる流体を導入するための連続相導入流路と、分散相となる流体を導入するための、前記連続相導入流路に合流する分散相導入流路と、前記分散相導入流路が前記連続相導入流路に合流する合流部において形成される前記分散相の微小粒子を含む流体を排出するための排出流路と、を有する微小流路構造体であって、前記微小流路構造体は石英ガラスからなり、少なくとも前記合流部における流路壁面の表面粗さＲａが１０．０ｎｍ以上であることにより、上記の従来技術の課題を解決することができることを見出し、遂に本発明を完成するに至った。   The present inventors include a continuous phase introduction flow path for introducing a fluid that becomes a continuous phase, a dispersed phase introduction flow path that joins the continuous phase introduction flow path for introducing a fluid that becomes a dispersed phase, and A discharge channel for discharging a fluid containing fine particles of the dispersed phase formed at a junction where the dispersed phase introduction channel joins the continuous phase introduction channel. The micro-channel structure is made of quartz glass, and at least the surface roughness Ra of the channel wall surface at the junction is 10.0 nm or more, so that the above-described problems of the prior art can be solved. The headline and finally the present invention was completed.

本発明の微小流路構造体及び該微小粒子構造体を用いる微小粒子の製造方法により、微小粒子をより確実に、また均一な大きさで安定して大量に生成させることができる。   According to the microchannel structure of the present invention and the method for producing microparticles using the microparticle structure, microparticles can be more reliably generated in a large amount stably with a uniform size.

実施例１で作製した微小流路構造体の概略図である。1 is a schematic view of a microchannel structure manufactured in Example 1. FIG. 実施例１で作製した微小流路構造体の断面図である。2 is a cross-sectional view of a microchannel structure manufactured in Example 1. FIG. 粗面化処理した微小流路構造体の観察写真である。It is an observation photograph of the fine channel structure subjected to the roughening treatment. 実施例１で作製した微小流路構造体を用いて作製した微小粒子を示す顕微鏡写真である。2 is a photomicrograph showing microparticles produced using the microchannel structure produced in Example 1.

以下、本発明の実施の形態について詳細に説明する。なお本発明は、これらの実施の形態のみに限定されるものではなく、発明の要旨を逸脱しない範囲で、任意に変更が可能であることは言うまでもない。
ここで、本発明でいう「微小流路」とは、流路の幅がサブミクロン〜１ｍｍ程度、流路の深さがサブミクロン〜１ｍｍ程度、流路の長さは特に制限はないが、数ｍｍ〜数ｃｍ程度を意味する。また、本発明における「流路」とは、上記の微小流路を含め、該微小流路よりも広い流路幅、該微小流路よりも深い流路深さ、該微小流路よりも長い流路長を有す
る流路をも含むものである。
また、本発明でいう微小粒子には、固体状の微小粒子の他にも微小液滴や微小液滴の表面だけが硬化した微小粒子や、非常に粘性が高い半固体状の微小粒子も含まれる。 Hereinafter, embodiments of the present invention will be described in detail. Needless to say, the present invention is not limited to these embodiments, and can be arbitrarily changed without departing from the scope of the invention.
Here, the “micro-channel” as used in the present invention means that the width of the channel is about submicron to 1 mm, the depth of the channel is about submicron to 1 mm, and the length of the channel is not particularly limited. It means several mm to several cm. In addition, the “channel” in the present invention includes the above-described microchannel, a channel width wider than the microchannel, a channel depth deeper than the microchannel, and longer than the microchannel. A channel having a channel length is also included.
In addition to the solid microparticles, the microparticles referred to in the present invention include microdroplets, microparticles in which only the surface of the microdroplets is cured, and semisolid microparticles with extremely high viscosity. It is.

＜微小流路構造体＞
本発明の微小流路構造体（以下、微小流路基板ということもある。）は、連続相となる流体を導入するための連続相導入流路と、分散相となる流体を導入するための、前記連続相導入流路に合流する分散相導入流路と、前記分散相導入流路が前記連続相導入流路に合流する合流部において形成される前記分散相の微小粒子を含む流体を排出するための排出流路と、を有する微小流路構造体であって、前記微小流路構造体は石英ガラスからなり、少なくとも前記排出流路の壁面の表面粗さＲａが１０．０ｎｍ以上である。
また、本発明の微小粒子構造体の好ましい態様では、前記分散相導入流路は、幹流路と、前記幹流路から分岐して前記連続相導入流路に合流する複数の枝流路とを有する。
本発明の微小流路構造体は、分散相となる流体を導入するための導入口、連続相となる流体を導入するための導入口、及び分散相の流体と連続相の流体と生成した微小粒子とを含む流体を排出するための排出口を有していてもよい。 <Microchannel structure>
The microchannel structure of the present invention (hereinafter sometimes referred to as a microchannel substrate) includes a continuous phase introduction channel for introducing a fluid that becomes a continuous phase and a fluid for introducing a fluid that becomes a dispersed phase. A fluid containing fine particles of the dispersed phase formed in a dispersed phase introduction channel that joins the continuous phase introduction channel, and a joining portion where the dispersed phase introduction channel joins the continuous phase introduction channel And a discharge channel for carrying out the flow path, wherein the channel structure is made of quartz glass, and at least the surface roughness Ra of the wall surface of the discharge channel is 10.0 nm or more. .
Further, in a preferred aspect of the fine particle structure of the present invention, the dispersed phase introduction flow path includes a main flow path and a plurality of branch flow paths that branch from the main flow path and join the continuous phase introduction flow path. .
The microchannel structure according to the present invention includes an inlet for introducing a fluid to be a dispersed phase, an inlet for introducing a fluid to be a continuous phase, and a microscopicity generated with the fluid of the dispersed phase and the fluid of the continuous phase. You may have the discharge port for discharging | emitting the fluid containing particle | grains.

前記分散相導入流路及び前記連続相導入流路の幅と深さは数〜数十μｍ程度であることが好ましく、前記排出流路の幅と深さは数十μｍ〜１ｍｍ程度であることが好ましい。分散相導入流路が幹流路と枝流路を有する場合には、幹流路の幅と深さが数十μｍ〜１ｍｍ程度であることが好ましく、枝流路の幅と深さが数〜数十μｍ程度であることが好ましい。
また、前記分散相導入流路、前記連続相導入流路、前記排出流路はそれぞれ異なる幅及び深さを有することが好ましい。前記分散相導入流路が幹流路と枝流路を有する場合には、幹流路の方が枝流路よりも幅が広く、深さが深い態様が好ましい。
本発明の微小流路構造体は、微小流路や貫通孔の形成加工が可能であって、耐薬品性に優れ、適度な剛性を備え、かつ微細な加工が可能である石英ガラスを材料として用いる。微小流路構造体の大きさや形状については特に限定はないが、厚みは数ｍｍ以下程度とすることが好ましい。 The width and depth of the dispersed phase introduction channel and the continuous phase introduction channel are preferably about several to several tens of micrometers, and the width and depth of the discharge channel are about several tens of μm to 1 mm. Is preferred. When the dispersed phase introduction flow path has a main flow path and a branch flow path, the width and depth of the main flow path is preferably about several tens of μm to 1 mm, and the width and depth of the branch flow path are several to several. It is preferably about 10 μm.
The dispersed phase introduction channel, the continuous phase introduction channel, and the discharge channel preferably have different widths and depths. When the dispersed phase introduction flow path has a main flow path and a branch flow path, it is preferable that the main flow path is wider and deeper than the branch flow path.
The microchannel structure according to the present invention is made of quartz glass, which is capable of forming microchannels and through-holes, is excellent in chemical resistance, has appropriate rigidity, and can be microprocessed. Use. Although there is no limitation in particular about the magnitude | size and shape of a microchannel structure, it is preferable that thickness is about several mm or less.

本発明の微小流路構造体は、前記連続相導入流路、前記分散相導入流路、および前記排出流路のパターンが形成された石英ガラス基板を２枚以上貼り合せることにより構成されている態様が好ましく、前記連続相導入流路、前記分散相導入流路、および前記排出流路の下側のパターンが形成された第１の石英ガラス基板と、前記連続相導入流路、前記分散相導入流路、および前記排出流路の上側のパターンが形成された第２の石英ガラス基板とを互いに貼り合せることにより構成されている態様が特に好ましい。
なお、ここでいう上側及び下側とは、微小流路構造体に含まれる微小流路が略水平に存在する場合のときに用いられる用語であって重力方向の上下を意味するわけではない。すなわち、微小流路構造体に含まれる微小流路が水平方向と略垂直に存在する（微小流路構造体を水平方向と垂直に立てる）場合には、右側及び左側を意味する。 The microchannel structure of the present invention is configured by bonding two or more quartz glass substrates on which patterns of the continuous phase introduction channel, the dispersed phase introduction channel, and the discharge channel are formed. A preferable aspect is the first quartz glass substrate on which the lower pattern of the continuous phase introduction flow path, the dispersed phase introduction flow path, and the discharge flow path is formed, the continuous phase introduction flow path, and the dispersed phase. A mode in which the introduction flow path and the second quartz glass substrate on which the pattern on the upper side of the discharge flow path is formed is bonded to each other is particularly preferable.
Here, the upper side and the lower side are terms used when the microchannel included in the microchannel structure exists substantially horizontally, and do not mean the upper and lower sides in the direction of gravity. That is, when the microchannel included in the microchannel structure is present substantially perpendicular to the horizontal direction (the microchannel structure is set up perpendicular to the horizontal direction), it means the right side and the left side.

本発明では、微小流路構造体のうち、少なくとも排出流路の壁面の表面粗さＲａが１０．０ｎｍ以上であることを規定しているが、これは、少なくとも排出流路の壁面がこのような性状を有していることにより、分散相である流体と排出流路の壁面との接触が低減し、分散相である流体に対する剪断力が効果的に働き、粒径が均一な微小粒子が生成するためである。この効果は、分散相である流体と連続相である流体を大きな流量で導入しても得られる。これにより、粒径が均一な微小粒子を大量に得ることができる。
この表面粗さＲａが１０．０ｎｍ未満であると、分散相である流体が排出流路壁面に付着しやすくなり、微小粒子の生成が困難になる。
上記の表面粗さＲａを有する部位については、少なくとも微小流路構造体の排出流路の
壁面であれば本願発明の効果が奏されるが、分散相である流体と連続相である流体が合流する合流部分、特にその下流側であって、かつ、分散相導入流路側の壁面が上記の表面粗さＲａを有していることが、本願発明の効果とよりよく結びつくと本願発明者らは推測している。そのような排出壁面の壁面では、分散相である流体が剪断力により***して微小粒子が生成する。
上記表面粗さＲａは、１３．０ｎｍ以上であることがより好ましく、１５．０ｎｍ以上であることが特に好ましい。 In the present invention, it is specified that at least the surface roughness Ra of the wall surface of the discharge channel is 10.0 nm or more in the microchannel structure, but this is at least the wall surface of the discharge channel. Therefore, the contact between the fluid that is the dispersed phase and the wall surface of the discharge channel is reduced, the shearing force against the fluid that is the dispersed phase effectively acts, and the microparticles having a uniform particle size are produced. It is for generating. This effect can be obtained even when a fluid that is a dispersed phase and a fluid that is a continuous phase are introduced at a large flow rate. Thereby, a large amount of fine particles having a uniform particle diameter can be obtained.
When the surface roughness Ra is less than 10.0 nm, the fluid that is the dispersed phase easily adheres to the wall surface of the discharge channel, and it becomes difficult to generate fine particles.
With respect to the portion having the above-mentioned surface roughness Ra, the effect of the present invention is exhibited as long as it is at least the wall surface of the discharge channel of the microchannel structure, but the fluid that is the dispersed phase and the fluid that is the continuous phase merge. The inventors of the present application have a better connection with the effect of the present invention that the wall portion on the side of the dispersed phase introduction flow path, which is on the downstream side thereof, and on the side of the dispersed phase introduction flow channel has the above surface roughness Ra. I guess. On the wall surface of such a discharge wall, the fluid that is the dispersed phase is split by shearing force to generate fine particles.
The surface roughness Ra is more preferably 13.0 nm or more, and particularly preferably 15.0 nm or more.

本発明において、微小流路構造体の排出流路の壁面を上記の表面粗さに調製すること（以下、粗面化ともいう）は、あらかじめ微小流路構造体を構成する石英ガラス基板に一般的なフォトリソグラフィーとウェットエッチング等により溝を形成し、さらに後述する粗面化のための処理剤を用いて処理することにより可能である。
石英ガラスはＳｉＯ2の純度が高く、不純物が少ないことから均一に溝を形成することが可能である。粗面化の工程としては、微小流路構造体を蓋基板と底基板の２枚の基板を用いて作製する場合には、各基板に溝を形成した後、蓋基板と底基板を張り合わせる前に流路となる溝を粗面化しても良いし、各基板を張り合わせた後、分散相導入流路の導入口、連続相導入流路の導入口及び排出流路の排出口のいずれか１以上から粗面化のための処理剤を導入し、処理を行っても良い。
各基板を張り合わせた後の処理では、流路内に処理剤が残存するので、適宜、処理後に送液や洗浄、焼処理などすることで、処理剤を除去することができる。 In the present invention, adjusting the wall surface of the discharge channel of the microchannel structure to the above-mentioned surface roughness (hereinafter also referred to as roughening) is generally applied to the quartz glass substrate constituting the microchannel structure in advance. It is possible to form grooves by typical photolithography, wet etching, etc., and further, using a processing agent for roughening which will be described later.
Quartz glass has a high SiO 2 purity and few impurities, so that grooves can be formed uniformly. As a roughening process, when a microchannel structure is manufactured using two substrates, a lid substrate and a bottom substrate, a groove is formed in each substrate, and then the lid substrate and the bottom substrate are bonded together. The groove that becomes the flow path may be roughened before, and after each substrate is bonded, any one of the introduction port of the dispersed phase introduction flow channel, the introduction port of the continuous phase introduction flow channel, and the discharge port of the discharge flow channel A treatment for roughening the surface may be introduced from one or more.
In the processing after the substrates are bonded together, the processing agent remains in the flow path. Therefore, the processing agent can be removed by performing liquid feeding, washing, or baking after the processing as appropriate.

粗面化のための処理剤としては、フッ化水素アンモニウムを含んだ薬剤や、リン酸水素二アンモニウムとフッ酸等の混合物など、流路内を粗面化できるものであれば特段の限定なく使用できる。このような処理剤を用いて処理を行うことで、少なくとも排出流路の壁面の表面粗さＲａを上記範囲に調整できる。また表面粗さＲａの値は、使用する処理剤の濃度や処理時間を適宜調整することによって、調整することができる。
上記のような処理を経ることにより、少なくとも排出流路の壁面の表面粗さを、生成させる微小粒子より細かく、また深くすることにより本願発明の効果が奏される。
また、本発明において表面粗さＲａとは、走査型プローブ顕微鏡を用いて測定される算術平均粗さの値であり、本発明では面分析を採用し、２０μｍ×２０μｍの範囲を測定する。
その算術平均粗さはＪＩＳ Ｂ０６０１（１９９４）で示される下記の式で算出する。粗さ曲線からその平均線の方向に基準長さｌだけを抜き取り、この抜取り部分の平均線の方向にＸ軸を、縦倍率の方向にＹ軸を取り、粗さ曲線をｙ＝ｆ（ｘ）で表したときに、次の式（１）によって求められる値をナノメートル（ｎｍ）で表したものである。
本発明では、Ｒａと同時に二乗平均平方根粗さＲｍｓも同様の操作により測定した。本発明では、微小流路構造体の排出流路の壁面の二乗平均平方根粗さＲｍｓが、１５．０ｎｍ以上であることが好ましく、２０．０ｎｍ以上であることがより好ましい。
なお、微小流路構造体における上記のＲａ等の値は、微小流路構造体が２枚の基板を接着等により張り合わせて形成されたものである場合には、接着面で基板を２枚に分離し、微小流路の壁面を測定すれば得られる。 The treatment agent for roughening is not particularly limited as long as it can roughen the flow path, such as a chemical containing ammonium hydrogen fluoride or a mixture of diammonium hydrogen phosphate and hydrofluoric acid. Can be used. By performing treatment using such a treatment agent, at least the surface roughness Ra of the wall surface of the discharge channel can be adjusted to the above range. The value of the surface roughness Ra can be adjusted by appropriately adjusting the concentration of the treatment agent to be used and the treatment time.
By performing the treatment as described above, the effect of the present invention can be obtained by making the surface roughness of at least the wall surface of the discharge channel finer and deeper than the fine particles to be generated.
In the present invention, the surface roughness Ra is a value of arithmetic average roughness measured using a scanning probe microscope. In the present invention, surface analysis is employed and a range of 20 μm × 20 μm is measured.
The arithmetic average roughness is calculated by the following formula shown in JIS B0601 (1994). Only the reference length l is extracted from the roughness curve in the direction of the average line, the X axis is taken in the direction of the average line of the extracted portion, the Y axis is taken in the direction of the vertical magnification, and the roughness curve is expressed as y = f (x ), The value obtained by the following formula (1) is expressed in nanometers (nm).
In the present invention, the root mean square roughness Rms was measured simultaneously with Ra by the same operation. In the present invention, the root mean square roughness Rms of the wall surface of the discharge channel of the microchannel structure is preferably 15.0 nm or more, and more preferably 20.0 nm or more.
In addition, the value of Ra or the like in the microchannel structure is such that when the microchannel structure is formed by bonding two substrates together by bonding or the like, the substrate is bonded to two on the bonding surface. It can be obtained by separating and measuring the wall surface of the microchannel.

＜微小粒子の製造方法＞
本発明では、上記の微小流路構造体を用いた微小粒子を製造する方法も提供する。
本発明の微小粒子の製造方法は、微小流路構造体の前記連続相導入流路に連続相となる
流体を導入し、前記分散相導入流路に分散相となる流体を導入する工程を含む。
本発明の微小粒子の製造方法では、分散相となる流体を、微小粒子が生成する排出流路の一本につき１〜３０ｃｍ／ｓｅｃ、より好ましくは３〜２０ｃｍ／ｓｅｃとなるように導入することが好ましい。
また、本発明の微小粒子の製造方法では、連続相となる流体を、微小粒子が生成する排出流路の一本につき３〜５０ｃｍ／ｓｅｃ、より好ましくは５〜４０ｃｍ／ｓｅｃとなるように導入することが好ましい。
そして、本発明の微小粒子の製造方法では、分散相となる流体と連続相となる流体の流量の比（分散相／連続相）が０．１〜０．７、より好ましくは０．２〜０．５となるように各流体を微小粒子に導入することが好ましい。 <Method for producing fine particles>
The present invention also provides a method for producing microparticles using the above microchannel structure.
The method for producing microparticles of the present invention includes a step of introducing a fluid that becomes a continuous phase into the continuous phase introduction channel of the microchannel structure and a fluid that becomes a dispersed phase into the dispersed phase introduction channel. .
In the method for producing microparticles of the present invention, the fluid that becomes the dispersed phase is introduced so that the flow rate is 1 to 30 cm / sec, more preferably 3 to 20 cm / sec, per one discharge channel in which the microparticles are generated. Is preferred.
Further, in the method for producing microparticles of the present invention, the fluid to be a continuous phase is introduced so as to be 3 to 50 cm / sec, more preferably 5 to 40 cm / sec per one discharge channel where the microparticles are generated. It is preferable to do.
And in the manufacturing method of the microparticles of this invention, ratio (dispersion phase / continuous phase) of the flow volume of the fluid used as a dispersed phase and the fluid used as a continuous phase is 0.1 to 0.7, more preferably 0.2 to It is preferable to introduce each fluid into the fine particles so as to be 0.5.

本発明の微小粒子の製造方法を用い、分散相となる流体として重合性モノマーを含む流体を用いた場合、粒径の揃った液滴の状態で微小粒子が生成する。
本発明の微小粒子の製造方法を用いた場合、平均粒径が１０〜２００μｍの微小粒子が得られる。本発明でいう微小粒子の粒径とは、粒子の投影面積に相当する大きさの円の直径を意味し、微小粒子の平均粒径は光学式顕微鏡で撮影した画像中の粒子３００個以上の粒径を単純に算術平均することにより求めることができる。
また、本発明の微小粒子の製造方法を用いた場合には、生成する微小粒子の分散が１５％以下となる。なお、ここでいう分散とは、微小粒子の粒径の標準偏差を平均粒径で除算した値である。分散が１５％以下の場合は、排出流路において微小粒子が均一に生成する。一方、分散が１５％を超えるような場合には、不均一な粒径の微小粒子が生成したり、あるいは、分散相である流体が微小流路構造体の一部の排出流路の壁面を伝いながら層流となって流出することがある。 When the method for producing microparticles of the present invention is used and a fluid containing a polymerizable monomer is used as a fluid to be a dispersed phase, microparticles are generated in a state of droplets having a uniform particle size.
When the method for producing fine particles of the present invention is used, fine particles having an average particle diameter of 10 to 200 μm are obtained. The particle diameter of the fine particles in the present invention means the diameter of a circle having a size corresponding to the projected area of the particles, and the average particle diameter of the fine particles is 300 or more particles in an image taken with an optical microscope. It can be determined by simply arithmetically averaging the particle size.
Further, when the method for producing fine particles of the present invention is used, the dispersion of the produced fine particles is 15% or less. In addition, dispersion | distribution here is the value which divided the standard deviation of the particle size of a microparticle by the average particle size. When the dispersion is 15% or less, fine particles are uniformly generated in the discharge channel. On the other hand, when the dispersion exceeds 15%, fine particles having a non-uniform particle size are generated, or the fluid that is a dispersed phase passes through the wall surface of a part of the discharge channel of the micro channel structure. It may flow out as a laminar flow.

また、本発明の微小粒子の製造方法では、連続相となる流体及び分散相となる流体のそれぞれが液体である場合には、前記連続相導入流路に連続相となる液体を導入し、前記分散相導入流路に分散相となる液体を導入する工程の前に、連続相となる液体と相溶性のある液体を、分散相導入流路および連続相導入流路の両方にそれぞれ導入する工程を含んでいてもよい。
分散相導入流路と連続相導入流路の両方に、連続相となる液体と相溶性のある液体を予め導入することにより、上記の特定の表面粗さＲａを有する排出流路の壁面に連続相となる液体と相溶性のある液体が付着して濡れることで、分散相である液体の上記壁面への付着を防止する効果が高まる。これにより、分散相である液体と連続相である液体とが合流する時に、均一な液体交差状態を達成することができる。均一な液体交差状態とは、たとえば均一な微小粒子の形成や、規則的な分散相である液体と連続相である液体の交互送液流、均等な混合比での送液などを意味する。
連続相となる液体と相溶性のある液体とは、連続相となる液体と相互に親和性を有し、溶液を形成する液体をいう。このような液体として、分散相となる液体が後述するポリビニルアルコール水溶液などの水系媒体である場合には、界面活性剤を含む溶液が挙げられる。 Further, in the method for producing fine particles of the present invention, when each of the fluid that becomes the continuous phase and the fluid that becomes the dispersed phase is a liquid, the liquid that becomes the continuous phase is introduced into the continuous phase introduction flow path, A step of introducing a liquid compatible with the liquid as the continuous phase into both the dispersed phase introduction channel and the continuous phase introduction channel before the step of introducing the liquid as the dispersed phase into the dispersed phase introduction channel. May be included.
Continuous introduction to the wall of the discharge channel having the specific surface roughness Ra described above is achieved by introducing a liquid compatible with the liquid to be the continuous phase into both the dispersed phase introduction channel and the continuous phase introduction channel. By adhering and getting wet with a liquid compatible with the phase liquid, the effect of preventing the liquid as the dispersed phase from adhering to the wall surface is enhanced. Thereby, when the liquid which is a dispersed phase and the liquid which is a continuous phase merge, a uniform liquid crossing state can be achieved. The uniform liquid crossing state means, for example, the formation of uniform fine particles, an alternating liquid flow of a liquid that is a regular dispersed phase and a liquid that is a continuous phase, and a liquid feed with an equal mixing ratio.
The liquid that is compatible with the liquid that becomes the continuous phase is a liquid that has a mutual affinity with the liquid that becomes the continuous phase and forms a solution. As such a liquid, when the liquid used as the dispersed phase is an aqueous medium such as an aqueous polyvinyl alcohol solution described later, a solution containing a surfactant is exemplified.

本発明における分散相とは、本発明の微小流路構造体を用いて作製される微小粒子を構成する液体やガスなどの流体からなり、そのような流体が液体である場合には、例えば、スチレンなどの重合性モノマー、ジビニルベンゼンなどの架橋剤、重合開始剤等のゲル製造用の原料を適当な溶媒に溶解したものが挙げられる。
ここで、分散相となる流体としては、微小粒子が効率的に生成するものであって、微小流路構造体に導入できるものであれば特に制限されず、その成分も特に制限されない。 The dispersed phase in the present invention is composed of a fluid such as a liquid or a gas constituting the microparticles produced using the microchannel structure of the present invention, and when such a fluid is a liquid, for example, Examples thereof include a polymerizable monomer such as styrene, a crosslinking agent such as divinylbenzene, and a gel production material such as a polymerization initiator dissolved in an appropriate solvent.
Here, the fluid to be the dispersed phase is not particularly limited as long as it is capable of efficiently generating microparticles and can be introduced into the microchannel structure, and the component is not particularly limited.

本発明における連続相とは、連続相導入流路から導入され、分散相である流体と合流した時に分散相である流体が分散する流体からなり、この連続相において微小粒子が生成す
る。このような連続相となる流体としては、該流体が液体である場合には、例えば、ポリビニルアルコールのゲル製造用の分散剤を水などの適当な溶媒に溶解した媒体が挙げられる。連続相となる流体としては、分散相となる流体と同様に、微小流路構造体に導入できるものであれば特に制限されない。また、微小粒子を形成させることができれば、その成分も特に制限されない。生成する微小粒子の組成の観点から見た場合は、微小粒子の最外層が有機相であれば連続相の最外層は水相となり、微小粒子の最外層が水相であれば連続相の最外層は有機相となる。 The continuous phase in the present invention is a fluid which is introduced from the continuous phase introduction flow path and is a fluid in which the fluid which is the dispersed phase is dispersed when joined with the fluid which is the dispersed phase, and microparticles are generated in the continuous phase. Examples of the fluid that forms such a continuous phase include a medium in which a dispersant for producing a gel of polyvinyl alcohol is dissolved in an appropriate solvent such as water when the fluid is a liquid. The fluid that becomes the continuous phase is not particularly limited as long as it can be introduced into the microchannel structure, similarly to the fluid that becomes the dispersed phase. Moreover, the component will not be restrict | limited especially if a microparticle can be formed. From the viewpoint of the composition of the generated fine particles, if the outermost layer of the fine particles is an organic phase, the outermost layer of the continuous phase is an aqueous phase, and if the outermost layer of the fine particles is an aqueous phase, the outermost layer of the continuous phase is the aqueous phase. The outer layer becomes the organic phase.

さらに、分散相となる流体と連続相となる流体は、微小流路構造体においてこれらが合流した際に微小粒子が生成するために、実質的に交じり合わない、あるいは、相溶性がないことが好ましい。例えば、分散相となる流体として水系媒体を用いた場合には、連続相となる流体として、水に実質的に溶解しない酢酸ブチルのような有機化合物からなる流体が用いられる。また、連続相として水系媒体を用いた場合にはその逆となる。   Furthermore, the fluid that becomes the dispersed phase and the fluid that becomes the continuous phase are not substantially mixed or incompatible because they generate microparticles when they merge in the microchannel structure. preferable. For example, when an aqueous medium is used as the fluid to be the dispersed phase, a fluid made of an organic compound such as butyl acetate that does not substantially dissolve in water is used as the fluid to be the continuous phase. The opposite is true when an aqueous medium is used as the continuous phase.

本発明の微小粒子構造体を、化学反応や微小粒子の生産以外の物理操作場としての用いる場合には、混合、抽出、溶解、吸収及び吸着など２以上の流体の界面を利用した物理操作や、液／液界面を形成する急激な発熱反応や、界面積の増大に応じて反応速度が向上するような反応に好適に用いられる。
また、本発明の微小粒子構造体を用いる微小粒子の製造方法で作製された微小粒子の用途の具体例としては、高速液体クロマトグラフィー用カラムの充填剤、シールロック剤などの接着剤、金属粒子の絶縁粒子、圧力測定フィルム、ノーカーボン（感圧複写）紙、トナー、熱膨張剤、熱媒体、調光ガラス、ギャップ剤（スペーサ）、サーモクロミック（感温液晶、感温染料）、磁気泳動カプセル、農薬、人工飼料、人工種子、芳香剤、マッサージクリーム、口紅、ビタミン類カプセル、活性炭、含酵素カプセル及びＤＤＳ（ドラッグデリバリーシステム）などのマイクロカプセルやゲルが挙げられる。 When the fine particle structure of the present invention is used as a physical operation field other than chemical reaction and production of fine particles, physical operation using an interface between two or more fluids such as mixing, extraction, dissolution, absorption and adsorption, It is preferably used for a rapid exothermic reaction that forms a liquid / liquid interface and a reaction that increases the reaction rate in accordance with an increase in the interfacial area.
Further, specific examples of the use of the fine particles produced by the method for producing fine particles using the fine particle structure of the present invention include adhesives such as packing materials and seal lock agents for high performance liquid chromatography columns, metal particles Insulating particles, pressure measuring film, carbonless (pressure-sensitive copying) paper, toner, thermal expansion agent, heat medium, light control glass, gap agent (spacer), thermochromic (thermosensitive liquid crystal, thermosensitive dye), magnetophoresis Examples include microcapsules and gels such as capsules, agricultural chemicals, artificial feeds, artificial seeds, fragrances, massage creams, lipsticks, vitamin capsules, activated carbon, enzyme-containing capsules, and DDS (drug delivery system).

以下、本発明を実施例により更に具体的に説明するが、これらは本発明をなんら限定するものではない。   EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but these do not limit the present invention.

＜微小流路構造体の作製＞
本発明で使用した微小流路構造体の概略図を図１に示した。
図１に示すように、本発明で使用した微小流路構造体は、分散相となる流体を導入するための分散相導入流路と、連続相となる流体を導入するための連続相導入流路（３）と、前記分散相導入流路が前記連続相導入流路に合流する合流部において形成される前記分散相となる流体からなる微小粒子を含む流体を排出するための排出流路とを備え、前記分散相導入流路は分散相となる流体を導入するための分散相導入口（４）を有し、前記連続相導入流路（３）は連続相となる流体を導入するための連続相導入口（２）を有し、前記排出流路は前記微粒子を含む流体を排出するための排出口（８）有している。そして、前記分散相導入流路は幹流路（５）と、前記幹流路から分岐して前記連続相導入流路に合流する複数の枝流路（１０）とから成っており、前記排出流路は、前記複数の枝流路と前記排出流路との複数の合流部のうち、最も下流側に位置する合流部よりも上流側の第一の排出流路（９）と下流側の第二の排出流路（７）とからなる。 <Preparation of microchannel structure>
A schematic view of the microchannel structure used in the present invention is shown in FIG.
As shown in FIG. 1, the microchannel structure used in the present invention includes a dispersed phase introduction channel for introducing a fluid that becomes a dispersed phase, and a continuous phase introduction flow for introducing a fluid that becomes a continuous phase. A discharge channel for discharging a fluid containing microparticles made of a fluid serving as the dispersed phase formed in a junction where the dispersed phase introducing channel joins the continuous phase introducing channel; The disperse phase introduction flow path has a disperse phase introduction port (4) for introducing a fluid to be a dispersed phase, and the continuous phase introduction flow path (3) is for introducing a fluid to be a continuous phase. And the discharge channel has a discharge port (8) for discharging the fluid containing the fine particles. The dispersed phase introduction flow path includes a main flow path (5) and a plurality of branch flow paths (10) branched from the main flow path and joined to the continuous phase introduction flow path. Is the first discharge channel (9) upstream of the junction located at the most downstream side and the second downstream of the plurality of junctions of the plurality of branch channels and the discharge channel. The discharge channel (7).

本実施例で用いた微小流路構造体では、３２０本の前記枝流路（１０）が、５０μｍの間隔で平行して前記幹流路（５）から分岐し、前記第一の排出流路（９）と合流している。前記幹流路（５）は、幅１４０μｍ、深さ６０μｍ、長さ２．５ｍの微小流路であり、連続相導入流路（３）は、幅１８３μｍ、深さ６０μｍ、長さ５ｍｍの微小流路であり、前記第一の排出流路（９）は、深さ６０μｍ、長さ１６ｍｍの微小流路であり、前記第二の排出流路（７）は、幅２５０μｍ、深さ６０μｍ、長さ６ｍｍの微小流路であり、前記
枝流路（１０）は、幅１５μｍ、深さ３．８μｍである。また、前記第一の排出流路（９）の幅は、下流側に向かって、１８３μｍから２５０μｍへと次第に大きくなっている。
また、最も上流側に位置する枝流路（１０）と最も下流側に位置する枝流路（１０）の流路長が、１．０ｍｍから３．０ｍｍへと下流側に向かって次第に長くなっている。ここで、前記の上流側とは、前記分散相導入口（４）または前記連続相導入口（２）に近い側を意味し、前記の下流側とは前記排出口（８）に近い側を意味する。 In the microchannel structure used in this example, 320 branch channels (10) branch from the trunk channel (5) in parallel at an interval of 50 μm, and the first discharge channel ( It merges with 9). The trunk channel (5) is a micro channel having a width of 140 μm, a depth of 60 μm, and a length of 2.5 m, and the continuous phase introduction channel (3) is a micro flow having a width of 183 μm, a depth of 60 μm, and a length of 5 mm. The first discharge channel (9) is a micro channel having a depth of 60 μm and a length of 16 mm, and the second discharge channel (7) is 250 μm in width, 60 μm in depth and long. The branch channel (10) has a width of 15 μm and a depth of 3.8 μm. In addition, the width of the first discharge channel (9) gradually increases from 183 μm to 250 μm toward the downstream side.
Further, the channel lengths of the branch channel (10) located on the most upstream side and the branch channel (10) located on the most downstream side are gradually increased from 1.0 mm to 3.0 mm toward the downstream side. ing. Here, the upstream side means a side close to the dispersed phase introduction port (4) or the continuous phase introduction port (2), and the downstream side means a side close to the discharge port (8). means.

上記で説明した微小流路構造体は、図２に示す枝流路のみを１枚の基板に作製した蓋基板（１２）と、幹流路、連続相導入流路、第一の排出流路及び第二の排出流路を１枚の基板に作製した底基板（１３）とを貼り合わせて作製した。
蓋基板（１２）と底基板（１３）には、それぞれ７０ｍｍ×３０ｍｍ×１ｍｍ（厚さ）の石英ガラス基板を用いた。ここで作製された微小流路構造体には、上記の微小流路群を１単位とすると、合計で５０単位が含まれており、その結果、微小流路構造体１つで合計１６０００本の枝流路が含まれている。 The microchannel structure described above includes a lid substrate (12) in which only the branch channel shown in FIG. 2 is produced on one substrate, a trunk channel, a continuous phase introduction channel, a first discharge channel, The second discharge channel was prepared by bonding the bottom substrate (13) prepared on one substrate.
As the lid substrate (12) and the bottom substrate (13), quartz glass substrates of 70 mm × 30 mm × 1 mm (thickness) were used. The microchannel structure produced here includes 50 units in total when the above microchannel group is defined as one unit. As a result, a total of 16000 microchannel structures are included in one microchannel structure. A branch channel is included.

また蓋基板、底基板のそれぞれに形成した微小流路は、一般的なフォトリソグラフィーとウェットエッチングにより形成した。そして、蓋基板と底基板を一般的な熱融着により接合した。また蓋基板には、連続相導入口（２）、分散相導入口（４）及び排出口（８）にあたる位置に予め直径１．５ｍｍの穴を、機械的加工手段を用いて設けた。なお、微小流路構造体の製作方法はこれに限定されるものではない。   The microchannels formed on the lid substrate and the bottom substrate were formed by general photolithography and wet etching. Then, the lid substrate and the bottom substrate were joined by general heat fusion. The lid substrate was previously provided with a hole having a diameter of 1.5 mm at a position corresponding to the continuous phase inlet (2), the dispersed phase inlet (4), and the outlet (8) using a mechanical processing means. In addition, the manufacturing method of a microchannel structure is not limited to this.

＜実施例１＞
上記で説明した微小流路構造体において、流路を形成した微小流路構造体の排出口に設けた穴からフロステック社製の石英ガラス用エッチング剤（フロストタイプ）ＱＥ−ＦＬ３Ａをピペットで付着及び浸透させて３０分放置した後水洗浄した。この操作により、第一及び第二の排出流路の壁面が粗面化された。
この粗面化処理した微小流路構造体に分散相であるトルエンの送液速度を２４０ｍｌ／ｈ、連続相であるポリビニルアルコール２％水溶液の送液速度を６００ｍｌ／ｈで送液したところ、送液速度が共に安定した状態で、微小流路構造体の分散相であるトルエン及び連続相であるポリビニルアルコール２％水溶液が交わる合流部にて、図４に示すような微小粒子（１１）の生成が観察された。
図４に示すように、生成した微小粒子（１１）を観察すると、微小粒子の平均粒径は２０．１μｍ、粒径の分散度を示すＣＶ値（％）は８．０％となり、粒径の揃った微小粒子（１１）であった。ここで、ＣＶ値とは、粒径の標準偏差を平均粒径で除算した値である。
なお、粗面化された壁面の表面粗さの程度は、走査型プローブ顕微鏡ＮａｎｏＳｃｏｐｅ IIIａ（Ｖｅｅｃｏ製）を用い、微小流路構造体の分散相であるトルエンと連続相であるポリビニルアルコール２％水溶液の合流部分、特にその下流側について２０μｍ×２０μｍの範囲を走査して測定を行った。
上記フロストタイプのエッチング剤による処理を行う前（フォトリソグラフィーとウェットエッチングによる流路の形成後）のＲａは０．４ｎｍ、Ｒｍｓは０．４ｎｍであった。一方、上記フロストタイプのエッチング剤（ＱＥ−ＦＬ３Ａ）により３０分処理した後の表面粗さは、Ｒａ＝６４．７ｎｍ、Ｒｍｓ＝７１．１ｎｍであった。 <Example 1>
In the micro-channel structure described above, a quartz glass etching agent (frost type) QE-FL3A manufactured by Flosstec Co. is attached with a pipette from the hole provided in the discharge port of the micro-channel structure in which the channel is formed. Then, the mixture was allowed to permeate for 30 minutes and then washed with water. By this operation, the wall surfaces of the first and second discharge channels were roughened.
When the liquid flow rate of toluene, which is a dispersed phase, is 240 ml / h, and the liquid flow rate of a 2% aqueous solution of polyvinyl alcohol, which is a continuous phase, is 600 ml / h. Production of microparticles (11) as shown in FIG. 4 at a junction where toluene, which is a dispersed phase of a microchannel structure, and a 2% aqueous solution of polyvinyl alcohol, which is a continuous phase, meet in a state where both liquid velocities are stable. Was observed.
As shown in FIG. 4, when the generated fine particles (11) are observed, the average particle size of the fine particles is 20.1 μm, and the CV value (%) indicating the degree of dispersion of the particle size is 8.0%. It was a fine particle (11) with uniform. Here, the CV value is a value obtained by dividing the standard deviation of the particle diameter by the average particle diameter.
The degree of surface roughness of the roughened wall surface was determined by using a scanning probe microscope NanoScope IIIa (manufactured by Veeco) and using toluene as a dispersed phase of a microchannel structure and a 2% aqueous solution of polyvinyl alcohol as a continuous phase. The measurement was carried out by scanning a range of 20 μm × 20 μm with respect to the confluence portion, particularly the downstream side thereof.
Ra was 0.4 nm and Rms was 0.4 nm before the treatment with the frost type etching agent (after the flow path was formed by photolithography and wet etching). On the other hand, the surface roughness after 30 minutes treatment with the frost type etching agent (QE-FL3A) was Ra = 64.7 nm and Rms = 71.1 nm.

＜実施例２＞
実施例１で使用した微小流路構造体の製造において、第一の排出流路及び第二の排出流路を粗面化するためのフロステック社製の石英ガラス用エッチング剤（フロストタイプ）をＱＥ−ＦＬＡ３−１Ｐに変更したこと以外は実施例１と同様の操作により、実施例２の微小流路構造体を作製した。
なお、実施例１と同様の方法により測定された上記フロストタイプのエッチング剤（Ｑ
Ｅ−ＦＬＡ３−１Ｐ）により３０分処理した後の表面粗さは、Ｒａ＝１５．１ｎｍ、Ｒｍｓ＝２３．３ｎｍであった。
この微小流路構造体に分散相であるトルエンの送液速度を４２０ｍｌ／ｈ、連続相であるポリビニルアルコール２％水溶液の送液速度を８４０ｍｌ／ｈで送液したところ、送液速度が共に安定した状態で、微小流路構造体の分散相であるトルエン及び連続相であるポリビニルアルコール２％水溶液が交わる合流部にて、微小粒子の生成が観察された。
生成した微小粒子を観察すると、微小粒子の平均粒径は２０．８μｍ、粒径の分散度を示すＣＶ値（％）は９．５％となり、粒径の揃った微小粒子であった。 <Example 2>
In the manufacture of the microchannel structure used in Example 1, an etching agent (frost type) manufactured by Flosstec for roughening the first discharge channel and the second discharge channel is used. A microchannel structure of Example 2 was produced in the same manner as in Example 1 except that it was changed to QE-FLA3-1P.
The frost type etching agent (Q
The surface roughness after 30 minutes treatment with E-FLA3-1P) was Ra = 15.1 nm and Rms = 23.3 nm.
When the liquid flow rate of toluene as a dispersed phase was 420 ml / h and the liquid flow rate of a 2% aqueous solution of polyvinyl alcohol as a continuous phase was fed to 840 ml / h, the liquid flow rate was stable. In this state, formation of microparticles was observed at the junction where the toluene as the dispersed phase of the microchannel structure and the 2% aqueous solution of polyvinyl alcohol as the continuous phase intersect.
When the generated fine particles were observed, the average particle diameter of the fine particles was 20.8 μm, and the CV value (%) indicating the degree of dispersion of the particle diameter was 9.5%, and the fine particles had a uniform particle diameter.

＜実施例３＞
実施例１で使用した微小流路構造体の製造において、第一の排出流路及び第二の排出流路を粗面化するためのフロステック社製の石英ガラス用エッチング剤（フロストタイプ）をＱＥ−ＦＬＡ４−１Ｐに変更したこと以外は実施例１と同様の操作により、実施例３の微小流路構造体を作製した。
なお、実施例１と同様の方法により測定された上記フロストタイプのエッチング剤（ＱＥ−ＦＬＡ４−１Ｐ）により３０分処理した後の表面粗さは、Ｒａ＝２６．６ｎｍ、Ｒｍｓ＝３１．９ｎｍであった。
この微小流路構造体に分散相であるトルエンの送液速度を４２０ｍｌ／ｈ、連続相であるポリビニルアルコール２％水溶液の送液速度を８４０ｍｌ／ｈで送液したところ、送液速度が共に安定した状態で、微小流路構造体の分散相であるトルエン及び連続相であるポリビニルアルコール２％水溶液が交わる合流部にて、微小粒子の生成が観察された。
生成した微小粒子を観察すると、微小粒子の平均粒径は１８．７μｍ、粒径の分散度を示すＣＶ値（％）は９．３％となり、粒径の揃った微小粒子であった。 <Example 3>
In the manufacture of the microchannel structure used in Example 1, an etching agent (frost type) manufactured by Flosstec for roughening the first discharge channel and the second discharge channel is used. A microchannel structure of Example 3 was produced in the same manner as in Example 1 except that it was changed to QE-FLA4-1P.
The surface roughness after 30 minutes treatment with the above-mentioned frost type etching agent (QE-FLA4-1P) measured by the same method as in Example 1 was Ra = 26.6 nm, Rms = 31.9 nm. there were.
When the liquid flow rate of toluene as a dispersed phase was 420 ml / h and the liquid flow rate of a 2% aqueous solution of polyvinyl alcohol as a continuous phase was fed to 840 ml / h, the liquid flow rate was stable. In this state, formation of microparticles was observed at the junction where the toluene as the dispersed phase of the microchannel structure and the 2% aqueous solution of polyvinyl alcohol as the continuous phase intersect.
When the generated fine particles were observed, the average particle size of the fine particles was 18.7 μm, and the CV value (%) indicating the degree of dispersion of the particle size was 9.3%.

＜実施例４＞
実施例２で使用した微小流路構造体の製造において、枝流路の深さを５．３μｍ、幅を２０μｍとし、第一の排出流路の深さを９１μｍとし、第一の排出流路の幅を、下流側に向かって、２４５μｍから３１２μｍへと次第に大きくしたこと以外は実施例２と同じ構造、同じ表面粗さを有する微小流路構造体を作製した。
この微小流路構造体に分散相であるトルエンの送液速度を４８０ｍｌ／ｈ、連続相であるポリビニルアルコール２％水溶液の送液速度を９６０ｍｌ／ｈで送液したところ、送液速度が共に安定した状態で、微小流路構造体の分散相であるトルエン及び連続相であるポリビニルアルコール２％水溶液が交わる合流部にて、微小粒子の生成が観察された。
生成した微小粒子を観察すると、微小粒子の平均粒径は２８．４μｍ、粒径の分散度を示すＣＶ値（％）は９．４％となり、粒径の揃った微小粒子であった。 <Example 4>
In the manufacture of the microchannel structure used in Example 2, the depth of the branch channel is 5.3 μm, the width is 20 μm, the depth of the first discharge channel is 91 μm, and the first discharge channel is formed. A microchannel structure having the same structure and the same surface roughness as that of Example 2 was manufactured except that the width of the film was gradually increased from 245 μm to 312 μm toward the downstream side.
When the liquid flow rate of toluene, which is a dispersed phase, is fed to this microchannel structure at 480 ml / h and the liquid feed rate of a 2% aqueous solution of polyvinyl alcohol, which is a continuous phase, is fed at 960 ml / h, both liquid feed rates are stable. In this state, formation of microparticles was observed at the junction where the toluene as the dispersed phase of the microchannel structure and the 2% aqueous solution of polyvinyl alcohol as the continuous phase intersect.
When the generated fine particles were observed, the average particle diameter of the fine particles was 28.4 μm, and the CV value (%) indicating the degree of dispersion of the particle diameter was 9.4%, and the fine particles had a uniform particle diameter.

＜比較例１＞
実施例１で使用した微小流路構造体において、上記フロストタイプのエッチング剤による粗面化処理を行っていないこと以外は実施例１の同様の構造を有する微小流路構造体を作製した。表面粗さは、Ｒａ＝０．４ｎｍ、Ｒｍｓ＝０．４ｎｍであった。
この微小流路構造体に分散相であるトルエンの送液速度を１２０ｍｌ／ｈ、連続相であるポリビニルアルコール２％水溶液の送液速度を４００ｍｌ／ｈで送液したところ、微小流路構造体の分散相であるトルエン及び連続相であるポリビニルアルコール２％水溶液が交わる合流部にて、微小粒子の生成は確認されたものの、略均一の粒径ではなく大粒の粒子も生成した。
生成した微小粒子を観察すると、微小粒子の平均粒径は１９．２μｍ、粒径の分散度を示すＣＶ値（％）は１６．５％となり、粒径が不揃いの粒子であった。 <Comparative Example 1>
In the microchannel structure used in Example 1, a microchannel structure having the same structure as in Example 1 was produced except that the roughening treatment with the frost type etching agent was not performed. The surface roughness was Ra = 0.4 nm and Rms = 0.4 nm.
When the liquid flow rate of toluene which is a dispersed phase was 120 ml / h and the liquid flow rate of a 2% aqueous solution of polyvinyl alcohol which was a continuous phase was 400 ml / h, the micro flow channel structure was subjected to Although formation of microparticles was confirmed at a junction where toluene as a dispersed phase and a 2% aqueous solution of polyvinyl alcohol as a continuous phase intersect, large particles were generated instead of a substantially uniform particle size.
When the generated fine particles were observed, the average particle size of the fine particles was 19.2 μm, the CV value (%) indicating the degree of dispersion of the particle size was 16.5%, and the particles had irregular particle sizes.

＜比較例２＞
実施例４で作製した微小流路構造体において、上記フロストタイプのエッチング剤によ
り粗面化処理を行わなかったこと以外は、実施例４で用いた微小流路構造体と同様の構造を有する微小流路構造体を作製した。
この微小流路構造体に分散相であるトルエンの送液速度を１２０ｍｌ／ｈ、連続相であるポリビニルアルコール２％水溶液の送液速度を４００ｍｌ／ｈで送液したところ、微小流路構造体の分散相であるトルエン及び連続相であるポリビニルアルコール２％水溶液が交わる合流部にて、微小粒子の生成は確認されたものの、略均一の粒径ではなく大粒の粒子も生成した。
生成した微小粒子を観察すると、微小粒子の平均粒径は４１．６μｍ、粒径の分散度を示すＣＶ値（％）は１５．１％となり、粒径が不揃いの粒子であった。 <Comparative example 2>
The microchannel structure manufactured in Example 4 has the same structure as the microchannel structure used in Example 4 except that the roughening treatment was not performed with the frost type etching agent. A flow channel structure was produced.
When the liquid flow rate of toluene which is a dispersed phase was 120 ml / h and the liquid flow rate of a 2% aqueous solution of polyvinyl alcohol which was a continuous phase was 400 ml / h, the micro flow channel structure was subjected to Although formation of microparticles was confirmed at a junction where toluene as a dispersed phase and a 2% aqueous solution of polyvinyl alcohol as a continuous phase intersect, large particles were generated instead of a substantially uniform particle size.
When the generated fine particles were observed, the average particle size of the fine particles was 41.6 μm, the CV value (%) indicating the degree of dispersion of the particle size was 15.1%, and the particles had irregular particle sizes.

＜比較例３＞
実施例１で使用した微小流路構造体において、材料を石英ガラスからテンパックスガラス（登録商標）に変え、枝流路の深さを７．３μｍ、幅を２２μｍとし、第一の排出流路の深さを１３８μｍとし、第一の排出流路の幅を、下流側に向かって、３３９μｍから４０６μｍへと次第に大きくし、枝流路の数を１００μｍ間隔で８０００本に変え、さらに上記フロストタイプのエッチング剤による粗面化処理を行っていない微小流路構造体を作製した。微小流路となる溝を形成した後の表面粗さは、Ｒａ＝１８．７ｎｍ、Ｒｍｓ＝２４．３ｎｍであった。
この微小流路構造体に分散相であるトルエンの送液速度を１５０ｍｌ／ｈ、連続相であるポリビニルアルコール２％水溶液の送液速度を６００ｍｌ／ｈで送液したところ、微小流路構造体の分散相であるトルエン及び連続相であるポリビニルアルコール２％水溶液が交わる合流部にて、微小粒子の生成は確認されたものの、略均一の粒径ではなく大粒の粒子も生成した。
生成した微小粒子を観察すると、微小粒子の平均粒径は６３．０μｍ、粒径の分散度を示すＣＶ値（％）は１７．９％となり、粒径が不揃いの粒子であった。 <Comparative Example 3>
In the microchannel structure used in Example 1, the material is changed from quartz glass to Tempax Glass (registered trademark), the depth of the branch channel is 7.3 μm, the width is 22 μm, and the first discharge channel The depth of the first discharge channel is 138 μm, the width of the first discharge channel is gradually increased from 339 μm to 406 μm toward the downstream side, the number of branch channels is changed to 8000 at intervals of 100 μm, and the above frost type A microchannel structure that was not roughened with an etching agent was prepared. The surface roughness after forming the groove to be a microchannel was Ra = 18.7 nm and Rms = 24.3 nm.
When the liquid flow rate of toluene as a dispersed phase was 150 ml / h and the liquid flow rate of a 2% aqueous solution of polyvinyl alcohol as a continuous phase was fed at 600 ml / h to this micro flow channel structure, Although formation of microparticles was confirmed at a junction where toluene as a dispersed phase and a 2% aqueous solution of polyvinyl alcohol as a continuous phase intersect, large particles were generated instead of a substantially uniform particle size.
When the generated fine particles were observed, the average particle size of the fine particles was 63.0 μm, the CV value (%) indicating the degree of dispersion of the particle size was 17.9%, and the particles had irregular particle sizes.

表１中、微粒子が生成する流路（排出流路）１本あたりの流体の送液速度について、その線速を求める場合には、流路の断面をほぼ半楕円であると近似計算して算出する。   In Table 1, when calculating the linear velocity of the flow rate of the fluid per flow path (discharge flow path) where fine particles are generated, the approximate cross section of the flow path is approximately semi-elliptical. calculate.

２：連続相導入口
３：連続相導入流路
４：分散相導入口
５：幹流路
７：第二の排出流路
８：排出口
９：第一の排出流路
１０：枝流路
１１：微小粒子
１２：蓋基板
１３：底基板 2: Continuous phase inlet port 3: Continuous phase inlet channel 4: Dispersed phase inlet port 5: Trunk channel 7: Second outlet channel 8: Outlet port 9: First outlet channel 10: Branch channel 11: Microparticle 12: Lid substrate 13: Bottom substrate

Claims (8)

連続相となる流体を導入するための連続相導入流路と、
分散相となる流体を導入するための、前記連続相導入流路に合流する分散相導入流路と、
前記分散相導入流路が前記連続相導入流路に合流する合流部において形成される前記分散相の微小粒子を含む流体を排出するための排出流路と、を有する微小流路構造体であって、
前記微小流路構造体は石英ガラスからなり、少なくとも前記排出流路の壁面の表面粗さＲａが１０．０ｎｍ以上であることを特徴とする微小流路構造体。 A continuous phase introduction flow path for introducing a fluid to be a continuous phase;
A dispersed phase introduction flow path that joins the continuous phase introduction flow path for introducing a fluid to be a dispersed phase;
A discharge channel for discharging a fluid containing fine particles of the dispersed phase formed at a junction where the dispersed phase introduction channel joins the continuous phase introduction channel. And
The microchannel structure is made of quartz glass, and at least the surface roughness Ra of the wall surface of the discharge channel is 10.0 nm or more. 前記分散相導入流路は、幹流路と、前記幹流路から分岐して前記連続相導入流路に合流する複数の枝流路とを有することを特徴とする請求項１に記載の微小流路構造体。   2. The microchannel according to claim 1, wherein the dispersed phase introduction channel includes a trunk channel and a plurality of branch channels that branch from the stem channel and merge with the continuous phase introduction channel. Structure. 前記連続相導入流路、前記分散相導入流路、および前記排出流路のパターンが形成された石英ガラス基板を２枚以上貼り合せることにより構成されていることを特徴とする請求項１又は２に記載の微小流路構造体。   3. The structure according to claim 1, wherein two or more quartz glass substrates each having a pattern of the continuous phase introduction channel, the dispersed phase introduction channel, and the discharge channel are bonded together. 2. A microchannel structure according to 1. 前記連続相導入流路、前記分散相導入流路、および前記排出流路の下側のパターンが形成された第１の石英ガラス基板と、前記連続相導入流路、前記分散相導入流路、および前記排出流路の上側のパターンが形成された第２の石英ガラス基板とを互いに貼り合せることにより構成されていることを特徴とする請求項１又は２に記載の微小流路構造体。   A first quartz glass substrate in which a pattern on the lower side of the continuous phase introduction channel, the dispersed phase introduction channel, and the discharge channel is formed; the continuous phase introduction channel; the dispersed phase introduction channel; 3. The microchannel structure according to claim 1, wherein the microchannel structure is formed by adhering together a second quartz glass substrate on which an upper pattern of the discharge channel is formed. 前記連続相導入流路が分散相となる流体を導入するための分散相導入口を有し、前記連続相導入流路が連続相となる流体を導入するための連続相導入口を有し、前記排出流路が前記微粒子を含む流体を排出するための排出口を有することを特徴とする、請求項１〜４のいずれか一項に記載の微小流路構造体。   The continuous phase introduction channel has a dispersed phase introduction port for introducing a fluid that becomes a dispersed phase, and the continuous phase introduction channel has a continuous phase introduction port for introducing a fluid that becomes a continuous phase, The microchannel structure according to any one of claims 1 to 4, wherein the discharge channel has a discharge port for discharging a fluid containing the fine particles. 前記分散相導入口、前記連続相導入口及び前記排出口からなる群から選ばれる１以上に、前記排出流路を粗面化するための処理剤を導入する工程を含むことを特徴とする、請求項５に記載の微小流路構造体の製造方法。   Including at least one selected from the group consisting of the dispersed phase inlet, the continuous phase inlet, and the outlet, by introducing a treatment agent for roughening the outlet flow path, The manufacturing method of the microchannel structure of Claim 5. 請求項１〜５のいずれか一項に記載の微小流路構造体の前記連続相導入流路に連続相となる流体を導入し、前記分散相導入流路に分散相となる流体を導入する工程を含むことを特徴とする、微小粒子の製造方法。   A fluid that becomes a continuous phase is introduced into the continuous phase introduction channel of the microchannel structure according to any one of claims 1 to 5, and a fluid that becomes a dispersed phase is introduced into the dispersed phase introduction channel. The manufacturing method of a microparticle characterized by including the process. 前記連続相となる流体及び前記分散相となる流体はそれぞれ液体であり、前記連続相導入流路に連続相となる液体を導入し、前記分散相導入流路に分散相となる液体を導入する工程の前に、連続相となる液体と相溶性のある液体を、前記分散相導入流路および前記連続相導入流路の両方に導入する工程を含むことを特徴とする請求項７に記載の微小粒子の製造方法。   The fluid that becomes the continuous phase and the fluid that becomes the dispersed phase are liquids, respectively, the liquid that becomes the continuous phase is introduced into the continuous phase introduction channel, and the liquid that becomes the dispersed phase is introduced into the dispersed phase introduction channel. 8. The method according to claim 7, further comprising a step of introducing a liquid compatible with the liquid to be a continuous phase into both the dispersed phase introduction channel and the continuous phase introduction channel before the step. A method for producing fine particles.
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