JP2004195338A

JP2004195338A - Particle production method and minute channel structure for the same

Info

Publication number: JP2004195338A
Application number: JP2002365668A
Authority: JP
Inventors: Hirotatsu Kusabe; 博達草部; Akira Kawai; 明川井; Koji Katayama; 晃治片山
Original assignee: Tosoh Corp
Current assignee: Tosoh Corp
Priority date: 2002-12-17
Filing date: 2002-12-17
Publication date: 2004-07-15
Anticipated expiration: 2022-12-17
Also published as: JP4356312B2

Abstract

<P>PROBLEM TO BE SOLVED: To provide a particle production method capable of producing particles in a minute channel, producing the particles by making use of a dispersed phase and a continuous phase even, reducing costs or the amount of wastewater, and correspond to industrial mass production and a minute channel structure for the method. <P>SOLUTION: In the method, the dispersed phase is introduced from one inlet of the minute channel having two inlets for introducing fluid, the continuous phase is introduced from the other inlet, the dispersed phase and the continuous phase are combined to produce particles, and the fluid containing the particles is discharged in an optional direction from the position where the two phases in the minute channel are combined. The minute channel structure has the minute channel having the dispersed phase introduction port for introducing the dispersed phase and a continuous phase introduction port for introducing the continuous phase, a discharge channel for discharging the particles produced by the two phases and a discharge opening communicating with the discharge channel. The aspect ratio (depth/width of channel) of the cross section of the channel is at least 0.30. The discharge channel is extended in the optional direction from the position where both phases are combined. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

【０００１】
【発明の属する技術分野】
本発明は、分取、分離用カラム充填剤等に用いられる微小なゲル粒子などの製造用として好適に用いられる粒子製造方法であり、また、微小な粒子を生成するための微小流路構造体に関する。
【０００２】
【従来の技術】
近年、数ｃｍ角のガラス基板あるいは樹脂製基板上に長さが数ｃｍ程度で、幅及び深さがサブ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て、液体の送液による微小液滴の生成を行う研究が注目されている（例えば非特許文献１参照）。
【０００３】
上記の例では図１に示すように、微小流路基板１の上に、連続相導入口２、連続相導入流路３、分散相導入口４、分散相導入流路５、排出流路７及び排出口８を有したＴ字型の構造体であり、導入された連続相と分散相とが合流する部分に合流部６が存在する。各流路の深さは１００μｍであり、分散相を導入する導入流路幅が１００μｍ、連続相を導入する導入流路幅は３００〜５００μｍのＴ字型微小流路を用いて、分散相と連続相の流れの速さを制御（コントロール）して送液を行うと、分散相と連続相が流路を通じて合流する地点（合流部）において極めて均一な微小粒子の生成が可能となる。また、分散相及び連続相の流量をコントロールすることで生成粒子径をコントロールすることも可能となる。
【０００４】
しかしながらこの方法は、連続相の導入流路幅が分散相の導入流路幅に対し、３〜５倍広い導入流路を用いており、分散相及び連続相を同一流速で送液した場合、流路幅が狭い分散相の導入流路内で線速は速くなってしまうため、分散相及び連続相がその合流部以降の流れにおいて層流となってしまうことがあり、結果として合流部において粒子生成が出来なくなってしまうという課題があった。
【０００５】
この課題を解決し微小な粒子を生成させるためには、連続相を過剰に供給する必要があるが、微小な粒子を生成させてゲル等を工業的に量産する場合には、分散相の使用量に対し連続相の使用量を過剰にすることが必要となり、低コスト化、あるいは廃液量の低減などの課題があり、さらなる改善が求められていた。
【０００６】
【非特許文献１】
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
【０００７】
【発明が解決しようとする課題】
以上のように従来の微小流路内における粒子製造技術は、Ｔ字型微小流路において連続相と分散相の合流部で極めて均一な液滴の生成が可能となるが、連続相の導入流路幅が分散相の導入流路幅に対し３〜５倍広い導入流路を用いているので、分散相及び連続相を同一の流速で送液すると、分散相及び連続相は層流を形成してしまい、合流部において粒子の生成ができなくなることがあった。そのために合流部での粒子生成には連続相を過剰に供給する必要があり、連続相の低コスト化、あるいは廃液量の低減などの課題があり、工業的に量産する場合にはさらなる改善が求められていた。
【０００８】
本発明は、上記課題を鑑みてなされたもので、微小流路内での粒子生成を可能とすると共に、分散相と連続相の使用量を均一にしての粒子製造も可能であり、また、低コスト化あるいは廃液量の低減を可能とし、工業的な量産にも対応できる粒子製造方法及びそのための微小流路構造体を提供することにある。
【０００９】
【課題を解決するための手段】
本発明者らは、流体を導入するための導入口を有した微小流路の一方の側より分散相を、もう一方の側より連続相を導入し、前記分散相と前記連続相とを合流させることで微小な粒子を生成させることができ、さらに、生成した粒子を含む流体を微小流路中の分散相と連続相とが合流した位置（以下、「合流部」という。）より任意の方向へ排出させることで上記課題を解決できることを見出した。さらに、このように粒子を生成させるために、分散相を導入するための導入口及びそれに連通する分散相導入流路と、連続相を導入するための導入口及びそれに連通する連続相導入流路と、分散相及び連続相により生成された粒子を排出させるための排出流路及びそれに連通する排出口とを備え、流路断面のアスペクト比（流路の深さ／幅の比）が０．３０以上であり、かつ、排出流路が微小流路中の分散相と連続相とが合流した位置より任意の方向へ延びている構造とすることで本発明の目的を達成できることも見出し、遂に本発明を完成するに至った。
【００１０】
すなわち本発明は、流体を導入するための導入口を有した微小流路の一方の側より分散相を、もう一方の側より連続相を導入し、分散相と連続相とを合流させて粒子を生成させ、生成した粒子を含む流体を、微小流路中の分散相と連続相とが合流した位置より任意の方向へ排出させる粒子製造方法であり、さらに、これを達成するための構造体であって、分散相を導入するための導入口及びそれに連通する分散相導入流路と、連続相を導入するための導入口及びそれに連通する連続相導入流路と、分散相及び連続相により生成された粒子を排出させるための排出流路及びそれに連通する排出口とを備えた微小流路構造体であって、流路断面のアスペクト比（流路の深さ／幅の比）が０．３０以上であり、かつ、前記排出流路が微小流路中の分散相と連続相とが合流した位置より任意の方向へ延びている構造となっている微小流路構造体である。
【００１１】
以下、本発明を詳細に説明する。
＜粒子製造方法＞
上記したように、本発明の粒子製造方法は、流体を導入するための導入口を有した微小流路の一方の側より分散相を、もう一方の側より連続相を導入し、分散相と連続相とを合流させて粒子を生成させ、生成した粒子を含む流体を、微小流路中の分散相と連続相とが合流した位置より任意の方向へ排出させるものである。
【００１２】
ここで、本発明において用いられる分散相とは、微小流路構造体により粒子を生成させるための液状物であり、例えば、スチレンなどの重合用のモノマー、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媒体を指す。ここで分散相としては、本発明が微小な粒子を効率的に生成させることを目的としており、この目的を達成させるためであれば微小流路構造体中の流路を送液できるものであれば特に制限されず、さらに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。また、分散相中に一部固体状物が混在したスラリー状のものであっても差し支えない。
【００１３】
本発明において用いられる連続相とは、微小流路構造体により分散相より粒子を生成させるために用いられる液状物であり、例えば、ポリビニルアルコールのゲル製造用の分散剤を適当な溶媒に溶解した媒体を指す。ここで連続相としては分散相と同様に、微小流路構造体中の流路を送液できるものであれば特に制限されず、さらに粒子を形成させることができればその成分は特に制限されない。また、連続相中に一部固体状物が混在したスラリー状のものであっても差し支えない。
【００１４】
さらに、分散相と連続相とは粒子を生成させるために、実質的に交じり合わないあるいは相溶性がないことが必要であり、例えば、分散相として水相を用いた場合には連続相としては水に実質的に溶解しない酢酸ブチルといった有機相が用いられることとなる。また、連続相として水相を用いた場合にはその逆となる。
【００１５】
本発明においては、流体を導入するための導入口を有した微小流路の一方の側より分散相を、もう一方の側より連続相を導入し、この微小流路内を分散相及び連続相は互いに向かって反対方向に送液される。そして、両者が合流する合流部の微小流路近傍あるいはその両側の面に設けられた排出流路に排出される際に液滴を生成させるものである。
【００１６】
ここで、分散相及び連続相を導入するための微小流路は、分散相及び連続相の送液速度や流路の構造、使用にあたっての目的等により一概には言えず、その形状が直線状であっても曲線を含んだ形状のいずれであっても差し支えないが、微小流路の粒子生成箇所を挟む両端あるいはその近傍に導入口が設けられており、その導入口より分散相及び連続相が導入できる構造となっておればよい。
【００１７】
導入された分散相と連続相は微小流路に沿って送液されるわけであるが、両者が合流する合流部近傍あるいはその両側には、合流し粒子が生成された後に、この粒子を含む流体が排出されるよう、１又は２以上の排出流路が設けられており、粒子を含む流体はこの排出流路より排出されることとなる。
【００１８】
分散相と連続相が合流して生成された粒子を含む流体が排出される場合、排出流路の配置は合流部より粒子を含む流体が滞りなく送液される構造を有しておれば良く、通常、合流部近傍の微小流路内壁に設けられた開口部を通じて排出流路へ送液される。
【００１９】
この排出流路は、微小流路中の分散相と連続相とが合流した位置より任意の方向に配置されておれば良く、例えば微小流路と同一平面上であっても垂直方向であってもよく、さらには、任意の角度を持った方向であってもよい。さらに、任意の２以上の方向へ排出させることで、粒子をより効率的に排出させることができると共に、ひいては粒子生成速度を大きくすることができるために工業的量産に好適となる。
【００２０】
また、微小流路中の分散相と連続相とが合流した合流部において、分散相の送液方向と連続相の送液方向とから形成される交差角度を変化させることで、生成する粒子の粒子径を制御することができ好ましい態様となる。この交差角度については、目的に応じ適宜設定すればよい。
【００２１】
さらに、排出された粒子を含む流体を、再度合流させて粒子を含む流体を回収することで微小流路を通じて生成された粒子は最終的に同一容器等にて回収することができ、工業プロセスとして有用なものとなる。
【００２２】
なお、本発明の方法により分散相と連続相とから得られる粒子は、当初は液滴のような液体状のものであるが、例えば、ゲル製造用の原料及び重合開始剤等を含んでおれば、これに光照射処理や加熱処理することで硬化させて固体状のゲルとすることができ、このような手法は公知の方法を用いることができる。また、ゲルを製造するにあたっては、以下で述べる微小流路構造体中で得ることもできるが、微小流路構造体からと出した後に処理をしてゲルを得てもよい。
＜微小流路構造体＞
本発明の微小流路構造体は、上記した粒子製造を行うための構造体であって、分散相を導入するための分散相導入口及び連続相を導入するための連続相導入口を有した微小流路と、分散相及び連続相により生成された粒子を排出させるための排出流路及びそれに連通する排出口とを備えた微小流路構造体であって、流路断面のアスペクト比（流路の深さ／幅の比）が０．３０以上であり、かつ、前記排出流路が前記微小流路中の分散相と連続相とが合流する位置より任意の方向へ延びている構造となっているものである。
【００２３】
ここで、分散相導入口は分散相を導入するための開口部を意味し微小流路と連通しており、さらに、この導入口に適当なアタッチメントを備えて分散相を連続的に導入する機構としてもよい。同様に、連続相導入口は連続相を導入するための開口部を意味し微小流路と連通しており、さらに、この導入口に適当なアタッチメントを備えて連続相を連続的に導入する機構としてもよい。
【００２４】
分散相導入口及び連続相導入口の位置は、通常は微小流路中の合流部から離れた微小流路の両端に配置される。
【００２５】
導入された分散相及び連続相は微小流路に沿って送液されるが、微小流路の形状は粒子の形状、粒子径を制御するにおいて影響を与えるものの、流路の幅は数１００μｍ以下であればよい。
【００２６】
導入された分散相と連続相とはこの微小流路の所定の部位である合流部にて合流することとなる。分散相と連続相との送液方向は必然的に微小流路の形状により決定されるわけであるが、合流部における両者の送液方向から形成される交差角度としては、合流により粒子が生成するものであれば特に制限されるものではなく任意の角度で交わる構造であればよく、さらに、この交差角度が実質的に１８０゜又は粒子生成箇所を挟む連続する曲線導入路上にあれば、分散相と連続相とが全くの反対方向からの流体が合流することとなって粒子形成に有効となり、好ましい。
【００２７】
微小流路の合流部より排出口を通じて延びている排出流路においては、上記の微小流路の任意の位置で連通していることから、分散相と連続相が合流して後に、排出口を通じて排出流路に排出される際に粒子化し、生成した粒子は送液され、排出口より排出される。排出流路の形状は特に制限されないが、その幅は数１００μｍ以下で、導入流路からの送液が排出口との交差部で液滴を形成し得る交差角度をなしておればよい。排出口は、生成された粒子を排出させるための開口部を意味し、さらに、この排出口に適当なアタッチメントを備えて生成された粒子を含む相を連続的に排出する機構としてもよい。
【００２８】
また、この交差角度や、合流部での微小流路や排出流路の幅と深さ、分散相と連続相の流速を、それぞれ独立してあるいは協同的に種々変えることにより生成する粒子を所望の粒子径へと制御することが可能となる。
【００２９】
さらに微小流路中の分散相と連続相とが合流した位置の近傍、すなわち合流部において、流路の底面あるいは上面あるいは側面から１つ以上の突起が形成されていることが好ましい。例えば、図６（ａ）のように、分散相流路側にＶ字形状等の突起物からなる障害物をおき、分散相幅を障害物部分で左右に均等に分割し、図６（ｂ）のようにより細い流路幅に分岐させることにより、より細粒で粒径の揃った液滴が排出流路で生成できる。さらに、図６（ｂ）のように、単なるＶ字形状の突起ではなく、角度の異なる２種類のＶ字を組合わせ、分岐して合流する二つの流れの方向が平行流にならないように設計し、安定な粒子生成が可能になる。また、排出流路に誘導する分岐路の外壁の向きを上記２種類のＶ字状突起物のそれぞれの方向と平行に設計し分散相が連続相によって剪断されやすい角度で合流するようにすることでより安定した粒子の生成が可能となる。
【００３０】
また、配置された突起物部分で流路から送液される一つの流体の流れを二つの排出流路に分割し、上記排出流路から同時に粒子を回収することにより、単位時間あたりの粒子個数収量を倍増させることができ、工業的な量産に適している。さらに、図６（ｃ）のように、このような突起を微小流路に複数設け、各導入口からの分散相と連続相の流れの向きに排出路及び突起物の向きをあわせ、設置された突起の両側及びその間の微小流路に設けた各導入口に分散相と連続相を交互に送液する構造とすることで粒子収量を一層大きくすることができる。
【００３１】
なお、分散相と連続相は分岐される数に応じた流路幅に流路設計を調整し、分岐後の流量が所望する粒径の粒子を形成できるようにし、排出流路の幅も連続相及び分散相の分岐される数に応じて流路幅が同じになるように設計し、突起物の形状、数、大きさを適宜変えて合流する２液が粒子を形成し得る交差角度をなすように設計すれば良い。
【００３２】
また、分散相の送液速度と連続相の送液速度とが実質的に同じであれば、粒子の粒径を揃えることが容易となると共に、粒子個数収量も倍増するなどコスト面においても優れている。尚、ここでいう分散相の送液速度と連続相の送液速度とが実質的に同じとは、送液速度が互いに多少変動しても生成する粒子の粒径には大きな影響を与えないことを意味している。
【００３３】
微小流路、排出流路において、その断面形状としては、流路断面のアスペクト比が０．３０以上であることが好ましく、さらに０．３０以上３．０未満であることがこのましい。アスペクト比がこの範囲にあれば、合流部において均一な粒子を生成させることができる。この範囲を逸脱して、アスペクト比が０．３０未満となると均一な粒子を生成させることが困難となることがある。
【００３４】
また、連続相、分散相として用いられる媒体の性質にもよるが、連続相導入流路と分散相導入流路とが交わる交差部及びその近傍が高分子材料で形成されていることで、耐溶媒性を高め、また、強度等を向上させることができるため、好ましい。
【００３５】
さらに、微小流路の分散相側の流路と連続相側の流路とが等しい幅、深さであれば、上記の効果に加え、微小流路構造体の設計が容易となり、また、送液時の制御もより容易となって、工業的量産に好適となる。
【００３６】
また、微小流路の幅と排出流路の幅との関係において、微小流路の幅≧排出流路の幅であれば、微小流路の幅＝排出流路の幅の場合よりも、送液流速を増加しても合流部において均一な粒子の生成が可能となり、粒子生成速度を増加させることができるという効果を奏することができ、好ましい態様となる。
【００３７】
本発明の微小流路構造体において、微小流路に連通し、生成された粒子を排出するための排出流路としては、微小流路中の分散相と連続相とが合流する位置より任意の方向へ延びている構造となっていることが好ましく、さらにこの排出流路は任意の２以上の方向へ延びている構造となっていることが好ましい。このような構造とすることで、分散相と連続相により形成される粒子を効率的に得ることができ、工業的量産に好適となる。
【００３８】
排出流路の幅としては、分散相と連続相とが交わり流れる合流部より排出口に至る排出流路中の一部の部位において、排出流路の幅が狭くなっていることが好ましい。すなわち、粒子排出口に至るまでの間の内、微小流路と排出流路との連結部において部分的に狭くするあるいは微小流路中の分散相側に沿った流路構成壁を凸状に形成することで送液流速を増加しても合流部において均一な粒子生成が可能でありかつ、送液圧力の上昇を緩和することが可能とすることができ、好ましい態様となる。
【００３９】
さらに、この排出流路の幅が狭くなっている部位が、排出流路中の分散相と連続相とが合流した位置又はその近傍にあることが好ましく、特に、排出流路の幅が狭くなっている部位が、排出流路中の分散相と連続相とが合流した位置の分散相導入流路側にあることが好ましい。
【００４０】
本発明の微小流路構造体は、以上に述べた構造、性能を有しているが、分散相と連続相とは微小流路に沿って互いに反対方向から合流させ、その後に生成された粒子を排出させるため、分散相及び連続相を導入し、また、粒子を含む流体を排出するための開口部を設ける必要があるが、このために微小流路が形成された基板面を覆うような構造で、上記の開口部に相当する所定の位置に、微小流路や排出流路と微小流路構造体の外部とを連通するための小穴が配置されたカバー体とが積層一体化されていてもよい。これにより、微小流路構造体外部から内部の流路へ流体を導入し、再び微小流路構造体外部へ流体を排出することができ、流体が微小量であったとしても、流体を安定して微小流路内を通過させる事が可能となる。流体の送液は、マイクロポンプなどの機械的手段によって可能となる。図６（ｃ）及び図６（ｄ）のように、粒子収量を一層大きくする場合には同一のマイクロポンプから複数の分散相導入口へ分岐して送液する。同様に複数の連続相導入口へも同一のマイクロポンプからの液を分岐して送液する。このような共通のマイクロポンプを用いる送液方法により、それぞれの排出路からは均一な粒子の生成が可能となる
微小流路が形成された基板及びカバー体の材質としては、微小流路の形成加工が可能であって、耐薬品性に優れ、適度な剛性を備えたものが望ましい。例えば、ガラス、石英、セラミック、シリコン、あるいは金属や樹脂等であっても良い。基板やカバー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望ましい。カバー体に配置された小穴は、微小流路と微小流路構造体外部とを連通し、流体の導入口または排出口として用いる場合には、その径が例えば数ｍｍ以下である事が望ましい。カバー体の小穴の加工には、化学的に、機械的に、あるいはレーザー照射やイオンエッチングなどの各種の手段によって可能とされる。
【００４１】
また本発明の微小流路構造体は、微小流路が形成された基板とカバー体は、熱処理接合あるいは光硬化樹脂や熱硬化樹脂などの接着剤を用いた接着等の手段により積層一体化することができる。
【００４２】
【発明の実施の形態】
以下では、本発明の実施例を示し、更に詳しく発明の実施の形態について説明する。なお、本発明は以下の実施例に限定されるものではなく、本発明の要旨を逸脱しない範囲で、任意に変更可能であることは言うまでもない。
【００４３】
また、実施例においては１枚の基板上に１本の微小流路を形成したが、工業的に量産する場合は、１枚の基板上に多数の微小流路を形成する、あるいは多数形成した１枚の基板を積層することで可能となる。
【００４４】
この粒子製造用微小流路構造体は図３に示す製作手順に従って以下のように作製した。厚さ１ｍｍで７０ｍｍ×２０ｍｍのガラス基板９の一方の面に、金などの金属膜１０を後述する露光光が透過しない程度の厚さに成膜し（図３（ａ）金属の成膜工程）、その金属膜上にフォトレジスト１１をコートした（図３（ｂ）フォトレジストの塗布工程）。更にフォトレジスト上に前記微小流路の形状を描いたパターンを有するフォトマスク１２を置き、そのフォトマスク上から露光し現像を行なった（図３（ｃ）露光〜現像工程）。次に、酸などで金属膜１０をエッチングした（図３（ｄ）金属膜のエッチング工程）後、レジストとガラスをフッ酸などでエッチィングし（図３（ｅ）レジスト、ガラスのエッチング工程）、さらに残った金属膜１０を酸などで溶かして（図３（ｆ）金属膜の除去工程）、微小流路が形成された基板１３を得た。実施例においては、微小流路の製作をガラス基板のエッチィングにより微小流路を形成したが、製作方法はこれに限定するものではない。
（実施例１）
本発明の第１の実施例における粒子製造用微小流路を図２に示す。微小流路は７０ｍｍ×２０ｍｍ×１ｔ（厚さ）のパイレックス（登録商標）ガラス上に、微小流路に相当する連続相導入流路２、分散相導入流路５及び排出流路７の幅がいずれも２２０μｍ、深さ８０μｍ、微小流路のアスペクト比＝０．３６である両側剪断層構造体形状とし、分散相導入流路５と両側面の２つの排出口８とそれぞれ６０度の角度にて交わる合流部６を持った両側剪断層構造体形状の流路を１本形成した。合流部６で分散相及び連続相の両流路が分岐し、両側面の排出流路では分岐した異なる種類の２相が合流した流れとなって排出される。この微小流路の幅及び深さについては、生成する粒子の粒子径に依存するが、微小流路のアスペクト比が０．３以上３未満の範囲を逸脱しなければよい。
【００４５】
この微小流路が形成された基板１３の微小流路を有する面に、微小流路の流体導入口（連続相導入口２、分散相導入口４）と流体排出口８にあたる位置に予め直径０．６ｍｍの小穴を、機械的加工手段を用いて設けた厚さ１ｍｍで７０ｍｍ×２０ｍｍのガラスカバー体１４を熱接合し、図４に示すように微小流路を備えた粒子製造用微小流路構造体を製作した。実施例においては、微小流路を形成する基板及びカバー体にガラス基板を用いたが、これに限定するものではない。
【００４６】
次に本発明の粒子製造方法について説明する。図５に示すように粒子製造用微小流路構造体１５に液体が送液可能なようにホルダー１６などで保持すると共に、テフロン（登録商標）チューブ１８及びフィレットジョイント１９をホルダー１６に固定する。テフロン（登録商標）チューブ１８のもう一方はマイクロシリンジ２１、２２に接続する。これで粒子製造用微小流路構造体１５に液体の送液が可能となる。次に粒子を生成するための分散相にモノマー（スチレン）、ジビニルベンゼン、酢酸ブチル及び過酸化ベンゾイルの混合溶液をマイクロシリンジ２１に、連続相にポリビニルアルコール３％水溶液をマイクロシリンジ２２に注入し、マイクロシリンジポンプ２０で送液を行った。送液流速は分散相及び連続相は共に２０μｌ／ｍｉｎである。送液流速が共に安定した状態で、粒子製造用微小流路構造体１５の分散相及び連続相が交わる合流部にて粒子生成が観察される（図６）。生成された粒子を観察すると図７に示すように平均粒子径２００μｍの極めて均一な粒子２３であった。また、送液流速を分散相及び連続相を共に１μｌ／ｍｉｎで行った場合、生成粒子の平均粒子径は２３０μｍの極めて均一な粒子であった。これにより分散相と連続相を同一の送液流速にて行っているので、連続相を過剰に送液することなく、分散度が１０％の均一な粒子を生成することが可能となる。
（実施例２）
本発明の第２の実施例における粒子製造用微小流路を図２に示す。微小流路は７０ｍｍ×２０ｍｍ×１ｔ（厚さ）のパイレックス（登録商標）ガラス上に、微小流路に相当する連続相導入流路２、分散相導入流路５の幅がいずれも２２０μｍ、深さ５０μｍ、排出流路７の幅が１１０μｍ、深さ５０μｍ、アスペクト比＝０．４５である両側剪断層構造体形状とし、分散相導入流路５と両側面の２つの排出口８とそれぞれ６０度の角度にて交わる合流部６を持った形状の流路を１本形成した。合流部６の拡大図は図６に示すように１辺８０μｍのＶ字形突起物２４を尖点側が分散相流路側に向くようにパターン作製時に合流部に設け、分散相及び連続相の両流路が両側面の排出流路に分岐される。この微小流路の幅及び深さについては、生成する粒子の粒子径に依存するが、微小流路の粒子が生成する場所でのアスペクト比が０．３以上３未満の範囲を逸脱しなければよい。また、実施例においては、合流部の突起物にＶ字形突起物を用いたが、流路の幅や角度に応じて粒子を形成しうるものであれば突起物のサイズや形状を限定するものではない。
【００４７】
この微小流路が形成された基板１３の微小流路を有する面に、微小流路の流体導入口（連続相導入口２、分散相導入口４）と流体排出口８にあたる位置に予め直径０．６ｍｍの小穴を、機械的加工手段を用いて設けた厚さ１ｍｍで７０ｍｍ×２０ｍｍのガラスカバー体１４を熱接合し、図４に示すように微小流路を備えた液滴生成用微小流路構造体を製作した。実施例においては、微小流路を形成する基板及びカバー体にガラス基板を用いたが、これに限定するものではない。
【００４８】
次に本発明の粒子製造方法について説明する。図５に示すように粒子製造用微小流路構造体１５に液体が送液可能なようにホルダー１６などで保持すると共に、テフロン（登録商標）チューブ１８及びフィレットジョイント１９をホルダー１６に固定する。テフロン（登録商標）チューブ１８のもう一方はマイクロシリンジ２１、２２に接続する。これで粒子製造用微小流路構造体１５に液体の送液が可能となる。次に粒子を生成するための分散相にモノマー（スチレン）、ジビニルベンゼン、酢酸ブチル及び過酸化ベンゾイルの混合溶液をマイクロシリンジ２１に、連続相にポリビニルアルコール３％水溶液をマイクロシリンジ２２に注入し、マイクロシリンジポンプ２０で送液を行った。送液流速は分散相及び連続相は共に２０μｌ／ｍｉｎである。送液流速が共に安定した状態で、粒子製造用微小流路構造体１５の分散相及び連続相が交わる合流部にて粒子生成が観察される。生成された粒子を観察すると平均粒子径１１０μｍの極めて均一な粒子であった。また、送液流速を分散相及び連続相を共に１μｌ／ｍｉｎで行った場合、生成粒子の平均粒子径は１００μｍの極めて均一な粒子であった。これにより分散相と連続相を同一の送液流速にて行っているので、連続相を過剰に送液することなく、合流部に突起物を形成することにより、分散度も８％に向上した。合流部に突起物を形成させることにより均一な粒子を安定に生成することが可能となる。
【００４９】
【発明の効果】
本発明の粒子製造方法は、上記のように構成された粒子製造用微小流路構造体の合流部で極めて均一な粒子生成が可能となる。分散相と連続相との合流部分に突起物や分岐路を形成することで、均一でより安定した所望の粒径の粒子を生成することができる。また、粒子製造用微小流路構造体は、分散相と連続相の導入流路の幅及び深さを同一とし、分散相と連続相の使用量を同一とすることが可能となる。分散相と連続相の両者がそれぞれ２方向に分岐し、それぞれの一方ずつが合流して異なる排出路から液滴が同時に排出される。これにより一つの粒子製造用微少流路構造体を用いて、同時に二つの粒子製造用微小流路構造体を用いたと同じ効果が得られ、粒子の収量が増加するので工業的量産に適している。また、分散相の流路は合流部で別れて二つの細い分岐路になるため、より小さい径の粒子の生成が可能になる。さらに、
図６（ｄ）のように１枚の基板上に多数の微小流路を環状に連続させて配置し、それぞれの排出路からの
均一で多数の粒子を同時に回収することが可能となる。
【００５０】
【図面の簡単な説明】
【図１】従来の粒子製造用微小流路を示す概略図である。図１中、Ａ−Ａ’、Ｂ−Ｂ’で示される部分は、それぞれ流路の断面部分を拡大したものである。
【図２】実施例１，２における粒子製造用微小流路構造体を示す概略図である。図２中、Ｃ−Ｃ’で示される部分は、それぞれ流路の断面部分を拡大したものである。
【図３】実施例１における粒子製造用微小流路の形成方法を示すフロー図である。
【図４】実施例１，２における粒子製造用微小流路構造体を示す概略図である。
【図５】実施例１，２における粒子製造法を示す概略図である。
【図６】液滴生成用微小流路を示す概略図である。図６（ａ）は実施例２における粒子製造用微小流路を示す概略図であり、図６（ｂ）は突起部の形状を替えた態様の一例であり、図６（ｃ）（ｄ）は微小流路の配置を替えた態様の一例である。
【図７】実施例２における生成粒子を示す図である。
【符号の説明】
１：微小流路基板
２：連続相導入口
３：連続相導入流路
４：分散相導入口
５：分散相導入流路
６：合流部
７：排出流路
８：排出口
９：ガラス基板
１０：金属膜
１１：フォトレジスト
１２：フォトマスク
１３：微小流路が形成された基板
１４：カバー体
１５：微小流路構造体
１６：ホルダー
１７：ビーカー
１８：テフロン（登録商標）チューブ
１９：フィレットジョイント
２０：マイクロシリンジポンプ
２１：マイクロシリンジ（連続相）
２２：マイクロシリンジ（分散相）
２３：生成粒子
２４：合流部突起物（Ｖ字形）[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention is a particle production method suitably used for production of fine gel particles and the like used for preparative and separation column packings, and a fine channel structure for producing fine particles. About.
[0002]
[Prior art]
In recent years, using a microchannel structure having a microchannel with a length of about several cm, a width and a depth of sub μm to several hundred μm on a glass substrate or a resin substrate of several cm square, Attention has been paid to research for generating microdroplets by sending liquid (for example, see Non-Patent Document 1).
[0003]
In the above example, as shown in FIG. 1, a continuous phase inlet 2, a continuous phase inlet 3, a dispersed phase inlet 4, a dispersed phase inlet 5, and a discharge channel 7 are placed on the microchannel substrate 1. And a T-shaped structure having a discharge port 8, and a junction 6 exists at a portion where the introduced continuous phase and the dispersed phase merge. The depth of each channel is 100 μm, the width of the introduction channel for introducing the dispersed phase is 100 μm, and the width of the introduction channel for introducing the continuous phase is 300 to 500 μm. When the flow rate of the continuous phase is controlled (controlled) and the liquid is sent, extremely uniform fine particles can be generated at a point where the dispersed phase and the continuous phase merge through the flow path (merging portion). Further, by controlling the flow rates of the dispersed phase and the continuous phase, it is possible to control the produced particle diameter.
[0004]
However, in this method, the introduction flow path width of the continuous phase is 3 to 5 times wider than the introduction flow path width of the dispersed phase, and when the dispersion phase and the continuous phase are sent at the same flow rate, Since the linear velocity becomes high in the introduction flow path of the dispersed phase having a narrow flow path width, the dispersed phase and the continuous phase may become laminar in the flow after the junction, and as a result, at the junction. There was a problem that particle generation became impossible.
[0005]
In order to solve this problem and generate fine particles, it is necessary to supply a continuous phase in excess.However, when the fine particles are generated and a gel or the like is mass-produced industrially, the use of a dispersed phase is required. It has become necessary to use an excessive amount of the continuous phase with respect to the amount, and there have been problems such as cost reduction and reduction of the amount of waste liquid, and further improvement has been demanded.
[0006]
[Non-patent document 1]
Takashi Nishisako et al., "Generation of microdroplets in liquid in microchannel", Proceedings of the 4th Technical Meeting of the Society for Chemistry and Microsystems, 59 pages, published in 2001 [0007]
[Problems to be solved by the invention]
As described above, the conventional particle production technology in a microchannel can generate extremely uniform droplets at the junction of the continuous phase and the dispersed phase in the T-shaped microchannel. Since the passage width is 3 to 5 times wider than the passage width of the dispersed phase, when the dispersed phase and the continuous phase are fed at the same flow rate, the dispersed phase and the continuous phase form a laminar flow. In some cases, particles could not be generated at the junction. For this reason, it is necessary to supply an excessive amount of the continuous phase for particle generation at the junction, and there are problems such as a reduction in the cost of the continuous phase and a reduction in the amount of waste liquid. Was sought.
[0008]
The present invention has been made in view of the above problems, it is possible to generate particles in the micro-channel, it is also possible to produce particles with uniform use of the dispersed phase and the continuous phase, An object of the present invention is to provide a method for producing particles that can be reduced in cost or reduce the amount of waste liquid and can be used for industrial mass production, and a microchannel structure for the method.
[0009]
[Means for Solving the Problems]
The present inventors introduce a dispersed phase from one side of a microchannel having an inlet for introducing a fluid and a continuous phase from the other side, and merge the dispersed phase and the continuous phase. By doing so, fine particles can be generated, and further, a fluid containing the generated particles can be arbitrarily set at a position where the dispersed phase and the continuous phase in the fine flow channel merge (hereinafter, referred to as a “merging portion”). It has been found that the above problem can be solved by discharging in the direction. Furthermore, in order to generate particles as described above, an inlet for introducing a dispersed phase and a dispersed phase introduction flow path communicating therewith, and an inlet for introducing a continuous phase and a continuous phase introduction flow path communicated therewith. And a discharge channel for discharging particles generated by the dispersed phase and the continuous phase, and a discharge port communicating with the discharge channel, and the aspect ratio (ratio of depth / width of the flow channel) of the cross section of the flow channel is 0. It has also been found that the object of the present invention can be achieved by adopting a structure in which the discharge channel is 30 or more, and the discharge channel extends in an arbitrary direction from a position where the dispersed phase and the continuous phase in the microchannel merge. The present invention has been completed.
[0010]
That is, the present invention introduces a dispersed phase from one side of a microchannel having an inlet for introducing a fluid and a continuous phase from the other side, and joins the dispersed phase and the continuous phase to form particles. Is a particle manufacturing method for discharging a fluid containing the generated particles in an arbitrary direction from a position where the dispersed phase and the continuous phase merge in the microchannel, and a structure for achieving this. An introduction port for introducing a dispersed phase and a dispersed phase introduction flow path communicating therewith, an introduction port for introducing a continuous phase and a continuous phase introduction flow path communicated therewith, and a dispersed phase and a continuous phase. A microchannel structure having a discharge channel for discharging generated particles and a discharge port communicating with the discharge channel, wherein an aspect ratio (ratio of depth / width of the channel) of a channel cross section is 0. 30 or more, and the discharge channel is a minute channel. A fine channel device which has a structure in which the phase and the continuous phase extends in any direction from the position confluence.
[0011]
Hereinafter, the present invention will be described in detail.
<Particle production method>
As described above, the particle production method of the present invention introduces a dispersed phase from one side of a microchannel having an inlet for introducing a fluid and a continuous phase from the other side, and forms a dispersed phase. The continuous phase and the continuous phase are merged to generate particles, and the fluid containing the generated particles is discharged in an arbitrary direction from the position where the dispersed phase and the continuous phase merge in the microchannel.
[0012]
Here, the dispersed phase used in the present invention is a liquid material for generating particles by the microchannel structure, for example, a monomer for polymerization such as styrene, a crosslinking agent such as divinylbenzene, and a polymerization initiator. Etc. refers to a medium in which a raw material for producing a gel is dissolved in a suitable solvent. Here, as the disperse phase, the purpose of the present invention is to efficiently generate fine particles, and if the purpose is to achieve this purpose, any liquid phase can be sent through the flow path in the fine flow path structure. There is no particular limitation on the components, as long as the particles can be further formed. Also, a slurry in which a solid material is partially mixed in the dispersed phase may be used.
[0013]
The continuous phase used in the present invention is a liquid substance used to generate particles from the dispersed phase by the microchannel structure, for example, a polyvinyl alcohol gel dispersant dissolved in an appropriate solvent. Refers to the medium. Here, as in the case of the dispersed phase, the continuous phase is not particularly limited as long as it can feed a flow path in the microchannel structure, and the components thereof are not particularly limited as long as particles can be formed. Further, a slurry in which a solid material is partially mixed in the continuous phase may be used.
[0014]
Further, in order to form particles, the dispersed phase and the continuous phase need to be substantially non-compounding or not compatible.For example, when an aqueous phase is used as the dispersed phase, An organic phase such as butyl acetate that is substantially insoluble in water will be used. When an aqueous phase is used as the continuous phase, the reverse is true.
[0015]
In the present invention, a dispersed phase is introduced from one side of a microchannel having an inlet for introducing a fluid, and a continuous phase is introduced from the other side. Are sent in opposite directions toward each other. Then, droplets are generated when the liquid droplets are discharged to discharge channels provided in the vicinity of the microchannel at the merging portion where the two merge, or at both sides thereof.
[0016]
Here, the microchannel for introducing the dispersed phase and the continuous phase cannot be described unconditionally due to the liquid sending speed of the dispersed phase and the continuous phase, the structure of the channel, the purpose of use, and the like, and the shape is linear. However, an inlet may be provided at or near both ends of the microchannel, sandwiching the particle generation point, and a dispersed phase and a continuous phase may be provided from the inlet. What is necessary is just to be the structure which can introduce.
[0017]
The introduced dispersed phase and the continuous phase are sent along the microchannel, but the particles are merged at or near the junction where they both merge, and after the particles are generated, these particles are contained. One or more discharge channels are provided so that the fluid is discharged, and the fluid containing particles is discharged from this discharge channel.
[0018]
When the fluid containing particles generated by the combined of the dispersed phase and the continuous phase is discharged, the arrangement of the discharge flow path may have a structure in which the fluid containing the particles is sent from the confluent portion without interruption. Usually, the liquid is sent to the discharge channel through an opening provided in the inner wall of the microchannel near the junction.
[0019]
The discharge channel may be arranged in any direction from the position where the dispersed phase and the continuous phase in the microchannel merge, and may be, for example, in the vertical direction even on the same plane as the microchannel. Or a direction having an arbitrary angle. Further, by discharging the particles in two or more arbitrary directions, the particles can be discharged more efficiently, and the particle generation rate can be increased, which is suitable for industrial mass production.
[0020]
Further, at the junction where the dispersed phase and the continuous phase merge in the microchannel, by changing the crossing angle formed from the liquid feeding direction of the dispersed phase and the liquid feeding direction of the continuous phase, the generated particles This is a preferable embodiment in which the particle diameter can be controlled. This intersection angle may be set as appropriate according to the purpose.
[0021]
Furthermore, by combining the discharged fluid containing particles again and collecting the fluid containing particles, the particles generated through the microchannel can be finally recovered in the same container or the like. It will be useful.
[0022]
The particles obtained from the dispersed phase and the continuous phase according to the method of the present invention are initially in a liquid state such as droplets, but include, for example, a raw material for gel production and a polymerization initiator. For example, this can be cured by light irradiation treatment or heat treatment to form a solid gel, and a known method can be used as such a method. In producing the gel, the gel can be obtained in the microchannel structure described below. Alternatively, the gel may be obtained by treating the gel after taking it out of the microchannel structure.
<Microchannel structure>
The microchannel structure of the present invention is a structure for performing the above-described particle production, and has a dispersed phase introduction port for introducing a dispersed phase and a continuous phase introduction port for introducing a continuous phase. A microchannel structure including a microchannel, a discharge channel for discharging particles generated by a dispersed phase and a continuous phase, and a discharge port communicating with the microchannel, wherein an aspect ratio (flow A depth / width ratio of the channel is 0.30 or more, and the discharge channel extends in an arbitrary direction from a position where the dispersed phase and the continuous phase in the micro channel merge. Is what it is.
[0023]
Here, the disperse phase introduction port means an opening for introducing the disperse phase and is in communication with the microchannel. Further, a mechanism for continuously introducing the disperse phase by providing an appropriate attachment to this inlet is provided. It may be. Similarly, the continuous phase introduction port means an opening for introducing the continuous phase and is in communication with the microchannel. Further, a mechanism for continuously introducing the continuous phase by providing an appropriate attachment to the introduction port is provided. It may be.
[0024]
The positions of the dispersed phase introduction port and the continuous phase introduction port are usually arranged at both ends of the microchannel separated from the junction in the microchannel.
[0025]
The introduced dispersed phase and continuous phase are sent along the microchannel, and the shape of the microchannel has an effect on controlling the shape and particle size of the particles, but the width of the channel is several hundred μm or less. Should be fine.
[0026]
The introduced dispersed phase and the continuous phase are merged at a junction, which is a predetermined portion of the microchannel. The liquid feeding direction of the dispersed phase and the continuous phase is necessarily determined by the shape of the microchannel, but the intersection angle formed from the liquid feeding directions of the two at the confluence is such that particles are generated by merging The structure is not particularly limited as long as it intersects at any angle, and if the intersection angle is substantially 180 ° or a continuous curve introducing path sandwiching the particle generation location, dispersion The phase and the continuous phase are merged with fluids from completely opposite directions, which is effective for particle formation and is preferable.
[0027]
In the discharge channel extending from the junction of the microchannels through the discharge port, since it communicates at an arbitrary position in the microchannel, after the dispersed phase and the continuous phase have joined, the When the particles are discharged into the discharge channel, the particles are formed, and the generated particles are sent and discharged from the discharge port. Although the shape of the discharge channel is not particularly limited, the width may be several hundreds μm or less, and may have an intersection angle at which the liquid sent from the introduction channel can form a droplet at the intersection with the discharge port. The outlet means an opening for discharging the generated particles, and furthermore, a suitable attachment may be provided at the outlet to provide a mechanism for continuously discharging the phase containing the generated particles.
[0028]
In addition, particles generated by variously changing the crossing angle, the width and depth of the microchannel and the discharge channel at the junction, and the flow rates of the dispersed phase and the continuous phase independently or cooperatively are desired. It is possible to control to a particle size of.
[0029]
Further, it is preferable that one or more projections are formed from the bottom surface, the top surface, or the side surface of the flow channel in the vicinity of the position where the dispersed phase and the continuous phase merge in the micro flow channel, that is, at the junction. For example, as shown in FIG. 6A, an obstacle made of a V-shaped protrusion or the like is placed on the dispersed phase flow path side, and the dispersed phase width is equally divided right and left at the obstacle portion. By branching into a narrower flow path width as described above, finer droplets having a uniform particle size can be generated in the discharge flow path. Further, as shown in FIG. 6 (b), two types of V-shaped members having different angles are combined and designed so that the directions of the two flows that are branched and merged are not parallel flows, instead of a mere V-shaped projection. In addition, stable particle generation becomes possible. In addition, the direction of the outer wall of the branch path leading to the discharge flow path is designed to be parallel to the respective directions of the two types of V-shaped projections so that the dispersed phases merge at an angle that is easily sheared by the continuous phase. Thus, more stable generation of particles becomes possible.
[0030]
Also, by dividing the flow of one fluid sent from the flow channel at the arranged protrusion portion into two discharge flow channels and simultaneously collecting particles from the discharge flow channel, the number of particles per unit time It can double the yield and is suitable for industrial mass production. Further, as shown in FIG. 6 (c), a plurality of such protrusions are provided in the microchannel, and the discharge path and the protrusions are set so that the directions of the flow of the dispersed phase and the continuous phase from each inlet are aligned. By adopting a structure in which the dispersed phase and the continuous phase are alternately sent to the inlets provided on both sides of the projection and the microchannels therebetween, the particle yield can be further increased.
[0031]
The dispersed phase and the continuous phase are adjusted to have a flow path width corresponding to the number of branches, so that the flow rate after branching can form particles having a desired particle size, and the width of the discharge flow path is also continuous. The width of the flow path is designed to be the same according to the number of branches of the phase and the dispersed phase, and the crossing angle at which the two liquids that join together by appropriately changing the shape, number, and size of the protrusions can form particles. What is necessary is just to design.
[0032]
Further, if the liquid sending speed of the dispersed phase and the liquid sending speed of the continuous phase are substantially the same, it is easy to make the particle diameters of the particles easy, and the cost is also excellent, such as doubling the particle number yield. ing. In addition, the fact that the liquid sending speed of the dispersed phase and the liquid sending speed of the continuous phase are substantially the same means that even if the liquid sending speed slightly fluctuates, the particle size of the generated particles is not significantly affected. Means that.
[0033]
Regarding the cross-sectional shape of the minute flow channel and the discharge flow channel, the aspect ratio of the flow channel cross section is preferably 0.30 or more, and more preferably 0.30 or more and less than 3.0. If the aspect ratio is within this range, uniform particles can be generated at the junction. Deviating from this range, if the aspect ratio is less than 0.30, it may be difficult to generate uniform particles.
[0034]
In addition, although it depends on the properties of the medium used as the continuous phase and the dispersed phase, the intersection between the continuous phase introduction flow path and the dispersed phase introduction flow path and the vicinity thereof are formed of a polymer material, so that the resistance is high. It is preferable because the solvent property can be improved and the strength and the like can be improved.
[0035]
Furthermore, if the flow path on the disperse phase side and the flow path on the continuous phase side of the micro flow path are equal in width and depth, in addition to the above effects, the design of the micro flow path structure becomes easy, and The control at the time of liquid is also easier, which is suitable for industrial mass production.
[0036]
In the relationship between the width of the microchannel and the width of the discharge channel, if the width of the microchannel ≥ the width of the discharge channel, the width of the microchannel = the width of the discharge channel is greater than the case where the width of the microchannel = the width of the discharge channel. Even if the liquid flow rate is increased, uniform particles can be generated at the junction, and the effect of increasing the particle generation rate can be obtained, which is a preferable embodiment.
[0037]
In the microchannel structure of the present invention, the discharge channel for communicating with the microchannel and discharging the generated particles is an arbitrary one from a position where the dispersed phase and the continuous phase in the microchannel merge. It is preferable that the discharge channel has a structure extending in any two or more directions. With such a structure, particles formed by the dispersed phase and the continuous phase can be efficiently obtained, which is suitable for industrial mass production.
[0038]
As the width of the discharge channel, it is preferable that the width of the discharge channel is narrow at a part of the discharge channel from the junction where the dispersed phase and the continuous phase intersect to the discharge port. That is, before reaching the particle outlet, the connecting portion between the microchannel and the discharging channel is partially narrowed or the channel forming wall along the dispersed phase side in the microchannel is made convex. By forming, even if the liquid sending flow rate is increased, uniform particles can be generated at the merging portion, and the rise in the liquid sending pressure can be reduced, which is a preferable embodiment.
[0039]
Further, it is preferable that the portion where the width of the discharge flow path is narrow is located at or near the position where the dispersed phase and the continuous phase in the discharge flow path are joined, and particularly, the width of the discharge flow path is narrow. Is preferably on the dispersed phase introduction flow channel side at a position where the dispersed phase and the continuous phase in the discharge flow channel merge.
[0040]
The microchannel structure of the present invention has the structure and performance described above, but the dispersed phase and the continuous phase are merged from opposite directions along the microchannel, and the particles generated thereafter It is necessary to introduce a disperse phase and a continuous phase, and to provide an opening for discharging a fluid containing particles. In a structure, at a predetermined position corresponding to the above-described opening, a cover body in which a small hole for communicating the microchannel or discharge channel with the outside of the microchannel structure is laminated and integrated. You may. As a result, the fluid can be introduced from the outside of the microchannel structure into the internal channel, and can be discharged again to the outside of the microchannel structure. Even if the amount of the fluid is minute, the fluid can be stabilized. Thus, it is possible to pass through the minute channel. Fluid delivery is enabled by mechanical means such as a micropump. As shown in FIGS. 6 (c) and 6 (d), when the particle yield is to be further increased, the liquid is branched from the same micro pump to a plurality of dispersed phase inlets. Similarly, the liquid from the same micro pump is branched and sent to a plurality of continuous phase inlets. By such a liquid sending method using a common micropump, the substrate and the cover body on which the fine channels are formed that enable uniform generation of particles from the respective discharge paths are formed. What can be processed, is excellent in chemical resistance, and has appropriate rigidity is desirable. For example, it may be glass, quartz, ceramic, silicon, metal or resin. The size and shape of the substrate and the cover are not particularly limited, but the thickness is desirably about several mm or less. When the small hole arranged in the cover body communicates the microchannel with the outside of the microchannel structure and is used as a fluid inlet or outlet, it is desirable that its diameter is, 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.
[0041]
Further, in the microchannel structure of the present invention, the substrate on which the microchannel is formed and the cover are laminated and integrated by means such as heat bonding or bonding using an adhesive such as a photo-curing resin or a thermosetting resin. be able to.
[0042]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, examples of the present invention will be described, and embodiments of the present invention will be described in more detail. It is needless to say that the present invention is not limited to the following embodiments, and can be arbitrarily changed without departing from the gist of the present invention.
[0043]
Further, in the embodiment, one fine channel is formed on one substrate. However, in the case of industrial mass production, a large number of micro channels are formed on one substrate, or many micro channels are formed. This becomes possible by laminating one substrate.
[0044]
This microchannel structure for producing particles was produced as follows according to the production procedure shown in FIG. On one surface of a glass substrate 9 having a thickness of 1 mm and a size of 70 mm × 20 mm, a metal film 10 such as gold is formed to a thickness such that exposure light to be described later is not transmitted (FIG. 3A). ), And a photoresist 11 was coated on the metal film (FIG. 3B). Further, a photomask 12 having a pattern depicting the shape of the microchannel was placed on the photoresist, and the photoresist was exposed and developed from above the photomask (FIG. 3 (c) exposure-development step). Next, after etching the metal film 10 with an acid or the like (FIG. 3D metal film etching step), the resist and the glass are etched with hydrofluoric acid or the like (FIG. 3E resist and glass etching step). Then, the remaining metal film 10 was dissolved with an acid or the like (FIG. 3 (f) metal film removing step) to obtain a substrate 13 on which a fine channel was formed. In the embodiment, the minute channel is formed by etching the glass substrate in the minute channel, but the manufacturing method is not limited to this.
(Example 1)
FIG. 2 shows a microchannel for producing particles according to the first embodiment of the present invention. The fine channels are formed on a Pyrex (registered trademark) glass of 70 mm × 20 mm × 1 t (thickness), and the widths of the continuous phase introduction channel 2, the dispersed phase introduction channel 5, and the discharge channel 7 corresponding to the micro channels are set. Each of them has a 220 μm depth, a depth of 80 μm, and a microchannel having an aspect ratio of 0.36 on both sides of a shear layer structure. The dispersion phase introduction channel 5 and the two outlets 8 on both side surfaces are each formed at an angle of 60 degrees. A single flow path in the form of a double-sided shear structure having a junction 6 intersecting with each other was formed. The disperse phase and the continuous phase flow paths are branched at the junction 6, and the branched two different types of phases are discharged in the discharge flow paths on both side surfaces. The width and depth of the microchannel depend on the particle diameter of the generated particles, but it is sufficient that the aspect ratio of the microchannel does not deviate from the range of 0.3 or more and less than 3.
[0045]
On the surface of the substrate 13 having the microchannels having the microchannels, a diameter of 0 μm is previously set at a position corresponding to the fluid inlets (continuous phase inlet 2 and dispersed phase inlet 4) and the fluid outlet 8 of the microchannel. A small hole having a diameter of 0.6 mm was thermally bonded to a glass cover body 14 having a thickness of 1 mm and a size of 70 mm × 20 mm provided by using a mechanical processing means, and as shown in FIG. The structure was manufactured. In the embodiment, the glass substrate is used for the substrate forming the microchannel and the cover body, but the present invention is not limited to this.
[0046]
Next, the method for producing particles of the present invention will be described. As shown in FIG. 5, the liquid is held by a holder 16 or the like so that the liquid can be sent to the microchannel structure 15 for particle production, and a Teflon (registered trademark) tube 18 and a fillet joint 19 are fixed to the holder 16. The other end of the Teflon (registered trademark) tube 18 is connected to micro syringes 21 and 22. This allows liquid to be sent to the microchannel structure 15 for particle production. Next, a mixed solution of monomer (styrene), divinylbenzene, butyl acetate and benzoyl peroxide is injected into a micro syringe 21 into a dispersed phase for generating particles, and a 3% aqueous solution of polyvinyl alcohol into a micro syringe 22 into a continuous phase, The liquid was sent by the micro syringe pump 20. The liquid sending flow rate is 20 μl / min for both the dispersed phase and the continuous phase. In a state where the liquid sending flow rates are both stable, the generation of particles is observed at the junction where the dispersed phase and the continuous phase of the microchannel structure for particle production 15 intersect (FIG. 6). When the generated particles were observed, they were extremely uniform particles 23 having an average particle diameter of 200 μm as shown in FIG. In addition, when the liquid sending flow rate was set to 1 μl / min for both the dispersed phase and the continuous phase, the produced particles were very uniform particles having an average particle diameter of 230 μm. As a result, since the dispersed phase and the continuous phase are performed at the same liquid sending flow rate, it is possible to generate uniform particles having a degree of dispersion of 10% without excessively sending the continuous phase.
(Example 2)
FIG. 2 shows a microchannel for producing particles according to a second embodiment of the present invention. The fine channels are formed on a Pyrex (registered trademark) glass of 70 mm × 20 mm × 1 t (thickness), and the continuous phase introduction channel 2 and the dispersed phase introduction channel 5 corresponding to the micro channels have a width of 220 μm and a depth of 220 μm. The shape is a double-sided shear layer structure having a length of 50 μm, a width of the discharge channel 7 of 110 μm, a depth of 50 μm, and an aspect ratio of 0.45. One channel having a shape having a merging portion 6 intersecting at an angle of degrees was formed. As shown in FIG. 6, a V-shaped projection 24 of 80 μm on a side is provided at the junction at the time of pattern formation so that the point of the cusp points toward the dispersed phase flow path side. The passage is branched into discharge passages on both sides. The width and depth of the microchannel depend on the particle diameter of the generated particles, but the aspect ratio at the location where the particles of the microchannel are generated does not deviate from the range of 0.3 or more and less than 3. Good. Further, in the embodiment, the V-shaped projection is used as the projection at the merging portion, but the size and shape of the projection are limited as long as the particles can be formed according to the width and angle of the flow path. is not.
[0047]
On the surface of the substrate 13 having the microchannels having the microchannels, a diameter of 0 μm is previously set at a position corresponding to the fluid inlets (continuous phase inlet 2 and dispersed phase inlet 4) and the fluid outlet 8 of the microchannel. A small hole of 0.6 mm was thermally bonded to a glass cover body 14 having a thickness of 1 mm and a size of 70 mm × 20 mm provided by using a mechanical processing means, and as shown in FIG. A road structure was built. In the embodiment, the glass substrate is used for the substrate forming the microchannel and the cover body, but the present invention is not limited to this.
[0048]
Next, the method for producing particles of the present invention will be described. As shown in FIG. 5, the liquid is held by a holder 16 or the like so that the liquid can be sent to the microchannel structure 15 for particle production, and a Teflon (registered trademark) tube 18 and a fillet joint 19 are fixed to the holder 16. The other end of the Teflon (registered trademark) tube 18 is connected to micro syringes 21 and 22. This allows liquid to be sent to the microchannel structure 15 for particle production. Next, a mixed solution of monomer (styrene), divinylbenzene, butyl acetate and benzoyl peroxide is injected into a micro syringe 21 into a dispersed phase for generating particles, and a 3% aqueous solution of polyvinyl alcohol into a micro syringe 22 into a continuous phase, The liquid was sent by the micro syringe pump 20. The liquid sending flow rate is 20 μl / min for both the dispersed phase and the continuous phase. In a state where both the liquid sending flow rates are stable, the generation of particles is observed at the junction where the dispersed phase and the continuous phase of the microchannel structure for particle production 15 intersect. Observation of the generated particles revealed that the particles were extremely uniform with an average particle diameter of 110 μm. When the liquid sending flow rate was set to 1 μl / min for both the dispersed phase and the continuous phase, the formed particles were extremely uniform particles having an average particle diameter of 100 μm. As a result, since the dispersed phase and the continuous phase are carried out at the same liquid sending flow rate, the degree of dispersion is also improved to 8% by forming projections at the junction without excessively sending the continuous phase. . By forming protrusions at the junction, uniform particles can be stably generated.
[0049]
【The invention's effect】
According to the method for producing particles of the present invention, extremely uniform particles can be generated at the confluence of the microchannel structure for producing particles configured as described above. By forming protrusions and branch paths at the confluence of the dispersed phase and the continuous phase, uniform and more stable particles having a desired particle size can be generated. Further, in the microchannel structure for producing particles, the width and depth of the introduction channels for the dispersed phase and the continuous phase can be made the same, and the amounts of the dispersed phase and the continuous phase used can be made the same. Both the disperse phase and the continuous phase are branched in two directions, respectively, and one of them merges to simultaneously discharge droplets from different discharge paths. As a result, the same effect as that obtained by using two microchannel structures for producing particles simultaneously using one microchannel structure for producing particles can be obtained, and the yield of particles is increased. Therefore, it is suitable for industrial mass production. . In addition, since the flow path of the dispersed phase is separated into two narrow branch paths at the junction, it is possible to generate particles having a smaller diameter. further,
As shown in FIG. 6 (d), a large number of minute flow paths are arranged in a ring on a single substrate, and it is possible to collect a large number of uniform and uniform particles from the respective discharge paths at the same time.
[0050]
[Brief description of the drawings]
FIG. 1 is a schematic view showing a conventional microchannel for producing particles. In FIG. 1, portions indicated by AA ′ and BB ′ are each an enlarged cross-sectional portion of the flow channel.
FIG. 2 is a schematic view showing a microchannel structure for producing particles in Examples 1 and 2. In FIG. 2, portions indicated by CC ′ are enlarged cross-sectional portions of the respective flow paths.
FIG. 3 is a flowchart showing a method for forming a microchannel for particle production in Example 1.
FIG. 4 is a schematic view showing a microchannel structure for particle production in Examples 1 and 2.
FIG. 5 is a schematic diagram showing a method for producing particles in Examples 1 and 2.
FIG. 6 is a schematic view showing a microchannel for droplet generation. FIG. 6 (a) is a schematic diagram showing a microchannel for particle production in Example 2, and FIG. 6 (b) is an example of an embodiment in which the shape of the projection is changed. Is an example of a mode in which the arrangement of the microchannels is changed.
FIG. 7 is a view showing generated particles in Example 2.
[Explanation of symbols]
1: microchannel substrate 2: continuous phase inlet 3: continuous phase inlet 4: disperse phase inlet 5: dispersed phase inlet 6: junction 7: outlet 8: outlet 9: glass substrate 10 : Metal film 11: Photoresist 12: Photomask 13: Substrate with microchannel formed 14: Cover 15: Microchannel structure 16: Holder 17: Beaker 18: Teflon (registered trademark) tube 19: Fillet joint 20: Micro syringe pump 21: Micro syringe (continuous phase)
22: micro syringe (dispersed phase)
23: Produced particles 24: Confluence projection (V-shape)

Claims

A dispersed phase is introduced from one side of a microchannel having two inlets for introducing a fluid, and a continuous phase is introduced from the other side, and the dispersed phase and the continuous phase are merged to form particles. A method for producing particles, wherein a fluid containing the produced particles is discharged in an arbitrary direction from a position where the dispersed phase and the continuous phase in the microchannel merge.

The method for producing particles according to claim 1, wherein the fluid containing the generated particles is discharged in two or more arbitrary directions.

At the position where the dispersed phase and the continuous phase merge in the microchannel, the particle diameter of the generated particles is controlled by changing the crossing angle formed between the liquid sending direction of the dispersed phase and the liquid sending direction of the continuous phase. The method for producing particles according to claim 1 or 2, wherein:

The method for producing particles according to claim 2 or 3, further comprising: joining the discharged fluid containing particles again to recover the fluid containing particles.

The method for producing particles according to any one of claims 1 to 4, wherein the introduction speed of the dispersed phase and the introduction speed of the continuous phase are substantially the same.

The method for producing particles according to any one of claims 1 to 5, wherein the dispersed phase is a medium containing a raw material for producing a gel.

The method for producing particles according to any one of claims 1 to 6, wherein the continuous phase is a medium containing a dispersant for producing a gel.

The method for producing particles according to claim 7, wherein the gel producing dispersant is polyvinyl alcohol.

A microchannel having a dispersed phase inlet for introducing the dispersed phase and a continuous phase inlet for introducing the continuous phase, and a discharge channel for discharging particles generated by the dispersed phase and the continuous phase, and A microchannel structure having a discharge port communicating therewith, wherein an aspect ratio (ratio of flow channel depth / width) of a cross section of the flow channel is 0.30 or more; A microchannel structure, wherein the microchannel structure extends in an arbitrary direction from a position where the dispersed phase and the continuous phase in the microchannel merge.

The microchannel structure according to claim 9, wherein the discharge channel has a structure extending in two or more arbitrary directions.

At a position where the dispersed phase and the continuous phase merge in the microchannel, the crossing angle formed from the liquid sending direction of the dispersed phase and the liquid sending direction of the continuous phase intersects at an arbitrary angle. The microchannel structure according to claim 9 or 10, wherein

The microchannel structure according to claim 10 or 11, wherein the discharge channel has a structure communicating with an arbitrary position.

The microchannel structure according to any one of claims 9 to 12, wherein the aspect ratio of the channel cross section is 0.30 or more and less than 3.0.

The microchannel structure according to any one of claims 9 to 13, wherein, of the inner walls of the microchannel, a position where the dispersed phase and the continuous phase join and a vicinity thereof are formed of a polymer material. body.

The microchannel structure according to any one of claims 9 to 14, wherein the width of the channel through which the dispersed phase is fed and the width of the channel through which the continuous phase is fed are equal.

The width of the discharge channel is reduced at a part of the discharge channel from the position where the dispersed phase and the continuous phase merge in the microchannel to the discharge port. 16. The microchannel structure according to any one of the above items 15.

17. The microchannel structure according to claim 16, wherein the portion where the width of the discharge channel is narrow is at or near a position where the dispersed phase and the continuous phase in the discharge channel join.

The part where the width of the discharge flow path is narrow is located on the dispersed phase introduction flow path side at a position where the dispersed phase and the continuous phase in the discharge flow path join. Micro channel structure.

19. The microparticle according to claim 9, wherein one or more protrusions are formed from a bottom surface, an upper surface, or a side surface of the flow channel in the vicinity of a position where the dispersed phase and the continuous phase have joined. Channel structure.