JPH10195103A - Porous spherical cellulose particle and production thereof - Google Patents
Porous spherical cellulose particle and production thereofInfo
- Publication number
- JPH10195103A JPH10195103A JP1758897A JP1758897A JPH10195103A JP H10195103 A JPH10195103 A JP H10195103A JP 1758897 A JP1758897 A JP 1758897A JP 1758897 A JP1758897 A JP 1758897A JP H10195103 A JPH10195103 A JP H10195103A
- Authority
- JP
- Japan
- Prior art keywords
- solution
- porous spherical
- cellulose particles
- spherical cellulose
- particles according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229920002678 cellulose Polymers 0.000 title claims abstract description 115
- 239000001913 cellulose Substances 0.000 title claims abstract description 114
- 239000002245 particle Substances 0.000 title claims abstract description 103
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 33
- 230000007717 exclusion Effects 0.000 claims abstract description 25
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 18
- ALWXETURCOIGIZ-UHFFFAOYSA-N 1-nitropropylbenzene Chemical compound CCC([N+]([O-])=O)C1=CC=CC=C1 ALWXETURCOIGIZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 239000002612 dispersion medium Substances 0.000 claims abstract description 7
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 56
- 239000007788 liquid Substances 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000006185 dispersion Substances 0.000 claims description 8
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 229940117389 dichlorobenzene Drugs 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000005469 granulation Methods 0.000 claims description 4
- 230000003179 granulation Effects 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 238000004132 cross linking Methods 0.000 abstract description 5
- 238000009826 distribution Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 4
- 239000000654 additive Substances 0.000 abstract description 3
- 230000000996 additive effect Effects 0.000 abstract 1
- 239000011148 porous material Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000011033 desalting Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 229920002307 Dextran Polymers 0.000 description 4
- 159000000007 calcium salts Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000004945 emulsification Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- -1 acetate ester Chemical class 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012798 spherical particle Substances 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- CXKCTMHTOKXKQT-UHFFFAOYSA-N cadmium oxide Inorganic materials [Cd]=O CXKCTMHTOKXKQT-UHFFFAOYSA-N 0.000 description 1
- CFEAAQFZALKQPA-UHFFFAOYSA-N cadmium(2+);oxygen(2-) Chemical compound [O-2].[Cd+2] CFEAAQFZALKQPA-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 239000007863 gel particle Substances 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 102000034238 globular proteins Human genes 0.000 description 1
- 108091005896 globular proteins Proteins 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007745 plasma electrolytic oxidation reaction Methods 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Processes Of Treating Macromolecular Substances (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、特定の排除限界分
子量、結晶化度を有し、真球度が0.9以上である均一な
球状の形態を持った多孔性球状セルロース粒子及びその
製造方法に関する。本発明の多孔性球状セルロース粒子
はクロマトグラフィー用分離剤、検査薬の担体、バイオ
リアクターの担体、治療用の吸着剤等に極めて好適に使
用することができる。近年、化学、医学などの分野で利
用されている液体クロマトグラフィーは急速に高性能化
し、広範に使用されるようになっている。この液体クロ
マトグラフィーに用いられる充填剤の機能は細孔径に大
きく依存している。例えばゲルクロマトグラフィーでは
充填剤を充填したカラムに混合物溶液を流し、溶出する
間に分子の大きさに従って篩い分ける原理で分離する。
このため細孔の大きさにより分離できる物質が限定され
ることになり、アミノ酸等の低分子物質から蛋白質など
の高分子物質までを分離精製対象にするためには多様な
細孔径をもつ充填剤をそろえる必要がある。従って細孔
径をコントロールする事が、その分画範囲と性能を決定
する上で大きな要因となる。また、充填剤の粒径の均一
性、真球度も分離の際の再現性等の性能に大きく影響す
る。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a porous spherical cellulose particle having a specific exclusion limit molecular weight, crystallinity and a uniform spherical shape having a sphericity of 0.9 or more, and a method for producing the same. . The porous spherical cellulose particles of the present invention can be very suitably used as a separating agent for chromatography, a carrier for a test agent, a carrier for a bioreactor, an adsorbent for therapy, and the like. In recent years, liquid chromatography used in fields such as chemistry and medicine has rapidly improved in performance, and has been widely used. The function of the filler used in this liquid chromatography greatly depends on the pore size. For example, in gel chromatography, a mixture solution is passed through a column packed with a packing material, and separation is performed according to the principle of sieving according to the size of molecules during elution.
For this reason, substances that can be separated are limited by the size of the pores, and packing materials with various pore diameters are required to separate and purify from low molecular substances such as amino acids to high molecular substances such as proteins. Need to be prepared. Therefore, controlling the pore size is a major factor in determining the fractionation range and performance. In addition, the uniformity of the particle size and the sphericity of the filler greatly affect the performance such as reproducibility at the time of separation.
【０００２】[0002]
【従来の技術】セルロースを溶解−再生してゲルビーズ
とする方法として、酢酸エステルを経由する方法が特公
昭５５−３９５６５号公報及び特公昭５５−４０６１８
号公報に開示されており、チオシアン酸カルシウム塩を
用いて溶液から造粒する方法が特公昭６３−６２２５２
号公報に記載されている。また、パラホルムアルデヒド
・ジメチルスルホキシド溶液から製造する方法が特公平
２−２２０９３号公報に開示されている。細孔径がコン
トロールされた多孔性球状セルロース粒子の製造方法と
しては、セルロース粒子の製造時に高級アルコールを
希釈剤として添加する方法、酸やアルカリを添加する
方法、結晶化度の異なるセルロースエステルを混合し
て製造する方法等があるが、では希釈剤の洗浄や回収
に多くの手間がかかり、またでは蛋白分子の大きさに
対応する細孔径が得られず、では特殊な原料を必要と
し、非常にコスト高になるなどの問題点があった。ま
た、これらの方法とは別に、一定の細孔径を持つセルロ
ース粒子を製造したのち、該セルロース粒子を架橋剤で
架橋する事で立体的な空間を狭めて細孔径をコントロー
ルしたセルロース粒子の製造法もあるが、この方法では
安定した構造のセルロース粒子が架橋反応により破壊さ
れるため、機械的強度が低下していくという問題点があ
った。また、これらの造粒法で得られる多孔性球状セル
ロースには粒径にかなりの幅があり、実際に使用する粒
径を得るには篩い分けが必要であるという問題、またポ
リマーくずや異形粒子が発生しやすく工業的に製造する
場合、非常にロスが大きいという問題点があった。2. Description of the Related Art As a method for dissolving and regenerating cellulose to form gel beads, a method via an acetate ester is disclosed in JP-B-55-39565 and JP-B-55-40618.
JP-B-63-62252 discloses a method of granulating from a solution using calcium thiocyanate.
No., published in Japanese Unexamined Patent Publication No. Further, a method for producing from a paraformaldehyde / dimethyl sulfoxide solution is disclosed in Japanese Patent Publication No. 22093/1990. As a method for producing porous spherical cellulose particles having a controlled pore diameter, a method of adding a higher alcohol as a diluent during the production of cellulose particles, a method of adding an acid or an alkali, and mixing cellulose esters having different crystallinities are used. However, it requires a lot of labor to wash and recover the diluent, and cannot obtain a pore size corresponding to the size of the protein molecule. There were problems such as an increase in cost. Separately from these methods, a method for producing cellulose particles in which a three-dimensional space is narrowed to control the pore diameter by producing cellulose particles having a fixed pore size and then crosslinking the cellulose particles with a crosslinking agent. However, this method has a problem that the mechanical strength decreases because cellulose particles having a stable structure are destroyed by a crosslinking reaction. In addition, the porous spherical cellulose obtained by these granulation methods has a considerable variation in the particle size, and it requires sieving to obtain the particle size actually used. In the case of industrial production, there is a problem that loss is extremely large.
【０００３】[0003]
【発明が解決しようとする課題】本発明者らは、このよ
うな問題点を解決するために鋭意検討した。その結果、
特定の平均分子量のセルロースの特定量をチオシアン酸
カルシウム水溶液に溶解した溶液（以下、Ｒ液という）
を分散媒液（以下、Ｄ液という）中に滴下し、加熱しな
がら撹拌、造粒したのち、特定速度以上で冷却すること
により、真球状で特定の結晶化度を有する多孔性セルロ
ース粒子が狭い粒度分布をもって得られる事を見い出し
た。すなわち、本発明の目的は特殊な原料や添加物を使
用せず、また架橋処理などの二次的な操作を行わずに、
一定のコントロールされた細孔径、すなわち、一定範囲
の排除限界分子量を持ち、真球状で結晶化度が低く、粒
度分布の狭い多孔性セルロース粒子及びそれを製造する
方法を提供することである。DISCLOSURE OF THE INVENTION The present inventors diligently studied to solve such a problem. as a result,
A solution in which a specific amount of cellulose having a specific average molecular weight is dissolved in an aqueous solution of calcium thiocyanate (hereinafter, referred to as R solution)
Is dropped into a dispersion medium solution (hereinafter, referred to as solution D), stirred and granulated while heating, and then cooled at a specific speed or more, whereby porous spherical spherical particles having a specific crystallinity are obtained. It has been found that it can be obtained with a narrow particle size distribution. That is, the object of the present invention is to use no special raw materials or additives, and without performing a secondary operation such as a crosslinking treatment.
It is an object of the present invention to provide a porous cellulose particle having a certain controlled pore size, that is, a spherical shape, a low crystallinity and a narrow particle size distribution, having a certain range of exclusion limit molecular weight, and a method for producing the same.
【０００４】[0004]
【課題を解決するための手段】本発明は下記から構成さ
れる。 （１）ポリエチレンオキサイドによる排除限界分子量が
50万〜500万で、Ｘ線回折法により求めた結晶化度が3〜
15％、真球度が0.9以上であることを特徴とする多孔性
球状セルロース粒子。 （２）ポリエチレンオキサイドによる排除限界分子量が
80万〜300万である前記第１項記載の多孔性球状セルロ
ース粒子。 （３）ポリエチレンオキサイドによる排除限界分子量が
100万〜200万である前記第１項記載の多孔性球状セルロ
ース粒子。 （４）結晶化度が6〜8％である前記第１項記載の多孔性
球状セルロース粒子。 （５）原料セルロースをチオシアン酸カルシウム水溶液
に溶解した溶液（以下、Ｒ液という）を分散媒液（以
下、Ｄ液という）に滴下して多孔性球状セルロース粒子
を製造する際に、原料セルロースの平均分子量と該セル
ロースのチオシアン酸カルシウム水溶液への溶解濃度と
を調節して分散媒液に滴下することを特徴とする前記第
１項〜第４項のいずれか１項記載の多孔性球状セルロー
スを製造する方法。 （６）平均分子量が１千〜１０万である原料セルロース
をチオシアン酸カルシウム水溶液に溶解させた溶解濃度
が3重量%〜15重量%のＲ液をＤ液に、Ｒ液／Ｄ液の体積
比が0.5以下となるように滴下し、撹拌、造粒したの
ち、冷却速度0.5℃／分以上で該反応液を冷却させるこ
とを特徴とする前記第５項記載の多孔性球状セルロース
粒子を製造する方法。 （７）Ｒ液／Ｄ液の体積比が0.3以下である前記第５項
もしくは第６項記載の多孔性球状セルロース粒子を製造
する方法。 （８）Ｄ液がハロゲン化炭化水素化合物である前記第５
項もしくは第７項のいずれか１項記載の多孔性球状セル
ロース粒子を製造する方法。 （９）ハロゲン化炭化水素化合物がジクロロエタンもし
くはジクロロベンゼンである前記第８項記載の多孔性球
状セルロース粒子を製造する方法。 （１０）冷却速度が2℃／分以上である前記第６項記載
の多孔性セルロース粒子を製造する方法。 （１１）平均粒径50〜2000μｍの前記第１項記載の多孔
性球状セルロース粒子が平均粒径の±10%の粒径範囲で7
0％以上得られる前記第５項もしくは第６項記載の多孔
性球状セルロース粒子を製造する方法。 （１２）原料セルロースの平均分子量が1万〜4万である
前記第５項もしくは第６項記載の多孔性球状セルロース
粒子を製造する方法。The present invention comprises the following. (1) Exclusion limit molecular weight due to polyethylene oxide
500,000-5,000,000, crystallinity determined by X-ray diffraction method is 3 ~
Porous spherical cellulose particles having a sphericity of 15% or more and 0.9 or more. (2) Exclusion limit molecular weight due to polyethylene oxide
2. The porous spherical cellulose particles according to the above item 1, wherein the number is from 800,000 to 3,000,000. (3) Exclusion limit molecular weight due to polyethylene oxide
2. The porous spherical cellulose particles according to the above item 1, wherein the number is from 1,000,000 to 2,000,000. (4) The porous spherical cellulose particles according to the above (1), which has a crystallinity of 6 to 8%. (5) When manufacturing a porous spherical cellulose particle by dropping a solution (hereinafter, referred to as R solution) obtained by dissolving raw cellulose in an aqueous calcium thiocyanate solution into a dispersion medium solution (hereinafter, referred to as D solution), The porous spherical cellulose according to any one of Items 1 to 4, wherein the average molecular weight and the concentration of the cellulose dissolved in an aqueous solution of calcium thiocyanate are adjusted and the solution is dropped into a dispersion medium. How to make. (6) A volume ratio of R solution / D solution, wherein R solution having a dissolution concentration of 3% to 15% by weight obtained by dissolving raw material cellulose having an average molecular weight of 1,000 to 100,000 in an aqueous solution of calcium thiocyanate is used as D solution. 6. The porous spherical cellulose particles according to the above item 5, wherein the reaction liquid is cooled at a cooling rate of 0.5 ° C./min or more after the mixture is dropped, stirred, and granulated so as to be 0.5 or less. Method. (7) The method for producing porous spherical cellulose particles according to the above (5) or (6), wherein the volume ratio of the R solution / D solution is 0.3 or less. (8) The fifth liquid, wherein the liquid D is a halogenated hydrocarbon compound.
A method for producing the porous spherical cellulose particles according to any one of the above items or 7. (9) The method for producing porous spherical cellulose particles according to the above (8), wherein the halogenated hydrocarbon compound is dichloroethane or dichlorobenzene. (10) The method for producing porous cellulose particles according to (6), wherein the cooling rate is 2 ° C./min or more. (11) The porous spherical cellulose particles according to the above (1) having an average particle diameter of 50 to 2,000 μm have a particle diameter of ± 10% of the average particle diameter.
7. The method for producing porous spherical cellulose particles according to the above item 5 or 6, wherein 0% or more is obtained. (12) The method for producing porous spherical cellulose particles according to the above (5) or (6), wherein the raw material cellulose has an average molecular weight of 10,000 to 40,000.
【０００５】以下、本発明を詳細に説明する。本発明の
多孔性球状セルロース粒子は、ポリエチレンオキサイド
による排除限界分子量が50〜500万の細孔径を有し、Ｘ
線回折法により求めた結晶化度が3〜15%、真球度が0.9
以上の多孔性球状セルロース粒子であり、該多孔性球状
セルロース粒子は次のような製造方法で製造することが
できる。すなわち、原料セルロースをチオシアン酸カル
シウム水溶液に溶解させた溶液の溶解濃度をある一定範
囲に調節したセルロース溶液（以下、Ｒ液という）をジ
クロロベンゼン等の分散媒液（以下、Ｄ液という）に滴
下し、撹拌、造粒したのち、冷却速度0.5℃／分以上で
該反応液を冷却させる方法により本発明の多孔性球状セ
ルロース粒子が得られる。Hereinafter, the present invention will be described in detail. The porous spherical cellulose particles of the present invention have a pore diameter of which the exclusion limit molecular weight by polyethylene oxide is 500 to 5,000,000, and X
Crystallinity determined by X-ray diffraction method is 3 to 15%, sphericity is 0.9
The above-described porous spherical cellulose particles can be produced by the following production method. That is, a cellulose solution (hereinafter referred to as R solution) in which the concentration of a solution obtained by dissolving the raw material cellulose in an aqueous calcium thiocyanate solution is adjusted to a certain range is dropped into a dispersion medium solution (hereinafter referred to as D solution) such as dichlorobenzene. After stirring and granulating, the porous spherical cellulose particles of the present invention can be obtained by cooling the reaction solution at a cooling rate of 0.5 ° C./min or more.
【０００６】本発明の多孔性球状セルロース粒子の原料
セルロースとしては、結晶性セルロース粉末などセルロ
ースを主成分とするものであり、また、チオシアン酸カ
ルシウム水溶液に溶解したあとの溶液の取り扱いの容易
さの点から、カドキセン法で求められた平均分子量が１
千〜１０万のセルロースが好ましく、１万〜４万のもの
がより好ましい。該原料セルロースを該チオシアン酸カ
ルシウム水溶液に溶解させた溶液すなわちＲ液のセルロ
ース濃度は３〜１５重量％、好ましくは６〜１０重量％
である。該セルロース濃度が１５重量％を大幅に越える
と、溶液の粘度が高くなり、取り扱いが困難になり、該
濃度が３重量％を大きく下回ると、溶液は低粘度で流動
性は良くなるが、異形粒子が発生しやすくなる。[0006] The raw material cellulose for the porous spherical cellulose particles of the present invention is mainly composed of cellulose, such as crystalline cellulose powder, and has an easy handling property after being dissolved in an aqueous calcium thiocyanate solution. From the viewpoint, the average molecular weight determined by the cadoxene method is 1
1,000 to 100,000 cellulose is preferable, and 10,000 to 40,000 is more preferable. The cellulose concentration of the solution in which the raw material cellulose is dissolved in the aqueous solution of calcium thiocyanate, that is, the R solution, is 3 to 15% by weight, preferably 6 to 10% by weight.
It is. If the cellulose concentration is significantly higher than 15% by weight, the viscosity of the solution becomes high and handling becomes difficult. If the cellulose concentration is much lower than 3% by weight, the solution becomes low in viscosity and has good fluidity. Particles are easily generated.
【０００７】原料セルロースの平均分子量とチオシアン
酸カルシウム水溶液への溶解濃度を上記の範囲内に調節
することにより、得られるセルロース粒子の細孔径を、
ポリエチレンオキサイド（以下、ＰＥＯという）による
排除限界分子量が50万〜500万にコントロールする事が
可能になる。原料セルロースの分子量が大きいほど、得
られる球状セルロースの細孔径は大きくなり、また溶解
濃度が低いほど得られる多孔性球状セルロース粒子の細
孔径が大きくなる傾向がある。この性質を利用すれば造
粒に支障のないセルロース濃度の範囲内で任意の細孔径
の球状セルロース粒子を調製することが可能である。本
発明の製造方法では、ＰＥＯによる排除限界分子量が上
述したように50万〜500万の範囲の粒子が得られる。[0007] By adjusting the average molecular weight of the raw material cellulose and the concentration of the cellulose cellulose dissolved in the aqueous solution of calcium thiocyanate within the above-mentioned ranges, the pore size of the obtained cellulose particles is reduced.
It is possible to control the exclusion limit molecular weight of polyethylene oxide (hereinafter, referred to as PEO) to 500,000 to 5,000,000. The larger the molecular weight of the starting cellulose, the larger the pore size of the obtained spherical cellulose, and the lower the dissolution concentration, the larger the pore size of the obtained porous spherical cellulose particles. If this property is utilized, it is possible to prepare spherical cellulose particles having an arbitrary pore size within a range of cellulose concentration that does not hinder granulation. In the production method of the present invention, particles having an exclusion limit molecular weight by PEO in the range of 500,000 to 5,000,000 are obtained as described above.
【０００８】本発明における排除限界分子量とは、ゲル
濾過法においてゲルのもつ細孔に入り込めない分子のう
ち最小の分子の分子量である。この排除限界分子量の値
は、測定に用いた試料分子の立体構造が大きく関与す
る。例えば、デキストランのように繊維状に伸びた分子
を用いた場合と、球状蛋白質のように緻密な分子を用い
た場合では排除限界点は異なってくるので、何を用いて
測定した値かを明示しておく必要がある。本発明で使用
した試料分子はＰＥＯであり、これらの試料を用いて得
られた本発明の多孔性球状セルロース粒子の排除限界分
子量の値は50万〜500万である。[0008] The exclusion limit molecular weight in the present invention is the minimum molecular weight of the molecules which cannot enter the pores of the gel in the gel filtration method. The value of the exclusion limit molecular weight largely depends on the three-dimensional structure of the sample molecule used for the measurement. For example, the exclusion limit is different between the case of using a fiber-extended molecule such as dextran and the case of using a dense molecule such as a globular protein. It is necessary to keep. The sample molecule used in the present invention is PEO, and the value of the exclusion limit molecular weight of the porous spherical cellulose particles of the present invention obtained using these samples is from 500,000 to 5,000,000.
【０００９】チオシアン酸カルシウム水溶液に溶解させ
て得られた特定濃度のＲ液を分散法により球状に成形す
る。分散法により球状セルロースを得る方法としては、
例えば、該Ｒ液を、界面活性剤を含むセルロース溶液の
溶剤と相溶性の低いＤ液に加え、撹拌などの操作により
乳化を行なう。本発明に用いる界面活性剤の性質として
は、セルロース溶液を内油層Ｏ1とし、この界面活性剤
を含むセルロース溶液の分散媒液を外油層Ｏ2とするＯ1
／Ｏ2型乳化物を作るのに適する親水基、疎水基の割合
を持った界面活性剤が好ましい。乳化操作としては公知
の分散法、例えば、プロペラ型撹拌機あるいはタービン
型撹拌機などのミキサーによる方法、コロイドミル法、
ホモジナイザー法、超音波照射法等が用いられる。この
乳化操作により球状セルロースの粒子径を制御する事が
できる。The R solution having a specific concentration obtained by dissolving in an aqueous solution of calcium thiocyanate is formed into a spherical shape by a dispersion method. As a method of obtaining spherical cellulose by a dispersion method,
For example, the R solution is added to a D solution having low compatibility with a solvent of a cellulose solution containing a surfactant, and emulsification is performed by an operation such as stirring. As the properties of the surfactant used in the present invention, the cellulose solution is used as the inner oil layer O1, and the dispersion medium of the cellulose solution containing the surfactant is used as the outer oil layer O2.
A surfactant having a ratio of a hydrophilic group and a hydrophobic group suitable for preparing a / O2 type emulsion is preferable. As the emulsification operation, a known dispersion method, for example, a method using a mixer such as a propeller-type stirrer or a turbine-type stirrer, a colloid mill method,
A homogenizer method, an ultrasonic irradiation method, or the like is used. The particle size of the spherical cellulose can be controlled by this emulsification operation.
【００１０】本発明に用いるＤ液としては、セルロース
溶液すなわちＲ液と任意の割合で混合し、乳化作用を行
なった際、該Ｒ液を内油層Ｏ1とし、該Ｄ液をＯ2とする
Ｏ1／Ｏ2型乳化物を形成するものであれば特に限定され
ないが、好ましくは、ハロゲン化炭化水素類等が挙げら
れ、ジクロロエタン、ジクロロベンゼン等を例示できる
が、ジクロロベンゼンが特に好ましい。また、内油層Ｏ
1と外油層Ｏ2の体積比（Ｏ1／Ｏ2）は乳化操作を行なっ
た際にＲ液を内油層Ｏ1とするＯ1／Ｏ2型乳化物を形成
する値であれば特に限定はされないが、この値が0.5以
上になると異形粒子が発生しやすくなる。好ましくは0.
3以下である。本発明の造粒時における反応温度はセル
ロースの分解が生じない温度であれば特に限定されない
が、好ましくは100℃〜130℃である。上記温度で撹拌時
間を調節し、その後、急激に冷却することによりゲルの
凝固を行う。この冷却時間が長くかかると異形粒子が発
生したり、ゲルが着色したりする。好ましい冷却速度は
0.5℃／分 以上である。さらに好ましくは2℃／分以上
である。上記のＯ1／Ｏ2比で反応後の冷却速度を速める
ことで、一定の撹拌速度で分散したＲ液が短時間で凝固
し、均一な粒径をもつ真球に近い粒子になる。また、セ
ルロースの再生も短時間で完了するため、結晶化の進行
が押さえられ、結晶化度の低い粒子が得られる。結晶化
度は冷却速度を調節することでコントロールできる。[0010] The liquid D used in the present invention is prepared by mixing a cellulose solution, that is, the liquid R, at an arbitrary ratio and performing an emulsifying action, wherein the liquid R becomes the inner oil layer O1, and the liquid D becomes O2. There is no particular limitation as long as it forms an O2 type emulsion, but preferred are halogenated hydrocarbons and the like, and examples thereof include dichloroethane and dichlorobenzene, with dichlorobenzene being particularly preferred. In addition, the inner oil layer O
The volume ratio (O1 / O2) of 1 to the outer oil layer O2 is not particularly limited as long as it is a value that forms an O1 / O2 emulsion in which the R liquid becomes the inner oil layer O1 when the emulsification operation is performed. When the value is 0.5 or more, irregular shaped particles are easily generated. Preferably 0.
3 or less. The reaction temperature at the time of granulation of the present invention is not particularly limited as long as it does not cause decomposition of cellulose, but is preferably 100 ° C to 130 ° C. The stirring time is adjusted at the above temperature, and then the gel is solidified by rapidly cooling. If the cooling time is long, irregular shaped particles are generated or the gel is colored. The preferred cooling rate is
0.5 ° C / min or more. More preferably, it is at least 2 ° C./min. By increasing the cooling rate after the reaction at the O1 / O2 ratio described above, the R liquid dispersed at a constant stirring speed is solidified in a short time, and becomes a nearly spherical particle having a uniform particle diameter. In addition, since regeneration of cellulose is completed in a short time, progress of crystallization is suppressed, and particles having low crystallinity are obtained. Crystallinity can be controlled by adjusting the cooling rate.
【００１１】以上の製造方法により得られる多孔性球状
セルロース粒子の結晶化度は3〜15％である。結晶化度
が高すぎると、付加反応や架橋反応等の反応性が低くな
る。しかし、結晶化度が低すぎるとゲルの立体的安定性
を損なう恐れがある。好ましい結晶化度としては6〜8%
である。本発明でいう真球度とは、粒子の短径／長径を
意味する。真球度が0.8より低いとクロマト剤として用
いたとき、均一に充填することができず、再現性が低
く、担体としての性能が悪くなる。本発明の多孔性球状
セルロース粒子の真球度は0.9以上である。また、得ら
れた多孔性球状セルロースの粒径範囲は平均粒径の±10
%のものが70％以上を占め、狭い粒径範囲のものが篩い
分けなどの操作なしで高収率で得られる。The crystallinity of the porous spherical cellulose particles obtained by the above production method is 3 to 15%. If the degree of crystallinity is too high, the reactivity such as an addition reaction and a cross-linking reaction becomes low. However, if the crystallinity is too low, the steric stability of the gel may be impaired. Preferred crystallinity is 6-8%
It is. The sphericity in the present invention means the minor axis / major axis of the particles. When the sphericity is lower than 0.8, when used as a chromatographic agent, it cannot be uniformly filled, the reproducibility is low, and the performance as a carrier is deteriorated. The sphericity of the porous spherical cellulose particles of the present invention is 0.9 or more. Further, the particle size range of the obtained porous spherical cellulose is ± 10 of the average particle size.
% Occupies 70% or more, and those having a narrow particle size range can be obtained in high yield without any operation such as sieving.
【００１２】ジクロロベンゼンのように水と相溶性の無
い有機溶媒はＲ液を溶解しないので、Ｄ液としてこの溶
液を用いた場合には、次の段階でセルロース塩を除去す
る必要がある。分散粒子からカルシウム塩を除去（脱
塩）してセルロースをゲル状に再生させるためには、Ｄ
液と混合し、かつカルシウム塩を溶解する溶媒（以下、
脱塩溶媒という）を用いて洗浄する。該脱塩溶媒として
は、低級アルコール例えばエタノール、特にメタノー
ル、ケトン例えばアセトン、エステル例えば酢酸エチル
エステル等が好ましい。これらの溶媒は単独でまたは２
種以上の混合物として用いられ、水を含んでいてもよ
い。脱塩再生操作は、分散液をそのまま脱塩溶媒中に注
いで静かに撹拌することにより行なう事ができるが、例
えばデカンテーション、ろ過などにより分散溶媒の大部
分を除去した後、脱塩溶媒を用いて洗浄してもよい。い
ずれの場合にも脱塩溶媒は分散溶媒と混合し、同時にゲ
ル粒子からカルシウム塩を抽出するのでセルロース粒子
として安定化される。有機溶媒、カルシウム塩及び場合
により分散剤を充分に除去するため、最後によく水洗す
る事が好ましい。Since an organic solvent having no compatibility with water, such as dichlorobenzene, does not dissolve the R solution, when this solution is used as the D solution, it is necessary to remove the cellulose salt in the next step. In order to remove calcium salt from the dispersed particles (desalting) and regenerate cellulose into a gel, D
Solvent that dissolves calcium salt while mixing with
(Referred to as a desalting solvent). As the desalting solvent, lower alcohols such as ethanol, particularly methanol, ketones such as acetone and esters such as ethyl acetate are preferred. These solvents can be used alone or
It is used as a mixture of more than one species and may contain water. The desalting regeneration operation can be performed by pouring the dispersion liquid directly into a desalting solvent and stirring gently.For example, after removing most of the dispersion solvent by decantation or filtration, the desalting solvent is removed. May be used for washing. In each case, the desalting solvent is mixed with the dispersion solvent, and at the same time, the calcium salt is extracted from the gel particles, so that the desalting solvent is stabilized as cellulose particles. In order to sufficiently remove the organic solvent, the calcium salt and, if necessary, the dispersing agent, it is preferable to wash well with water at the end.
【００１３】[0013]
【実施例】次に、本発明について実施例及び比較例を用
いて詳細に説明するが、本発明はこれらの実施例に限定
されるものではない。以下の実施例で製造した多孔性球
状セルロース粒子における（１）結晶化度、（２）真球
度及び粒径、（３）原料セルロースの平均分子量の測定
法（４）排除限界分子量の測定法は次の通りである。Next, the present invention will be described in detail with reference to examples and comparative examples, but the present invention is not limited to these examples. (1) Crystallinity, (2) Sphericity and particle size, (3) Measurement method of average molecular weight of raw cellulose, (4) Measurement method of exclusion limit molecular weight in porous spherical cellulose particles produced in the following examples Is as follows.
【００１４】（１）結晶化度の測定法 微粉砕したセルロース粒子または再生セルロース0.2gを
アルミホルダーに押し付け、Ｘ線回折の回折角度を5〜3
0°まで操作して測定する。図１に示すように結晶性セ
ルロースにはA1,A2の結晶散乱ピークがある。これに対
し非結晶部分はバックグラウンド散乱となりBの部分と
なる。従って結晶化度は次式(A1+A2)×100／(A1+A2+B)
(%)で表される。A1,A2,Bの面積は5゜および30゜の点１
と２を直線で結び、更に18.5゜での散乱点３と１−３、
２−３のように結んで求める。(1) Method of measuring crystallinity 0.2 g of finely pulverized cellulose particles or regenerated cellulose is pressed against an aluminum holder, and the diffraction angle of X-ray diffraction is 5 to 3
Operate to 0 ° and measure. As shown in FIG. 1, crystalline cellulose has crystal scattering peaks of A1 and A2. On the other hand, the non-crystal part becomes background scattering and becomes part B. Therefore, the crystallinity is given by the following equation (A1 + A2) × 100 / (A1 + A2 + B)
(%). A1, A2, B area is 5 ゜ and 30 ゜ point 1
And 2 are connected by a straight line, and scattering points 3 and 1-3 at 18.5 ゜
Find it by tying it like 2-3.
【００１５】（２）真球度及び粒径の測定法 本発明によって得られた球状セルロースを顕微鏡観察
し、図２に示すように、各粒子の長径（R1）及び短径
（R2）を測定する。 真球度＝Ｒ２／Ｒ１ 粒径＝（Ｒ１＋Ｒ２）／２ 粒子1000個について真球度及び粒径を求めその平均を平
均真球度、平均粒径とした。(2) Measuring method of sphericity and particle diameter The spherical cellulose obtained by the present invention is observed with a microscope, and the major axis (R1) and minor axis (R2) of each particle are measured as shown in FIG. I do. Sphericity = R2 / R1 Particle size = (R1 + R2) / 2 The sphericity and particle size of 1000 particles were determined, and the average was defined as the average sphericity and average particle size.
【００１６】（３）原料セルロースの平均分子量の測定
法 粘度測定法を用いて原料セルロースの分子量を求めた。 ○方法 カドキセンの調整 １．エチレンジアミン（ＥＤＡ）90gに蒸留水231.4gを0
℃にて徐々に加える。 ２．酸化カドミウム31.8gをＥＤＡ溶液に0℃に徐々に加
える。（乳白色又は透明） ３．-15℃で一昼夜放置 ４．上澄み液190mlにＥＤＡ12ml+H2O 31ml+NaOH 2.8gを
0℃にて加える。 ５．4〜6℃の暗所にて密栓保存 粘度測定 １．カドキセン50mlにセルロース0.5gを6℃以下にて溶
解する。 ２．オストワルド粘度計により25℃で流下時間を測定し
た。濃度勾配は原液（1.で調製したもの）に対し、2
倍、3倍希釈液を作って設定する。これらのプロットか
ら極限粘度[η]を求める。 ３．平均分子量 Ｍ を次式から求める。 [η]＝ＫＭa ここで、Ｋ，ａは光散乱法により求められた係数で、Ｋ
＝1.8×10-2、ａ＝0.77を用いた。(3) Method for measuring average molecular weight of raw material cellulose The molecular weight of raw material cellulose was determined by using a viscosity measuring method. ○ Method Adjustment of cadoxene 1. 90 g of ethylenediamine (EDA) and 231.4 g of distilled water
Add slowly at ° C. 2. 31.8 g of cadmium oxide are slowly added to the EDA solution at 0 ° C. (Milky or transparent) 3. Leave at -15 ° C all day and night. EDA12ml + H2O31ml + NaOH2.8g to 190ml of supernatant
Add at 0 ° C. 5. Viscosity storage in a dark place at 4-6 ° C. In 50 ml of cadoxene, 0.5 g of cellulose is dissolved at 6 ° C. or less. 2. The flow time was measured at 25 ° C. using an Ostwald viscometer. The concentration gradient was 2% for the stock solution (prepared in 1.).
Make and set up 1-fold and 3-fold dilutions. The intrinsic viscosity [η] is determined from these plots. 3. The average molecular weight M is determined from the following equation. [η] = KMa where K and a are coefficients obtained by the light scattering method,
= 1.8 × 10 −2 and a = 0.77.
【００１７】（４）排除限界分子量の測定法 本発明で得られたセルロース粒子の細孔は液体クロマト
グラフィーによって排除限界分子量を測定して評価し
た。測定法を以下に示す。○Kav：直径2.2 cmのカラム
にゲルを高さ50cmに詰め、ブルーデキストラン、及び以
下に示した各種分子量のＰＥＯ（ポリエチレンオキサイ
ド）を添加し、流速100ml/hでゲル濾過クロマトグラフ
ィーを行い溶出位置をRI検出器で求める。Kavは次式で
求められる。 Kav＝（Ve−Vo）／（Vt−Vo） ここでVeは各種ＰＥＯの溶出量（ml）、Voはセルロース
粒子外の溶媒容量であり、粒子から完全に排除される高
分子性物質であるブルーデキストランの溶出量（ml）と
して求める。Vtはゲルベッド容量であり、カラムの横断
面積とゲル床の高さの式として求める。 ○Kavグラフ：片対数グラフの対数目盛り側にPEOの分子
量を、通常目盛り側にKavをプロットして得られたグラ
フ。 本発明における排除限界分子量は、プロットして得られ
たKav曲線の延長線上のＸ軸との接点部の分子量とし
た。(4) Method of Measuring Exclusion Limit Molecular Weight The pores of the cellulose particles obtained in the present invention were evaluated by measuring the exclusion limit molecular weight by liquid chromatography. The measuring method is shown below. ○ Kav: The gel was packed into a column of 2.2 cm in diameter to a height of 50 cm, blue dextran and PEO (polyethylene oxide) of various molecular weights shown below were added, and gel filtration chromatography was performed at a flow rate of 100 ml / h to elute. Is determined with an RI detector. Kav is obtained by the following equation. Kav = (Ve−Vo) / (Vt−Vo) where Ve is the amount of elution of various PEO (ml), and Vo is the solvent volume outside the cellulose particles, and is a high molecular substance completely excluded from the particles. Determined as the elution amount (ml) of blue dextran. Vt is the gel bed capacity, which is calculated as an equation of the cross-sectional area of the column and the height of the gel bed. O Kav graph: A graph obtained by plotting the molecular weight of PEO on the logarithmic scale side and Kav on the normal scale side of a semilogarithmic graph. The exclusion limit molecular weight in the present invention was defined as the molecular weight at the contact point with the X axis on the extension of the Kav curve obtained by plotting.
【００１８】 ＜各種PEO＞ １．PEO SE-70 （東ソー TSK 標準ポリエチレンオキサイド）分子量：57万 ２．PEO SE-15 （東ソー TSK 同上 ）分子量：16万 ３．PEO SE-2 （東ソー TSK 同上 ）分子量：2.1万 ４．ブルーデキストラン（Blue Dextran 2000）（ファルマシア LKB ファインケミカル）<Various PEOs> 1. PEO SE-70 (Tosoh TSK standard polyethylene oxide) molecular weight: 570,000 2. PEO SE-15 (Tosoh TSK same as above) Molecular weight: 160,000 3. PEO SE-2 (Tosoh TSK, same as above) Molecular weight: 21,000 Blue Dextran 2000 (Pharmacia LKB Fine Chemical)
【００１９】実施例１ 平均分子量が１万のセルロース粉末35.0gをチオシアン
酸カルシウム水溶液0.5Lに加え、100℃に加熱して溶解
した。得られた液を130℃に加熱したソルビタンモノオ
レート3.1gを含むO-ジクロロベンゼン2.5Lに滴下し、撹
拌数200rpmで造粒した。その後冷却速度2.0℃／minで常
温まで冷却し、1.8Lのメタノールを数回にわけて滴下し
て洗浄したのち、大量の水で洗浄し、多孔性球状セルロ
ース420g（乾燥重量42g）を得た。その結果、平均真球
度が0.96、排除限界分子量が240万、結晶化度が8%、粒
径85〜100μm の粒子が71%得られた。Example 1 35.0 g of cellulose powder having an average molecular weight of 10,000 was added to 0.5 L of an aqueous solution of calcium thiocyanate and dissolved by heating to 100 ° C. The obtained liquid was dropped into 2.5 L of O-dichlorobenzene containing 3.1 g of sorbitan monooleate heated to 130 ° C., and granulated at a stirring speed of 200 rpm. Thereafter, the mixture was cooled to room temperature at a cooling rate of 2.0 ° C./min, washed by dripping 1.8 L of methanol in several portions, and then washed with a large amount of water to obtain 420 g of porous spherical cellulose (dry weight: 42 g). . As a result, an average sphericity of 0.96, an exclusion limit molecular weight of 2.4 million, a crystallinity of 8%, and 71% of particles having a particle size of 85 to 100 μm were obtained.
【００２０】実施例２〜６ 原料セルロースの分子量とセルロース溶液濃度を後述の
表１のように変える以外は実施例１に準拠して多孔性球
状セルロース粒子の製造をおこない、得られた多孔性球
状セルロース粒子について、上記排除限界分子量、結晶
化度及び真球度の測定法に従い、排除限界分子量、結晶
化度及び真球度を求めた。その結果を表１に示した。ま
た、Kavグラフを図３に示した。Examples 2 to 6 Porous spherical cellulose particles were produced in accordance with Example 1 except that the molecular weight of the starting cellulose and the concentration of the cellulose solution were changed as shown in Table 1 below. With respect to the cellulose particles, the exclusion limit molecular weight, crystallinity, and sphericity were determined according to the methods for measuring the exclusion limit molecular weight, crystallinity, and sphericity described above. The results are shown in Table 1. FIG. 3 shows a Kav graph.
【００２１】比較例１ 特公昭63-62252公報記載の方法に従って多孔性球状セル
ロースを製造した。すなわち、チオシアン酸カルシウム
60重量％を含む水溶液100gにセルロース粉末（Whatman
社製、ＣＦ−１タイプ）6gを加え、120℃に加熱し溶解
した。得られた液をｍ−キシレン200gに分散させ130℃
〜140℃に加熱し、次いで分散液を冷メタノール500ml中
に注ぎ、粒子を得た。500mlのメタノールを数回に分け
て、このセルロース粒子に注いで洗浄した後、大量の水
で洗浄し、球状セルロース 48gを得た。Comparative Example 1 Porous spherical cellulose was produced according to the method described in JP-B-63-62252. That is, calcium thiocyanate
100 g of an aqueous solution containing 60% by weight of cellulose powder (Whatman
6 g (manufactured by KK Corporation, CF-1 type) was added and heated to 120 ° C. to dissolve. The obtained liquid was dispersed in 200 g of m-xylene and 130 ° C.
Heat to 140140 ° C. and then pour the dispersion into 500 ml of cold methanol to obtain particles. 500 ml of methanol was divided into several portions, poured into the cellulose particles and washed, and then washed with a large amount of water to obtain 48 g of spherical cellulose.
【００２２】実施例７ 実施例１と比較例１で製造された多孔性球状セルロース
粒子について、結晶化度、真球度、排除限界分子量、粒
径範囲（粒径分布において70%を占める範囲）の比較を
行った。その結果を表２に示した。Example 7 Regarding the porous spherical cellulose particles produced in Example 1 and Comparative Example 1, crystallinity, sphericity, exclusion limit molecular weight, particle size range (range occupying 70% in the particle size distribution) Was compared. The results are shown in Table 2.
【００２３】[0023]
【発明の効果】本発明の多孔性球状セルロース粒子は真
球度が高く、結晶化度が低くて反応性や安定性が高い多
孔性球状セルロース粒子であり、しかも粒径分布がシャ
ープであり、クロマト剤や医薬品基材として高性能の担
体として好適に使用することができる。また、本発明の
製造方法によれば、特殊な原料や添加物、二次的な操作
を行うことなく一定のコントロールされた細孔径をもつ
多孔性球状セルロース粒子を得ることができ、多様な物
質の分離精製に対応できる。さらに、工業的に製造する
場合も異形粒子、微粒子などのロスが非常に少ないの
で、篩い分けなどの工程を軽減でき、安定した生産がで
きる。The porous spherical cellulose particles of the present invention have high sphericity, low crystallinity, high reactivity and high stability, and have a sharp particle size distribution. It can be suitably used as a high-performance carrier as a chromatographic agent or pharmaceutical base material. Further, according to the production method of the present invention, it is possible to obtain porous spherical cellulose particles having a specific controlled pore diameter without performing special raw materials and additives, secondary operations, and various substances. Can be separated and purified. Furthermore, even in the case of industrial production, the loss of irregularly shaped particles and fine particles is very small, so that steps such as sieving can be reduced, and stable production can be achieved.
【００２４】[0024]
【表１】 [Table 1]
【００２５】[0025]
【表２】 [Table 2]
【図１】セルロースのＸ線回折図。FIG. 1 is an X-ray diffraction diagram of cellulose.
【図２】真球度および粒径の測定の模式図。FIG. 2 is a schematic diagram of measurement of sphericity and particle size.
【図３】実施例２〜６で製造した多孔性球状セルロース
粒子のKav曲線を示した説明図。FIG. 3 is an explanatory diagram showing a Kav curve of the porous spherical cellulose particles produced in Examples 2 to 6.
Claims (12)
子量が50万〜500万で、Ｘ線回折法により求めた結晶化
度が3〜15％、真球度が0.9以上であることを特徴とする
多孔性球状セルロース粒子。1. A porosity characterized by a polyethylene oxide having an exclusion limit molecular weight of 500,000 to 5,000,000, a crystallinity determined by an X-ray diffraction method of 3 to 15%, and a sphericity of 0.9 or more. Spherical cellulose particles.
子量が80万〜300万である請求項１記載の多孔性球状セ
ルロース粒子。2. The porous spherical cellulose particles according to claim 1, wherein the exclusion limit molecular weight of polyethylene oxide is 800,000 to 3,000,000.
子量が100万〜200万である請求項１記載の多孔性球状セ
ルロース粒子。3. The porous spherical cellulose particles according to claim 1, wherein the exclusion limit molecular weight by polyethylene oxide is 1,000,000 to 2,000,000.
孔性球状セルロース粒子。4. The porous spherical cellulose particles according to claim 1, having a crystallinity of 6 to 8%.
水溶液に溶解した溶液（以下、Ｒ液という）を分散溶液
（以下、Ｄ液という）に滴下して多孔性球状セルロース
粒子を製造する際に、原料セルロースの平均分子量と該
セルロースのチオシアン酸カルシウム水溶液への溶解濃
度とを調節して分散媒液に滴下することを特徴とする請
求項１〜請求項４のいずれか１項記載の多孔性球状セル
ロース粒子を製造する方法。5. A method for producing porous spherical cellulose particles by dropping a solution (hereinafter, referred to as R solution) of a raw cellulose in an aqueous calcium thiocyanate solution into a dispersion solution (hereinafter, referred to as D solution). The porous spherical cellulose particles according to any one of claims 1 to 4, wherein the average molecular weight of the cellulose and the dissolution concentration of the cellulose in an aqueous solution of calcium thiocyanate are adjusted and the solution is dropped into a dispersion medium. How to manufacture.
ロースをチオシアン酸カルシウム水溶液に溶解させた溶
解濃度が3重量%〜15重量%の溶液のＲ液をＤ液に、Ｒ液
／Ｄ液の体積比が0.5以下となるように滴下し、撹拌、
造粒したのち、冷却速度0.5℃／分以上で該反応液を冷
却させることを特徴とする請求項５記載の多孔性球状セ
ルロース粒子を製造する方法。6. An R solution of a solution in which raw cellulose having an average molecular weight of 1,000 to 100,000 is dissolved in an aqueous solution of calcium thiocyanate and having a dissolution concentration of 3% by weight to 15% by weight is used as a D solution, and an R solution / D The solution was dropped so that the volume ratio of the solution was 0.5 or less, stirred,
6. The method for producing porous spherical cellulose particles according to claim 5, wherein the reaction solution is cooled at a cooling rate of 0.5 ° C./min or more after granulation.
項５もしくは請求項６のいずれか１項記載の多孔性球状
セルロース粒子を製造する方法。7. The method for producing porous spherical cellulose particles according to claim 5, wherein the volume ratio of R liquid / D liquid is 0.3 or less.
求項５もしくは請求項７のいずれか１項記載の多孔性球
状セルロース粒子を製造する方法。8. The method for producing porous spherical cellulose particles according to claim 5, wherein the liquid D is a halogenated hydrocarbon compound.
ンもしくはジクロロベンゼンである請求項８記載の多孔
性球状セルロース粒子を製造する方法9. The method for producing porous spherical cellulose particles according to claim 8, wherein the halogenated hydrocarbon compound is dichloroethane or dichlorobenzene.
記載の多孔性球状セルロース粒子を製造する方法。10. The cooling rate is 2 ° C./min or more.
A method for producing the porous spherical cellulose particles according to the above.
多孔性球状セルロース粒子が平均粒径の±10%の粒径範
囲で70％以上得られる請求項５記載もしくは請求項６の
いずれか１項記載の多孔性球状セルロース粒子を製造す
る方法。11. The porous spherical cellulose particles according to claim 1 having an average particle diameter of 50 to 2000 μm, wherein 70% or more of the porous spherical cellulose particles are obtained within a particle size range of ± 10% of the average particle diameter. A method for producing the porous spherical cellulose particles according to claim 1.
である請求項５もしくは請求項６のいずれか１項記載の
多孔性球状セルロース粒子を製造する方法。12. The method for producing porous spherical cellulose particles according to claim 5, wherein the raw material cellulose has an average molecular weight of 10,000 to 40,000.
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|---|---|---|---|
| JP01758897A JP3601229B2 (en) | 1997-01-14 | 1997-01-14 | Porous spherical cellulose particles |
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