CN1008081B - 球形二氧化硅粒子—的制备方法 - Google Patents

球形二氧化硅粒子—的制备方法

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CN1008081B
CN1008081B CN86106689A CN86106689A CN1008081B CN 1008081 B CN1008081 B CN 1008081B CN 86106689 A CN86106689 A CN 86106689A CN 86106689 A CN86106689 A CN 86106689A CN 1008081 B CN1008081 B CN 1008081B
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particle
sio
tetraalkoxysilane
standard error
alcohol
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CN86106689A (zh
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克劳斯·昂格尔
赫伯特·吉舒
乔基姆·金克尔
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Merck Patent GmbH
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Merck Patent GmbH
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Abstract

本发明是关于制备高单分散、无孔隙球形SiO2粒子的方法，该方法是在水/醇氨介质中通过对四烷氧基硅烷进行水解缩聚，先制备成初级粒子溶胶，然后由反应程度控制，通过连续定量加入四烷氧基硅烷，使所得的SiO2粒子转换成理想的粒径；所述粒子的平均粒径为0.05-10μm，标准误差不超过5%；该SiO2粒子可作为色谱中的吸着材料。

Description

本发明涉及到一种制备高单分散、无孔隙的球形SiO2粒子的方法及其所述的粒子。
球形SiO2粒子在科技领域中是具有特殊意义的有价值的工具，也是科学研究中有趣的研究项目。这种粒子的一个重要应用领域，就是用于标准化，特别是当这种粒子具有确定和均匀的直径（主要在nm和μm范围内）情况下，例如用作为决定诸如粉粒或细胞之类微小物体粒度的标准。在色谱领域中及由此派生出来的分离技术中，用作吸着材料或载体材料，是这种粒子的又一应用领域。在所有应用中，粒径和粒径分布起着相当重要的作用。因此，能够根据所述粒子的特点以可预期及可重复的方式来制备这种粒子，是很重要的。
从现有技术，例如从W.STOBER等人在“胶体与界面科学杂志”1968，Vol 62，No 26和1969，Vol 568，No 30上发表的文章以及从美国专利3，634，588号，已知可通过对四烷氧基硅烷进行水解缩聚得到球形SiO粒子。上述这些文献并指出了为实现此目所需的基本反应条件，具体做法是将四烷氧基硅烷导入过量的水/醇氨水解混合物中，同时用适当的方式，如搅拌、振摇或超声波处理等，将其彻底混合。在这种情况下，随着特定实验参数的选择，就能得到不同平均粒径的SiO2粒子和不同的粒径分布。所引用的出版物的数据，表明获得了平均粒径为0.05-2μm（少数情况下，高达3μm）的SiO2粒子，同时还研究了在水解混合物中不同的硅酸酯，氨和水的浓度以及不同的醇的影响。从内部研 究证实的结果，可以推断，在某种程度上仅仅在最大为2μm的粒度范围内，可获得单分散球形的粒子，但到目前为止还不具备充分控制重复生产这种粒子的能力。因此，粒径的标准误差通常落在约5～15%之间。在少数情况下，标准误差高达50%。在制备较大直径的单分散粒子上是不成功的;还未见过描述制备直径超过3μm的粒子。根据引用的出版物，仅仅制备了水溶胶形式的粒子，但并未将粒子本身从水解混合物中分离出。结果，缺乏任何关于这类粒子的其他性质的数据，尤其是关于其孔隙性的数据。
在对用STOBER等人的方法制备以及通过淀积或离心干燥而分离出的SiO2粒子所作的内部研究中，就体现这样的粒子有显著的微孔性。这种情况可从比表面数值反映出来，例如，可通过气体吸收（例如通过BET方法）来测定其比表面;根据给定的实验条件，测定的比表面可以为理论计算表面的10-100倍。
粒子的微孔性必然会极大地影响粒子的性质。尽管如此，就上述许多应用而言，倘若粒子实质上没有孔隙，即粒子表面是完全封闭的话，就认为是有益的。
从而，本发明是建立在制备得到尽可能没有孔隙、且具高度单分散性的球形SiO2粒子的目标基础上的。应该尽可能容易地进行制备和供应具有预定的可重复生产的粒径的粒子。若可能的话，甚至其粒径可高达10μm。此外，应该可以改性这类粒子，使其在SiO2基质中包含有机基团，例如，通常用于来改良硅胶的那些有机基团。
令人惊奇的是，现已发现，如果通过在水/醇氨介质中，用已知的方法，对四烷氧基硅烷进行水解缩聚，首先获得一个初级粒子的溶胶，然后通过连续定量地加入四烷氧基硅烷（通过反应程度来控制）将所得到的SiO2粒子转换成希望得到的粒径，那么，就能得到平均粒径在0.05和10μm之间、标准误差不超过5%的无孔隙球形SiO2粒子。在这种情 况下，最终获得的SiO2粒子，作为具有严格的球形状和均匀的粒径，即高度单分散、无孔隙的离散微粒而聚集。
另外，也可以得到同样满足无孔隙、单分散要求的有机改性SiO2粒子。
更进一步发现，由于其特殊性质，以这种方式制备的SiO2粒子，非常适合在色谱中作为特殊的吸着材料。因此，当有机改性SiO2用作为高分子量生物分子（如蛋白质）的反相色谱法的吸着材料时，表现出优越性。就这一点来说，用传统的吸着剂，是达不到这种优点的。
因而，本发明的主题是：通过对四烷氧基硅烷在水/醇氨介质中水解缩聚，来制备球形SiO2粒子的方法。在此方法中，首先生产出一种溶胶或初级粒子，然后，通过连续地、定量地加入四烷氧基硅烷（通过反应的程度来控制），将所得的SiO2粒子转换成希望得到的粒径，从而得到高单分散、无孔隙、平均粒径在0.05和10μm之间、标准误差不超过5%的粒子。
本发明的主题也是由这样一种具有独特性质的SiO2粒子构成的。
此外，本发明的主题还包括将按本发明的方法所制备SiO2粒子用作为色谱中的吸着材料，特别是用作为高分子量生物分子（如蛋白质、核酸）反相色谱的吸着材料。
按本发明所述的制备高单分散、无孔隙球形SiO2粒子的方法，是分两步进行的。
第一步，按已知的方法，制备初级粒子溶胶。为此，将四烷氧基硅烷导入水/醇氨水解混合物，并彻底混合。所有可令人满意地被水解的脂族醇原硅酸酯均适合作四烷氧基硅烷。在此情况下主要就考虑含有1-5个碳原子的脂族醇酯，例如，甲醇、乙醇、正或异丙醇及同分异构的丁醇和戊醇。它们可单个地使用，也可以混合的使用。最好是C1-C3醇的原硅酸脂，特别是四乙氧基硅烷。除脂族醇外，水解混合物应含有约 0.5至约8摩尔/升的氨，约1至15摩尔/升的水。适合作醇成分的有脂族C1-C5醇，最佳的为C1-C3醇，如甲醇，乙醇，还有正或异丙醇。这些可单独地用于水解混合中，也可以几种醇混用。最好一次性地将四烷氧基硅烷加到水解混合物中，反应物可以一种纯的形式或在上述醇中的溶液的形式加入。水解混合物中四烷氧基硅烷的浓度约在0.01至1摩尔/升之间，用来制备初级粒子。反应物被放在一起后，反应立即开始或几分钟后便开始，这可由立刻产生的粒子所造成的反应物的乳白色或混浊显示出来。一般说来，在不超过15至30分钟的时间内反应完成，在不利的情况下，时间会更长一点。随着反应物的选择及其反应混合物的浓度的变化，按已知的方法，就能得到平均直径在约0.01和约2μm之间的粒子。
按本发明方法的第一步，最好是使用含3-13摩尔/升的水，0.5至4.5摩尔/升的氨，10至25摩尔/升的醇以及0.1-0.5摩尔/升的四烷氧基硅烷的反应混合物。在此情况下，可得到平均直径在0.01和1μm之间的初级粒子。在这一阶段，可从初级粒子溶胶中取出试样，例如，使用电子显微对粒子的粒径、形状的精确性和粒径分布进行研究。通过分离粒子试样，就有可能测出初级粒子的孔隙性（例如通过气体吸收测定）。
已经证明，在高温下进行制备初级粒子的反应是有利的。在这种情况下，35至75℃之间的温度，特别是40-65℃的温度是有利的。已表明，在高温时，粒径分布变窄，然而平均粒径减小。在较低的温度时，即大约在室温下，在其他条件都相同时，得到粒径分布较宽的较大粒子。另外，在此情况下，还会观察到形成了更多的不希望的凝结物。
在按本发明所述的方法第二步里，缓慢地、连续定量地将四烷氧基硅烷加到初级粒子溶胶里，并将其混合均匀。在这里，控制定量的加入的速率，以保证四烷氧基硅烷能迅速完全的与溶胶中的粒子反应，而不 致从过量的四烷氧基硅烷形成能产生新的初级粒子的核，这一点是很重要的。用计量加入四烷氧基硅烷的方法（通过反应程度来控制的），可以控制溶胶中粒子的二次生长。所以，获得的最终粒径取决于总的加入四烷氧基硅烷的数量。总的加入的烷氧基硅烷的数量，在原则上不是最重要的，只要水解混合物是过量的，或通过补加水解混合物，保持其过量就可以。添加水解混合物时，没有时间限制;可持续若干小时至若干天。中间停止和重新开始二次生长，也是允许的，因为粒子在其生长的各个阶段都是稳定的。同样，在二次过程中，最佳的是采用较高温度（约40℃）。
约0.05μm，即规定的初级粒子的最小粒径，应被定为下限粒径。按本发明得到的粒子具有均匀的球形状，没有任何孔隙。由气体吸收所测定的比表面为理论计算表面的1至1.5倍。这样充其量不过是表面稍微粗糙一些，但排除了孔隙的存在。可以这样解释，原来存在于初级粒子的孔隙，被缓慢的、连续的二次生长所封闭，同时又不能形成新的孔隙。
令人惊奇和出乎意料的是，在初级粒子中出现的较宽的粒径分布（在那种情况下，标准误差平均为5-10%）现象，在通过二次生长步骤的方法获得的粒子中未发现。这样得到的粒子的标准误差不超过5%，通常在2%左右或以下，因而是高度单分散的，显然，在这第二步，发生了对原有的各种粒径的调整，并且发生了随着相对标准误差的相应减少而出现的所有粒子的均匀的进一步生长。
从而，按本发明的方法，本专业领域内的人员可以制备直径可达10μm，高度单分散、无孔隙的球形SiO2粒子。特别是，在这个范围内，现在可利用这类粒子作为系统尺寸等级的精确的标准，这种标准大致是与“标准尺”一致的。
在一个实施例中，制备了这类含有机改性基团（即含有共价键有机 基）的粒子。制备这类粒子的方法在原则上为已知的。为此，在按本发明的方法里，最好是在二次生长步骤，用一种或多种已知的有机三烷氧基硅烷来取代所用四烷氧基硅烷中的0.1至100%，最好为1-30%，以改性硅胶。这些化合物中的有机基可以是具有1-20个碳原子的脂族基;这类脂族基是可以任选地通过诸如羟基、硫代、氨基或羧基或囟素及链烯基被功能化。将功能化的有机基结合到粒子的SiO2基质中，就可以用已知的方式，通过共价键连接，容易地使后面的进一步改性变成可能。这类有机三烷氧基硅烷的例子有：
甲基三乙氧基硅烷
乙基三乙氧基硅烷
己基三乙氧基硅烷
辛基三乙氧基硅烷
十二烷基三乙氧基硅烷
十八烷基三乙氧基硅烷
乙烯基三乙氧基硅烷
3-羟基丙基三乙氧基硅烷
3-氯丙基三乙氧基硅烷
3-氨基丙基三乙氧基硅烷
3-glycidoxypropyltriethoxysilane
3-巯基丙基三乙氧基硅烷
3-异硫氰酸根合丙基三乙氧基硅烷
3-（氨基乙氨基）丙基三乙氧基硅烷
3-甲丙烯酰基丙氧三乙氧基硅烷
3-乙酸基丙基三乙氧基硅烷
N-（3-三乙氧基甲硅烷丙基）-N′-（1-苯基-1-羟基异丙基）-硫脲
N-（3-三乙氧基甲基硅烷丙基）-N′-（α-苯乙基）硫脲
就无孔隙性和单分散性而言，粒子的性质是不受这种有机改性的影响的;而在另一些方面，又可以保留改性的硅胶已知的有益性质。自然还可以通过用已知的诸如用于孔隙材料的后处理方法，对本发明的方法制备的未经改性的SiO2粒子进行表面有机改性（例如，在制备反相色谱吸着剂中）。
这种有机改性SiO2粒子，可应用于众多的其他领域，例如作为色谱中的特制吸着剂。
特别是，所述的按本发明方法制备的有机改性SiO2粒子，适用于反相色谱。
所述的粒子的使用，使得高分子量生物分子（如肽、蛋白质或核酸）的分离变成可能。例如，这类分子是：溶菌酶、核糖核酸酶A、脲酶、转铁蛋白、胰岛素、醛缩酶、肌红蛋白、触酶、卵清蛋白、乳酸脱氢酶、吡啶偶氮苯酚、α-糜蛋白酶、过氧化物酶、牛血清清蛋白、铁蛋白、Cl-INA、肌酸激酶、碳酸酐酶、戊基葡糖苷酶、血红蛋白、inter-leucin及其他。当本发明的粒子用于这类生物分子的分离时，便体现出这样的优点，即用传统的材料，是不可能取得这种良好的效果的。
这种低平均粒径，窄粒径分布以及与孔隙材料相比较小的扩散阻碍，使得可以达到更高的柱效率，从而也就达到了一个更高的检测极限。进一步的优越性在于缩短了分析时间。与用传统材料所需要的（分析）时间相比，大减少到原来的五分之一。另外，与用孔隙材料时的情况相比，物质损失也明显地低。
在溶液的选择上，没有任何的限制，所有已知的溶液系统都可使用。
实施例一
制备一个水解混合物，其包含11.9克（0.66摩尔）水，62.7克（1.96摩尔）甲醇，2克（0.12摩尔）氨。把所述的水解混合物调温在40℃，将4.4克（0.02摩尔）同样调温的四烷氧基硅烷，一次加入该水 解混合物里，并彻底混合。得到平均粒径为0.07μm、标准误差为11%的初级粒子溶胶。
将36克（0.17摩尔）四烷氧基硅烷、450克具有上述成分的水解混合物滴加到所得的初级粒子溶胶，同时搅拌24小时以上。（离心分离或淀积和干燥后）得到平均粒径为0.145μm、标准误差为5%的球形SiO2粒子。按BET方法，得其比表面为23m2/g（理论计算表面为19m2/g）。
实施例二
制备一个水解混合物，其包含13.5克（0.75摩尔）水，80克（2.5摩尔）甲醇和0.85（0.05摩尔）氨。把这一水解混合物调温在40℃，一次将4.2克（0.02摩尔）同样调温的四烷氧基硅烷加入该水解混合物里，并彻底混合。得到平均粒径为0.015μm、标准误差为15%的初级粒子溶胶。
将170克（0.82摩尔）四烷氧基硅烷、1.9升水解混合物滴加到所得到的初级粒子溶胶里，同时搅拌100小时。得到平均粒径为0.05μm、标准误差为5%的球形SiO2粒子。用BET方法得到的比表面为64m2/g（理论计算表面为55m2/g）。
实施例三
制备一个水解混合物，其包含13.5克（0.75摩尔）水，64.4克（14摩尔）乙醇和6.4（0.38摩尔）氨。把这一水解混合物调温在40℃，一次将4.2克（0.02摩尔）同样调温的四烷氧基硅烷加入该水解混合物里，同时彻底混合。得到平均粒径为0.58μm、标准误差为5%的初级粒子溶胶。比表面：Sbet＝340m2/g;S理论＝4.7m2/g。
将650克（3.1摩尔）四烷氧基硅烷，5.9公斤水解混合物滴加到所得到的初级粒子溶胶，同时搅拌5天。得到平均粒径为3.1μm、标准误差为1.3%的球形SiO2粒子。通过BET方法得到的比表面为 1.1m2/g（理论计算表面：0.88m2/g）。
实施例四
按例一的方法制备初级粒子溶胶。以相似的方法，进行二次生长步骤，但使用含4克（0.09摩尔）的四烷氧基硅烷、0.4克（1.8毫摩尔）的氨丙基-三氧甲基硅烷的混合物。
得到平均粒径为0.09μm、标准误差为5%的有机改性球形SiO2粒子。比表面为44m2/g（理论计算表面：30m2/g）。所述粒子的碳成分为2.4%。
实施例五至八
制备一种水解混合物，其包含16.2克（0.9摩尔）水，64.8克（1.8摩尔）甲醇和2.7克（0.16摩尔）氨。把这一水解混合物调温在40℃，一批地将4.2克（0.02摩尔）同样调温的四烷氧基硅烷加入该水解混合物中，并彻底混合。得到平均粒径为0.13μm、标准误差为10%的初级粒子溶胶。比表面：Sbet＝280m2/g;S理论＝4.7m2/g。
在2天的过程中，每次滴加特定数量的四烷氧基硅烷及水解混合物到原有的100毫升的溶胶里，直到将其加至600毫升为止，在此步骤中就发生了二次生长。下面的表一说明了每一步加入的硅烷的数量及得到的有关数据。
表一
实施    加入的四    平均粒径/    比    表    面
例号    烷氧基硅    标准误差
No.    烷数量    Sbet    S理论
5 35克 0.265μm/5% 14m2/g 10.3m2/g
6 54克 0.56μm/3.4% 5.5m2/g 4.9m2/g
7 55.3克 1.15μm/2.6% 2.6m2/g 2.4m2/g
8 55.3克 2.4μm/1.7% 1.5m2/g 1.1m2/g
实施例九
在3公升的含有1摩尔氨/公升、8摩尔水/公升、和乙醇（剩余数量）、且调温在40℃的水解混合物中，有按例三所制备的170克粒径为1.55μm的硅胶粒子。将含有2.4克辛基三甲氧基硅烷和17.6克四烷氧基硅烷的混合物滴加到上述溶液中，滴加时间为1.5至2小时。得到有机改性的球形SiO2粒子。所述粒子的碳成分为1.0%。
实施例A
一含有5种蛋白质的混合物，通过填充有例九制备的1.5μm的无孔隙、单分散的辛基改性SiO2粒子的柱（长40cm，直径8cm）而进行分离。
蛋白质混合物包含：
1）核糖核酸酶A    （分子量＝13，700）
2）细胞色素C    （分子量＝12，500）
3）醛缩酶    （分子量＝156，000）
4）触酶    （分子量＝24.000）
5）卵清蛋白    （分子量＝45，000）
使用了下列溶剂：
溶剂A：水100%，含HCLO，PH值调节在2.0\\
溶剂B：乙腈75%/溶剂A25%。
以1.5毫升/分钟的流速进行分离。
梯度变化：
在所有情况下，起始条件为75%的溶剂A，在3，10，20和40分钟后，达到溶剂B的终值100%。
各蛋白质的洗脱品级比较于表二。
表二
蛋白质    tg    （分钟）    3    10    20    40
核糖核酸酶A    3.2    4.2    5.4    7.9te（分钟）
细胞色素C    3.6    5.8    7.6    12.1
醛缩酶    4.2    7.1    10.8    18.8
触酶    4.5    7.6    11.9    20.7
卵清蛋白    4.8    8.2    13.2    23.9
tg＝以分钟计的梯度时间
te＝以分钟计的的物质洗脱时间
该表表明，即使只用了10分钟的分析时间，仍然可得到令人满意的良好分离，因为在此情况下，洗脱品级相距已足够远。

Claims (6)

1、在水/醇氨介质中，通过对四烷氧基硅烷水解缩聚而制备球形SiO2粒子的方法，其特征在于先制备初级粒子溶胶，然后，由反应程度控制，通过连续定量地加入四烷氧基硅烷，使所得到的SiO2粒子转换成理想的粒径，得到平均粒径在0.05和10μm之间标准误差不超过5%的高度单分散、无孔隙的粒子。
2、按权利要求1所述的方法，其特征在于水解缩聚是在35至75℃，最佳的是在40至65℃的温度进行的。
3、按权利要求1所述的方法，其特征在于用低级脂族醇（C1-C3）的硅酸酯作为所用的四烷氧基硅烷。
4、按权利要求1所述的方法，其特征在于用三烷氧基硅烷代替所用四烷氧基硅烷中的0.1至100%，最佳的为1-30%。
5、按权利要求1的方法制备的SiO2粒子，其特征在于平均粒径在0.05和10μm之间，标准误差不超过5%，以高度单分散、无孔隙形式存在。
6、按权利要求5所述的SiO2粒子，其特征在于这些粒子在其基质中含有通常用来改性硅胶的共价键合的有机基团。
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CN86106689A (zh) 1987-05-27
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JPH0825739B2 (ja) 1996-03-13
US4911903A (en) 1990-03-27
EP0216278A2 (de) 1987-04-01
AU6246986A (en) 1987-03-26
DE3616133A1 (de) 1987-11-19
AU588363B2 (en) 1989-09-14
US4775520A (en) 1988-10-04
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