JP2506682B2 - Manufacturing method of spherical particles - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing porous spherical particles of an organic acid ester of cellulose, and more specifically to the uniformity of particle size, sphericity, porosity and the like. The present invention relates to an excellent method for producing spherical particles, and particularly to saponify the spherical particles to obtain spherical cellulose particles useful as a carrier for chromatography.

(B) Conventional technology Microparticles of polymeric substances are used in the fields of plastic additives, chemical excipients, anti-blocking agents, cosmetics, printing, etc. in their original shape, but in recent years, enzyme,
It has also attracted attention as a carrier for microorganisms and as a packing material for chromatography. As a polymeric substance, cellulose organic acid ester is highly soluble in solvents and is easy to obtain as particles, so it can be used as it is for the above purposes, or it can be hydrolyzed to convert it into fine particles of cellulose, or other functional groups. For example, it is possible to introduce a functional group having an ion-exchange ability, and it can be used for various purposes. In particular, several patent applications have been made for cellulose particles obtained by this method.

Japanese Examined Patent Publication No. 55-39565 discloses a method of dry-spinning a cellulose fatty acid ester as a method for producing spherical particles, cutting the obtained filament into chips, and heating them in a high-boiling point solvent to form spherical particles, and a celluloque fatty acid ester. Is dissolved in a low boiling point solvent and suspended in a high boiling point poor solvent,
A method for obtaining spherical particles by heating to evaporate the low boiling point solvent is shown, and the obtained cellulose fatty acid ester particles are hydrolyzed to obtain spherical cellulose particles. These are manufacturing methods that require a long process and consume a large amount of energy. Further, since the obtained cellulose fatty acid ester particles are relatively dense, the cellulose particles obtained therefrom are also relatively dense, and as a chromatographic carrier or drug sustained-release agent, only those having too small a porosity can be obtained. Absent.

As a method for obtaining particles having a large porosity, JP-A-54-55
As disclosed in 055 and JP-A-56-24429, when a cellulose fatty acid ester is dissolved in a low boiling point solvent, a polymer compound having a different solvent solubility from the high boiling point solvent or the cellulose ester, for example, water-soluble After adding the polymer compound and dispersing and suspending the mixed solution in an aqueous solution to form droplets,
By heating to evaporate the low boiling point solvent and solidify the droplets, a polymer compound or a cellulose fatty acid ester microsphere containing a high boiling point solvent is obtained, which is before or after saponification. A method has been proposed in which the boiling point solvent is removed by washing to obtain cellulose particles having a high porosity.

(C) Problems to be Solved by the Invention In the above conventional technique, the latter method for obtaining particles having a large porosity has the following problems.

When the low boiling point solvent is removed by heating the droplets or the coagulated particles from the droplets, the physical properties such as pore size, particle size, and density easily change due to the thermoplasticity of the cellulose fatty acid ester, The process control to obtain reproducible physical property values is troublesome. Further, in the method of removing the polymer compound from the coagulated particles by washing, a large numerical value can be obtained as the porosity, but the individual pores are large and the number thereof is limited. That is, particles in which individual pores are relatively large are obtained. Such particles can be used as an oxygen-fixing carrier or a raw material for an ion-exchange ceruce derivative, but are not so suitable as a carrier for chromatography.

The inventors of the present invention formed a three-dimensional network structure by gelling a cellulose organic acid ester under appropriate conditions, and this structure is relatively stable, which is advantageous for forming a large number of small pores. The present invention has been reached and the present invention has been reached.

(D) Means and Actions for Solving Problems This invention is directed to adding an organic solvent solution in which a cellulose organic acid ester and a gelling agent for the cellulose organic acid ester are dissolved into an aqueous medium to form droplets. A porous gel characterized by gelling the cellulose organic acid ester in the droplets into spherical gel particles while the droplets are present in an aqueous medium, and removing the gelling agent and the organic solvent from the generated particles. The present invention provides a method for producing hydrophilic spherical particles.

Examples of the cellulose organic acid ester used in the present invention include cellulose triacetate, cellulose diacetate, cellulose benzoate, cellulose carbamate, and cellulose acetate butyrate. Both have solvent solubility and thermoplasticity, and when treated with alkali, they are hydrolyzed to regenerate cellulose. Cellulose triacetate is particularly suitable for the purpose of the present invention in terms of price, solvent solubility, gel forming property and the like.

The organic solvent that dissolves the cellulose organic acid ester needs to be a solvent that does not dissolve in water, and methylene chloride, halogenated hydrocarbons such as chloroform, and halogenated hydrocarbons are the main constituents of these aliphatic alcohols, It is possible to select and use a mixed solvent containing a small amount of a ketone, an ester or a hydrocarbon. The amount of the organic solvent used depends on the concentration of the cellulose organic acid ester being 3 to 15
It is appropriate that the amount is in the range of% by weight. In general, the lower the concentration, the more likely the particles have a high porosity.

The gelling agent is compatible with the cellulose organic acid ester and dissolves in a common solvent to form a mixed solution, but when the solvent's dissolving power decreases, a substance having the ability to gel the cellulose organic acid ester is used. Point to. The gelling agent can be selected from long-chain aliphatic carboxylic acids, long-chain aliphatic alcohols, aromatic carboxylic acid aliphatic esters, and the like.

Examples of the long-chain aliphatic carboxylic acid include oleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid and n-octanoic acid.

As the long-chain aliphatic alcohol, n-hexanol,
Examples thereof include n-heptanol, n-octanol, decyl alcohol, tridecanol, 2-ethylhexanol, and n-nonanol.

Aromatic carboxylic acid aliphatic esters include butyl benzoate, hexyl benzoate, monobutyl phthalate, monooctyl phthalate, dibutyl phthalate, dioctyl phthalate, diethyl phthalate, dilauryl phthalate, butylbenzyl phthalate, phthalic acid. Examples include diheptyl and dicyclohexyl phthalate.

The addition amount of these gelling agents is appropriately 5 to 30% by volume with respect to the organic solvent.

Examples of the aqueous medium used in the present invention include water or a small amount of water such as 0.2 to 10% by weight of gelatin, water-soluble polymer such as CMC and PVA, and / or 0.05 to 3% by weight of a surfactant.
A solution in which an antifoaming agent is dissolved is used. It is for stabilizing the droplets generated in these drugs added to water.

The size of the spherical particles of the cellulose organic acid ester obtained by the method of the present invention depends on the size of the droplet since one particle is formed from one droplet in principle, but it is formed in an aqueous medium. The size of the droplets depends on the stirring efficiency when the organic solvent solution is added to the aqueous medium, and the higher the stirring efficiency, the smaller the droplet size. When the concentration of the cellulose organic acid ester in the solution is low, the viscosity of the solution is low, so that the efficiency is improved and small droplets can be obtained even at the same stirring speed. The concentration of the cellulose organic acid ester is also a factor that determines the porosity of the particles, and the porosity increases as the solute concentration decreases.

The formation mechanism of the porous spherical particles of the organic acid ester of cellulose of the present invention will be described below in the case of using methylene chloride containing methanol as the organic solvent.

A cellulose organic acid ester and a gelling agent are dissolved in a methylene chloride / methanol solvent, and this solution is added to an aqueous medium at room temperature with stirring to form droplets, and stirring is performed at room temperature. In the meantime, a part of the methanol in the droplet and a small amount of methylene chloride are diffused and lost in the aqueous medium, and a small amount of water is dissolved in the droplet. When in this state, the cellulose organic acid ester in the droplets gels to form particles having a network structure. The particles are already solid, elastic and return to their original shape when the force is removed even if they are pressed and deformed with a finger. The particles are recovered from the aqueous medium and washed with a suitable solvent to remove the gelling agent and methylene chloride contained in the particles. In this state, particles having a porous structure are obtained. Since the particles still contain methylene chloride, under these conditions where the residual solvent is heated by heating in an aqueous medium, the cellulose organic acid ester does not show sufficient thermoplasticity, so that the generated pores are blocked. Does not happen.

(E) Examples The present invention will be described below with reference to examples, but the present invention is not limited thereto.

Example 1 Cellulose triacetate [Daicel Chemical Industry Co., Ltd.
Manufactured, acetylation degree 61%] 25 g was dissolved in 170 ml of methylene chloride containing 30 ml of methanol. Dibutyl phthalate 3 in this solution
A mixture of 0 ml and 30 ml of methylene chloride was added and stirred to form a uniform solution. Water containing 0.5% of antifoaming agent Antihome E-20 (manufactured by Kao Corporation) and 1% of gelatin was added.
It was dispersed therein while stirring at a rotation speed of about 7500 rpm. The obtained suspension was poured into 1% gelatin water 1 with slow stirring, and the stirring was continued for 1 hour. After standing, the supernatant was removed, water-isopropanol (1: 1) mixture 1 was added, and the mixture was stirred for a while. After filtration, wash thoroughly with water. Then, the cellulose ester beads are suspended in isopropanol 1 and heated to 70 ° C to 80 ° C.
Stir for 3 hours. After filtration, 2 with isopropanol 0.5
Wash twice, suspend in water and heat. After treating at 80 ° C for 2 hours, filter and wash with sufficient water. When separated in a wet state, 10 ml of particles with a diameter of 10-30 μm, 30 μ
m-75μm particles 40ml, 75-150μm particles 80ml, 150-
20 ml of 250 μm particles were obtained. The obtained cellulose acetate beads (particle size: 75 to 150 μm) were hydrolyzed by adding 300 ml of 75% ethanol and 600 ml of 1.0% NaOH to 100 g of beads and stirring at room temperature for 1 day. Then, it was neutralized with dilute acetic acid and sufficiently washed with water to obtain cellulose beads. When the density of this cellulose bead was measured by the following method, it was 0.32.

The swollen sample is packed into a glass column having an inner diameter of 8 mm at a height of about 10 cm. The volume Vo of the cellulose particles is calculated from the inner diameter (8 mm) of the column and the height of the packed cellulose particles.

Vo = (0.4) ² πh h; Height of packed cellulose particles (cm) Next, dextrin (using 0.5% aqueous solution) was eluted with blue having a molecular weight of 2,000,000 and the elution amount (Vt m
l) is required. The packed cellulose particles are taken out from the column, filtered, thoroughly washed, and dried to obtain the weight (W (g)). The density was calculated from these data by the following formula.

When the obtained cellulose beads were evaluated as a column chromatography packing material for gel filtration, the exclusion limit molecular weight was about 70,000 for dextran molecules.
Met.

Comparative example (when no gelling agent is added) Cellulose triacetate (Daicel Chemical Industry Co., Ltd.)
25% (produced, acetylation degree 61%) was dissolved in 200 ml of methylene chloride containing 30 ml of methanol. This solution was dispersed in 0.5% of 1% gelatin water containing the antifoaming agent Antihome E-20 at a rotation speed of 7500 rpm, and the obtained suspension was added to 1% gelatin water 1 with slow stirring. The stirring was continued for 1 hour. When the same treatment as in Example 1 was carried out, agglomeration of droplets occurred during the treatment, cellulose ester particles were not obtained at all, and only cellulose triacetate lumps were obtained.

Example 2 Cellulose triacetate (Daicel Chemical Industry Co., Ltd.)
25% (produced, acetylation degree 61%) was dissolved in 170 ml of methylene chloride containing 30 ml of methanol. To this solution, a mixed solution of 30 ml of oleic acid and 30 ml of methylene chloride was added and stirred to make a uniform solution. The solution was mixed with 0.5% of 1% gelatin water containing antifoam anti-home E-20 at about 7500 rpm. Stir to disperse. The resulting suspension was poured into 1% gelatin water 1 with slow stirring and stirred for about 1 hour. Then, the same treatment as in Example 1 was carried out to obtain the same cellulose triacetate particles as in Example 1. Cellulose ester particles having a particle size of 75 to 150 μm were hydrolyzed in the same manner as in Example 1 to obtain cellulose beads having a density of 0.3.

(F) Effect of the Invention The present invention is a method for easily and economically producing porous spherical particles of a cellulose organic acid ester and has extremely good reproducibility. In the conventional method, the physical properties of the particles were affected by the temperature conditions when removing the low boiling point solvent, but in the method of the present invention, the solvent composition, the concentration of the cellulose organic acid ester and the gelling agent, and the stirring conditions during particle generation. By defining such as, spherical particles with high sphericity can be obtained with good reproducibility.

The cellulose organic acid ester particles obtained by the method of the present invention can be used as an antiblocking agent, a plastic additive, a soil conditioner and the like. Furthermore, since the cellulose particles obtained by hydrolyzing the ester particles have many small pores, they are suitable for cosmetics, gel filtration chromatography carriers, sustained-release drug carriers and the like. Further, the cellulose particles can be chemically modified and applied to an ion exchange chromatographic carrier, an affinity chromatographic carrier and the like.

Claims (2)

(57) [Claims] 1. An organic solvent solution in which a cellulose organic acid ester and a gelling agent selected from long-chain aliphatic carboxylic acids, long-chain aliphatic alcohols and aromatic carboxylic acid aliphatic esters are dissolved in an aqueous medium. In addition to forming droplets,
Porous characterized in that the cellulose organic acid ester in the droplets is gelled while the droplets are present in the aqueous medium to form spherical gel particles, and the gelling agent and the organic solvent are removed from the produced particles. Method for producing spherical particles. 2. The method for producing spherical particles according to claim 1, wherein the organic solvent is methylene chloride containing methanol.