JPS6395238A - Production of spherical particle - Google Patents

Abstract

PURPOSE:To obtain particles having excellent particle size uniformity, sphericity and porosity and giving a useful carrier for chromatography by saponification, by forming a droplet of a solution of a cellulose organic acid ester in an aqueous medium and coagulating the droplet with a polyhydric alcohol. CONSTITUTION:An organic solvent solution of a cellulose organic acid ester is dripped into an aqueous medium to form liquid droplets and a water-soluble polyhydric alcohol is added to the resultant droplet/aqueous medium dispersion system to coagulate the ester in the liquid droplet. The water-soluble polyhydric alcohol is selected from ethylene glycol, glycerol and 1,3-propanediol. The cellulose organic acid ester is e.g. cellulose triacetate, cellulose acetate butyrate, etc., and the solvent is preferably a mixed solvent containing methanol, propionic acid ester, acetone, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application This invention relates to a method for producing porous spherical particles of cellulose organic acid ester. For details, see the uniformity of particle size,
This is a method for producing spherical particles of cellulose organic acid ester with excellent sphericity and porosity, and is for obtaining cellulose spherical particles useful as chromatography carriers by saponifying the spherical particles.

(b) Conventional technology and problems Microparticles of cylindrical molecular substances are used in plastic additives, pharmaceutical excipients, anti-inflammatory agents, cosmetic additives, etc. In particular, porous microspheres of cellulose are In recent years, it has been used as a gel chromatography carrier for the purification and separation of proteins and microorganisms, and by chemical modification, it has been used as a carrier for ion exchange chromatography and affinity chromatography. Furthermore, since it has good biocompatibility, its use as a sustained release agent for drugs and as a cosmetic additive that is harmless to living organisms is being considered.

The most common method for obtaining microparticles of polymeric substances is by precipitation from solution. This method was applied to cellulose in Japanese Patent Publication No. 45254/1983 and Japanese Patent Publication No. 57/1983.
No. 159801, Japanese Patent Publication No. 1983-44812, Special Publication No. 1983
There are inventions such as No. g-21761. Cellulose is not soluble in common solvents, and its solutions are manufactured using special solvents. Even in this case, the concentration remains at a low a degree, and submerging from this solution makes it difficult to form particles with sufficient grindability for practical use, which has the drawback that it is difficult to produce particles as small as 100 μm. In addition, in general, the unit price of solvents, etc., and the recovery rate are 1!
There are also problems with D4 characteristics. On the other hand, several methods have been proposed in which cellulose fatty acid ester is first made into spherical particles and then hydrolyzed to produce cellulose particles.

Special Publication No. 55-39565 and Special Publication No. 55-4061
No. 8 describes a method for producing spherical particles by dry spinning cellulose fatty acid ester, cutting the rolled filament into chips, and heating it in a high boiling point solvent to produce spherical particles.
In addition, cellulose fatty acid ester is dissolved in a low boiling point solvent, suspended in a high boiling point poor solvent, and heated as it is to evaporate the low boiling point solvent in the suspended particles to obtain spherical particles, and the cellulose fatty acid ester particles are Cellulose spherical particles are obtained by hydrolysis. These manufacturing methods require long steps and consume a lot of energy. Furthermore, since the obtained cellulose fatty acid ester particles are relatively dense, the cellulose particles obtained therefrom are also relatively too dense, and the porosity is too small to be used as a chromatography carrier.

As a method for obtaining particles with a large porosity, JP-A-54-5
As seen in No. 5055 and JP-A-56-24429, when cellulose fatty acid ester is dissolved in a low boiling point solvent to form a solution, a high boiling point solvent or a polymer compound having a different solubility from that of cellulose fatty acid ester (e.g. water-soluble polymer compound) and disperse the mixed solution in the aqueous solution! After heating to form droplets, the low-boiling solvent is heated to evaporate the droplets to obtain cellulose fatty acid ester microspheres, which are then saponified before and after saponification to form a polymer compound or A method has been proposed in which high-boiling solvents are removed by washing to obtain cellulose particles with large porosity.

However, the above method has the following problems.

When removing a low-boiling point solvent by heating droplets or coagulated particles from droplets, due to the thermoplasticity of cellulose myh fatty acid esters, the particle size, density, pores, etc. are likely to fluctuate, making it difficult to reproduce. The process behind obtaining certain physical properties is surface bonding. In addition, the method of removing high molecular compounds by washing can return a large vacancy 15FA ratio of 77 (f+6), but the individual vacancies are large and therefore a small number can be obtained.In other words, the individual vacancies are too axially large. Particles are obtained.Such particles can be used as raw materials for fermentation fixation materials and ion-exchange cellulose carriers, but are not very acid-friendly as carriers for chromatography.

Furthermore, in order to solidify the solute from droplets obtained by dispersing a solvent solution of cellulose organic acid ester in an aqueous medium, it is known to heat the system and volatilize the solvent in the droplets ( JP-A No. 56-24429). In this method, since the solvent is removed from the surface of the droplet, a concentration gradient occurs inside the droplet, and the surface density of the particles after solidification tends to be higher than that inside the droplet. In addition, the cellulose organic acid ester swollen by the solvent at the heating temperature exhibits thermoplastic behavior, and the small pores formed when the solvent vapor escapes close again, resulting in particles with reproducible physical properties. It's difficult to pick up.

(/1 Means and action for solving the 41 points) This invention was made in view of the above situation, and the inventor of this invention made cellulose organic acid ester into spherical particles,
We conducted intensive research on a method to obtain highly porous cellulose particles by saponifying it, and then dissolved the cellulose organic acid ester in an organic solvent to form a solution, and added the organic solvent solution to a larger amount of aqueous medium to form droplets. and that spherical particles can be obtained by coagulating the cellulose organic m-ester from the droplets, and that the coagulation of the cellulose organic acid ester is achieved by adding a water-soluble polyhydric alcohol to the aqueous medium in which the droplets are suspended. The inventors have discovered that the process progresses and that cellulose particles with large porosity can be obtained by saponifying the cellulose organic acid ester spherical particles obtained by the above method, and have thus arrived at the present invention.

According to the method of this invention, the coagulated body of cellulose organic acid ester obtained by adding a polyhydric alcohol forms a gel structure, and particles with a network structure can be changed by removing the organic solvent. Porous particles can be obtained with good reproducibility without clogging of small pores even after treatment.

In this invention, an organic solvent solution of cellulose organic acid ester is added to an aqueous medium to form droplets, and a water-soluble polyhydric alcohol is added to the dispersion system of the droplets/aqueous medium to form droplets. The present invention relates to a method for producing spherical particles of cellulose organic acid ester, characterized by coagulating cellulose organic acid ester therein.

Examples of cellulose organic acid esters used in this invention include cellulose triacetate, cellulose diacetate, cellulose benzoate, cellulose carbamate, and cellulose acetate butyrate. Both exhibit solvent solubility and thermoplasticity, and when buried in alkali, they hydrolyze and regenerate cellulose.

For the purpose of this invention, cellulose triacetate is particularly suitable in terms of price, solvent solubility, ease of treatment after hydrolysis, etc.

The organic solvent that dissolves the cellulose organic acid ester is a low boiling point solvent that is not freely miscible with water. Specifically, halogenated hydrocarbons and halogenated hydrocarbons such as methylene chloride and chloroform are mainly used, and methanol,
C1- like ethanol, propatool, isopropanol, butanol, pentanol, octatool etc.
A mixed solvent containing about 5 to 80 volume percent of 10 aliphatic alcohols, esters of these alcohols such as acetate, filobionate, and benzoate, acetone, and ketones such as methyl ethyl ketone or Keishin is a cellulose organic acid ester. It is useful for this invention because of its high solubility in

The appropriate amount of organic solvent to be used is such that the concentration of cellulose organic acid ester is 8 to 15%.

The aqueous medium used in the present invention is water or a small amount in water, for example, 0.2 to 10 wt% gelatin, a water-soluble polymer such as CMCPVA, and/or 0.05 to 8 wt% surfactant. , a solution containing an antifoaming agent. These agents added to water have the effect of stabilizing the resulting droplets.

The polyhydric alcohol used in this invention is preferably one that is freely miscible with water and has a relatively low molecular weight.

Examples include ethylene glycol, glycerin, 1,8-propanediothyl, etc., but ethylene glycol is most suitable in terms of cost and effectiveness.

The size of the spherical particles of cellulose organic acid ester obtained by the method of this invention depends on the size of the droplets. That is, 1
One particle is generated from each droplet. The higher the stirring efficiency, the smaller the size of droplets generated in the aqueous medium.

When the concentration of cellulose organic acid ester in the solution is low, the viscosity of the solution is low, and even at the same stirring rotation speed, stirring efficiency is improved and small droplets can be obtained. At the same time, the solution concentration of the cellulose organic acid ester is also related to the porosity of the particles, and the smaller the solute concentration is, the larger the porosity becomes.

When a polyhydric alcohol is added to an aqueous medium in which droplets of a solution containing a halogenated hydrocarbon/lower alcohol as a solvent are dispersed and suspended, the solubility balance changes, and a portion of the methano-d-logonated hydrocarbon is diffused into the aqueous medium, and a small amount of polyhydric alcohol and water are diffused into the droplet.

As a result, the cellulose organic acid ester within the droplet gels to form particles having a network structure. As described above, it is necessary to use a considerably large amount of polyhydric alcohol to coagulate the cellulose organic acid ester, and the amount is 0.5 to 8 times the amount of water in the aqueous medium. Such coagulation does not occur even if other polar solvents that are freely miscible with water, such as acetone or tetrahydrofuran, are used instead of polyhydric alcohols.

The particles of cellulose organic acid ester produced by the addition of polyhydric alcohol are washed with water/alcohol system.
The remaining methylene chloride is vaporized by heating. Under these conditions, the particles do not have sufficient thermoplasticity so that subsequent heating to expel only small amounts of 10-genated hydrocarbons does not cause blockage of the pores already formed.

The cellulose ester spherical particles obtained by the present invention are used as soil conditioners and plastic additive blocking agents, and can be easily hydrolyzed to obtain spherical cellulose particles, which can be used as cosmetic additives and gels. Carriers for filtration chromatography, sustained release drug carriers, and carriers for ion exchange chromatography by further chemical modification.
It can be used as a carrier for Affinity chromatography.

The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples.

Examples Example 1 A solution of cellulose triacetate (acetate f60%) 50F dissolved in a mixed solvent of 50 g of methanol and 450 ml of methylene chloride was dissolved at about 100° in 500 m of 1% gelatin water containing 100 ml of methanol. Dispersion was performed at a rotation speed of rpm.

With stirring at goorpm, ethylene glycol l! was slowly dripped. After stirring for about 80 minutes after dropping, it was observed that the droplets solidified and became particles. After standing still, the particles settled and a supernatant was formed, and the supernatant was removed by decantation. water,.

0.54' of a mixed solvent of Improper Tool 1:1 was added to the container while stirring gently, and after the container was allowed to stand still, I looked at the top again. Furthermore, isopropanol (0.614r'Q") was added and the beads were observed after standing. The particles were collected by filtration and dispersed in Impropanol II, heated at about 60°C for several minutes and stirred. Residual methylene chloride in the particles was extruded.After filtration, the particles were thoroughly washed with isopropanol, dispersed in 1 liter of water, heated to about 80°C and stirred, and the particles from which methylene chloride had been completely extruded were separated. Filter.Wash thoroughly with water to obtain spherical beads of cellulose triacetate.When classified in a wet state, the diameter was 80 μm to 75 μm.
particles, 60d, 75-1504m particles 150w/,
A particle bowl of 150-250 μm was obtained.

When observed with an optical microscope, all particles were perfectly spherical.

Among the obtained cellulose triacetate particles, the particle size was 75
~150μmf) The density of the particles was determined as follows: A sample of the swollen paper was placed in a glass column with an inner diameter of 8N about 10cm.
Fill to a height of . Based on the inner diameter of the column 18N and the height of the packed cellulose particles, the cellulose particles vO is 1-
Put out 1.

Vo=(0,4)2πh h, height of packed L-cellulose particles) Then, molecular weight 2. o o o, o o o Elute the probe strain (using a 2.6% aqueous solution) and determine the eluted hBvt waste. The packed cellulose particles are taken out from the column, filtered, thoroughly washed, and dried to determine the amount of H (W(f)). The density was calculated from these data using the following formula.

The density of the cellulose triacetate particles (particle size 76 to 150 μm) obtained in Example 1 was 40%.

Add this acetate beads to 75% of 100f of beads.
Et/-ol 9001111 and 1.0% Na011600
ml was added, and the mixture was stirred at room temperature for 1 hour for hydrolysis.

Next, the beads were neutralized using dilute acetic acid and thoroughly washed with water to obtain cellulose beads. The density of the cellulose beads was measured by the method described above and was found to be 80%.

When gel filtration chromatography was performed using cellulose beads as a carrier and blue dextran with a molecular weight of t'i million and various PEGs with known molecular weights, the exclusion limit molecular weight was about 20,000 (polyethylene glycol).

Example 2 Cellulose diacetate 50f and methanol 50zl
A solution dissolved in a mixed solvent of 45 C) xl of methylene chloride and 45 C) xl of methylene chloride was dispersed in 500 g of 1% gelatin water containing 100* of ethylene glycol at a rotational speed of about 70 Orpm for 1 hour.

Stirring at 80 Orpm, ethylene glycol 11
was slowly added dropwise at room temperature. After the dropwise addition, the solution was stirred for about 80 minutes to make the rt'lt droplets into particles, and after being allowed to stand still, the upper layer was removed by decantation.

0.51 of a 1:1 mixture of water and ituburobanol was slowly added and washed while stirring. After standing still, remove the beads,
Additionally, slowly add o, a bit of isopropanol,
It was washed and then washed.

After thorough washing with water, the spherical particles of cell[]-sudaacetate were classified using a wet avj-like rib.
~75μm 20tttl, 75~150pm 150nl, 150~250pm 1001
1Il was obtained.

The density of acetate particles with a particle size of 75 to 150 μm was determined using the same method as in Example 1, and the density of 35% was 20.
%, and the exclusion limit molecule fl is 20000 for PEG.
Met.

Example 8 A solution of 50f of cellulose triacetate (60% acetylation, manufactured by Daicel Chemical Industries, Ltd.) dissolved in 50d of methanol, 850ml of methylene chloride, and 100g of n-octatool was mixed with 500ml of 1% gelatin water and 500g of ethylene glycol. Dispersed in solvent. One liter of ethylene glycol was slowly added dropwise to this suspension to solidify the droplets and form particles. After standing still and removing the supernatant, the same procedure as in Example 1 was performed to obtain cellulose triacetate microparticles having a particle size of 80 μm to 250 μm.

The density of acetate particles with a particle size of 75 to 100 μm is 25%
Met.

Cellulose beads obtained from the acetate particles in the same manner as in Example 1 had a density of 20% and an exclusion limit molecular weight of 40,000 dextran molecules.

(E) Effects of the Invention According to the present invention, spherical particles can be obtained with good reproducibility without heating the system to remove a low-boiling point solvent when solidifying droplets.On the other hand, in the conventional technology, heating Controlling the evaporation temperature when removing low-boiling point solvents has a great impact on the quality of the garments, and process control is often difficult.

The present invention does not require such a process and can obtain cellulose ester particles in a very simple process of nN. Furthermore, by saponifying this cellulose ester by a conventional method, porous cellulose particles can be obtained, which are suitable for cosmetics, gel filtration chromatography carriers, sustained release '8: drug carriers, and the like.

Furthermore, cellulose particles can be chemically modified and applied to ion exchange chromatography carriers, Affinity chromatography carriers, etc.

Claims (2)

[Claims] (1) A solution of cellulose organic acid ester in an organic solvent is added to an aqueous medium to form droplets, and a water-soluble polyhydric alcohol is added to the dispersion of the droplets/aqueous medium. A method for producing spherical particles of cellulose organic acid ester, which comprises coagulating cellulose organic acid ester. (2) The method for producing spherical particles according to claim 1, wherein the water-soluble polyhydric alcohol is ethylene glycol, glycerin, or 1,3 propanediol.