JPH06142505A - Production of monodisperse fine spherical particle - Google Patents

Abstract

PURPOSE:To efficiently produce fine spherical particles large in monodispersibility. CONSTITUTION:O/W emulsion is produced by using the organic solvent solution (oil phase, dispersed phase) of hydrophobia polyamino acid or hydrophobic cellulose and an aqueous medium (aqueous phase, continuous phase) as material and applying the same to membrane emulsification by means of a microporous glass tube. The organic solvent is vaporized and removed from the emulsion to obtain a dispersing element in the aqueous medium of fine spherical particles of polyamino acid or cellulose. Monodisperse fine spherical particles are produced by separating the fine spherical particles from the dispersing element in accordance with desire. An additive for making the fine spherical particles porous may be added to the organic solvent solution.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention has various uses such as a packing material for column chromatography as it is, and further, by chemically modifying the surface thereof, a heat-generating substance adsorbent (eg
Japanese Patent Application Laid-Open No. 4-16943), etc., and to a method for producing microsphere particles of polyamino acid or cellulose that can be used.

[0002]

2. Description of the Related Art Polyamino acid or cellulose microspheres having the above-mentioned applications have the advantage that the closer they are to a monodisperse system, the smaller the packing pressure loss when used as a packing material for column chromatography. .

Looking at this in the production stage of such fine spherical particles, the narrower the particle size distribution of the obtained fine spherical particles, the less the loss in classifying monodisperse particles becomes, which is extremely preferable. In other words, a production method that can easily control the particle size of the obtained microsphere particles is preferable.

As for such polyamino acids as such a production method, for example, Hirayama et al. Have already described, "By adding a solution in which a hydrophobic polyamino acid is dissolved in an organic solvent to an aqueous medium and stirring the mixture, the organic solvent is removed. While evaporating
A method for producing spherical particles of polyamino acid, which comprises a step of obtaining a dispersion in which the spherical particles of the polyamino acid are dispersed in the aqueous medium, and a step of taking out spherical particles of the polyamino acid from the dispersion " Has been proposed (see JP-A-62-1728, Claims 4 and paragraphs from page 3, upper right column to lower left column).

However, there is a demand for the development of a production method having further improved monodispersity.

[0006]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for producing microsphere particles of polyamino acid or cellulose which can realize further improved monodispersity.

[0007]

The present inventors have completed the present invention as a result of earnest research to solve the above problems.

That is, the present invention is a solution of a hydrophobic polyamino acid or hydrophobic cellulose in an organic solvent (oil phase, dispersed phase).
And an aqueous medium (aqueous phase, continuous phase) as a material, which is subjected to membrane emulsification with a microporous glass tube to prepare an O / W emulsion, and the organic solvent is removed from this emulsion by evaporation to remove the polyamino acid or the polyamino acid. It relates to a process for the production of monodisperse microspheres, characterized in that a dispersion of cellulose microspheres in the aqueous medium is obtained and, if desired, the microspheres are separated from the dispersion.

The present invention will be described in detail below.

First of all, it should be pointed out that the method of the present invention can be applied to the method of Hirayama et al. Mentioned above except that the O / W emulsion is produced by the membrane emulsification method using a microporous glass tube.

That is, as in the method of Maeda Hirayama et al., The hydrophobic polyamino acids of the present invention include not only inherently hydrophobic polyamino acids (homopolymers and copolymers) but also hydrophilic polyamino acids. Partially or completely hydrophobized, and copolymers of hydrophilic amino acids and hydrophobic amino acids are also included. The organic solvent may be the same as in the method of Hirayama et al., Such as 1,2-dichloroethane (EDC). Also, as the organic solvent solution of the hydrophobic polyamino acid, the polymerization solution at the time of producing the polyamino acid can be used as it is, as in the method of Hirayama et al. Examples of the aqueous solvent include water and water in which a suitable viscosity modifier (dispersion stabilizer) is dissolved. As mentioned above, the above-mentioned JP-A-62-1723, page 2, lower left column, third to bottom
See line 7, bottom left column, line 7.

Examples of the hydrophobic cellulose of the present invention include hydrophobic derivatives of cellulose such as cellulose triacetate. Examples of the organic solvent include organic solvents used as solvents for cellulose derivatives such as methylene chloride, chloroform, methyl acetate and acetone.

The difference between the method of the present invention and the method of Maedai Hirayama et al. Lies in the emulsification method, but the details of the emulsification method of the method of the present invention are as follows.

Microporous tubes include sintered metal and ceramics, and microporous glass tubes include Siraus porous glass (SPG) and CaO, which have been recently developed at Miyazaki Industrial Research Institute.
_{-Al 2 O 3 -B 2 O 3} -SiO 2 based porous glass) can be mentioned tube. This tube has a pore size in the range of about 0.008 to 15 μm, and within this range, the pore size is uniform and the pore distribution is nearly monodisperse. Therefore, by pushing the oil phase into the water phase through the pores, an O / W emulsion (oi
l / water emulsion) can be created. This is attracting attention as a new emulsification technology, and many reports have already been made. In the method of the present invention, the method itself for emulsifying a membrane using a microporous glass tube is not particularly limited and can be based on the method already reported. Incidentally, the SPG tube is available in the form of a so-called module and, of course, can be used in that form.

In addition, for example, Japanese Examined Patent Publication No. 62-25618
Disclosed in _{JP-CaO-B 2 O 3 -SiO 2} -Al
₂ O ₃ -based porous glass, CaO-B ₂ O disclosed in JP-A-61-40841 (US Pat. No. 4,657,875)
_{3 -SiO 2 -Al 2 O 3 -Na} 2 O -based porous glass and _{CaO-B 2 O 3 -SiO 2} -Al 2 O 3 -Na 2
A tube made of O-MgO-based porous glass or the like can be used. See JP-A-2-95433, page 3, upper right column.

A solution of a hydrophobic polyamino acid or hydrophobic cellulose in an organic solvent is incompatible with the polyamino acid or the cellulose, compatible with the organic solvent, insoluble in the aqueous medium, and organic. It is also the same as Hirayama et al. That when a solvent and an additive having a higher boiling point than the aqueous medium (additive for porosity) are added and the film is emulsified, the resulting microspheres become porous. The additive for porosity can be the same as Hirayama et al. See JP-A-62-1723, page 3, lower left column, line 8 to lower right column, line 14.

The subsequent treatment of the O / W emulsion prepared by the film emulsification as described above can be carried out again according to the method of Maede Hirayama et al. That is, for example, the organic solvent can be evaporated and removed from the emulsion by stirring the emulsion with or without heating. The dispersion obtained by removing the organic solvent, in which the spherical particles of the hydrophobic polyamino acid or the hydrophobic cellulose are dispersed in the aqueous medium, can be put into circulation in this state, but an appropriate separation operation (for example, filtration , Centrifugation) to separate the spherical particles from the dispersion.
See JP-A-62-1723, page 2, upper right column, line 9 to lower left column, line 17 and Examples.

When a porosity additive is used,
The removal of the porosifying additive from the microsphere particles can also be carried out according to the method of Hirayama et al. That is, the microsphere particles of the hydrophobic polyamino acid or the hydrophobic cellulose separated from the dispersion by the appropriate separation operation as described above are mixed with the polyamino acid or the cellulose and an additive for porosification. Is washed with a compatible organic solvent,
It can be removed by applying a Soxhlet extraction method using such an organic solvent. Japanese Patent Laid-Open No. 62
-1728, see Examples 4 to 8.

It goes without saying that the method of the present invention can be carried out batchwise or continuously.

[0020]

EXAMPLES The present invention will be further described below with reference to examples.

Example 1 (polyamino acid, batch type) FIG. 1 is a schematic view of the apparatus for producing microsphere particles used in this example.

The microporous glass tube has an average pore diameter of 2.4 μm, 4.2 μm, 5.7 μm, 7.5 μm and
A total of 5 types of SPG tubes (modules) having a size of 11 μm were used.

360 ml of 1,2-dichloroethane (EDC, organic solvent) and di (2-ethylhexyl) phthalate (DE
HP, additive for porosity) 10.1 ml was put in a beaker and stirred for about 15 minutes with a stirrer, and commercial poly (γ-methyl L-glutamate) (PMLG, degree of polymerization 780, hydrophobic polyamino acid) was added thereto. 40 ml of a 10 wt% EDC solution was added and the mixture was further stirred for about 2 hours. In the oil phase, this PMLG 10 wt% EDC
The solution was used.

24 g of polyvinyl alcohol (PVA) was dissolved in 2400 ml of boiling water, and the aqueous phase was prepared by returning the 1 wt% PVA aqueous solution to room temperature.

After filling the oil phase liquid inside the SPG tube and the water phase liquid outside, the oil phase liquid permeates the water phase liquid by applying pressure to the oil phase liquid to form a monodispersed O / W emulsion. To be able to form.

2400 ml of a 1 wt% PVA aqueous solution was placed in a stirring vessel, a stirring blade was installed, and then the degassed SPG tube was fixed so as not to contact the inner wall of the vessel and the blade. During this time, the SPG tube was touched as little as possible, and the tube was quickly fixed without exposing it to the air for a long time.

Next, while slowly rotating (150 rpm) the stirring blade, PMLG 1 wt% EDC solution was gear pumped (voltage setting device was set to 5.0 V, discharge amount was about 4.5 ml).
Air was sent to the inside of the SPG tube so that it would not collect, and the mixture was squeezed out from the inside of the tube toward the PVA aqueous solution outside to obtain an O / W emulsion. This emulsification operation was continued for about 4 hours, and during this period, heating was performed at room temperature without heating. A polyethylene (PE) tube was used as the connecting pipe.

The emulsified liquid was heated (50 ° C.) while slowly stirring (150 rpm) as in the emulsification, and spherical particles were prepared by removing EDC by evaporation for about 24 hours.

After the formation of particles, the particles are cloth (Toray Silk # 87
00, the size of the mesh is about 10 μm or less), and collect it on a Buchner funnel lined with water.
A was removed. However, for small particles of 10 μm or less, PVA was removed by using a centrifuge (3000 rpm, 30 minutes).

The obtained 5 kinds of particles were respectively stored in distilled water.

Example 2 (polyamino acid, continuous type) FIG. 2 shows a schematic view of the continuous microsphere particle-forming apparatus used in this example.

In this embodiment, continuous particle formation was carried out by combining the membrane emulsification method using an SPG tube and a circulating particle formation device. The emulsion produced by the SPG tube circulates in the stirred tank, during which the solvent is evaporated off and beads are formed. Since the beaded PMLG particles cannot stay in the stirring tank and flow out, the particles can be continuously made into particles.

In the same manner as in the previous Example 1, PMLG 1 wt% EDC solution of oil phase liquid and PVA 1 wt% of aqueous phase liquid.
An aqueous solution was prepared. SPG tubes (modules) have average pore sizes of 2.4 μm, 4.2 μm, 5.7 μm,
Those of 7.5 μm and 11 μm (5 types in total) were used.

The membrane emulsification section was fixed at a position several cm higher than the emulsion inlet of the condenser so that the emulsion could flow smoothly. The inclination of the condenser and the circulation stirring tank was set to about 20 °, and the stirring tank was rotated at about 150 rpm.

Put the oil phase liquid and the water phase liquid in their respective containers,
Set the voltage of pump B to 10.0V (about 9.0ml / min),
The aqueous phase liquid was allowed to flow into the circulation stirring tank for about 1 hour. At this time about 55
The shower pump for storing warm water, which had been set to ℃, was operated to maintain the temperature in the circulation stirring tank at 50 ℃, and the aspirator and cooler of the condenser were started to operate.

Only after the above operation is completed, the SPG tube is attached to the membrane emulsification section, and the pump A is used as in the previous embodiment.
Particle formation was started with the voltage of 5.0 V (about 4.5 ml / min).

Particles started to be obtained after about 5 minutes, and further 4
Pump A was stopped after a period of time. After that, the SPG tube was removed, the membrane surface was rinsed with water, and then ultrasonically washed with chloroform. However, even after removing the membrane, pump B
Was moved for about 1 hour, and the particles in the circulation stirring tank were discharged.

PVA was removed from the obtained 5 kinds of particles in the same manner as in the previous example, and the particles were stored in distilled water.

Comparative Example 1 (Conventional Method) In this comparative example, PMLG spherical particles were formed by a conventional suspension evaporation method using a stirring blade.

FIG. 3 shows a schematic view of the apparatus.

PMLG 1 wt% EDC containing di (2-hexylhexyl) phthalate as in Example 1.
A solution (200 ml) and a 1 wt% PVA aqueous solution (1200 ml) were prepared.

These were suspended in a stirring vessel and EDC was removed by evaporation at 50 ° C. to prepare PMLG spherical particles. However, the stirring speed is 800 rpm for 15 minutes after starting suspension,
After that, 400 rpm was maintained for about 24 hours.

The particles thus obtained were stored in distilled water after removing PVA.

Evaluation / Inspection Example 1 (optical micrograph, particle size distribution) Regarding the fine spherical particles obtained in the above Examples 1 (batch type) and 2 (continuous type) and Comparative Example 1 (batch type, conventional method), Optical micrograph observation was performed and the particle size distribution was also inspected.

(A) Optical Microscope Photographs of a total of 11 kinds of microspherical particles obtained in Examples and Comparative Examples,
Optical microscope "OLYMPUS Neopark microscope BHM31 2N
From the photographs taken using "E", all the particles (10 types) obtained in Examples 1 and 2 have uniform particle diameters, while the particles obtained in Comparative Example It was observed that various particle sizes were mixed.
Also, the shape of the particles is not so different between the example and the comparative example, and it is possible to mass-produce PMLG microsphere particles by continuously forming particles from Example 2. Was confirmed.

(B) Particle size distribution For particles having a small particle size, the particle size distribution was measured with a light scattering photometer. Place the particles in the measuring cell with a pipette and
The sample was diluted about twice with filtered distilled water and then installed in the measuring section.
Computer analysis was performed by applying laser light to the sample.
As the optical system, "Dynamic light scattering photometer DLS-700" manufactured by Union Giken Co., Ltd. was used. Also, for large particles, measure an optical micrograph with a caliper,
A distribution map was created.

In FIGS. 4A and 4B, the average pore diameter is
The particle size distributions of the PMLG spherical particles prepared in Example 1 and the particles prepared in Comparative Example 1 are shown using an SPG tube of 11 μm, respectively. 5 (a) and 5 (b), the particle size distribution of the PMLG spherical particles prepared in Example 1 and the particles prepared in Comparative Example 1 was measured using an SPG tube having an average pore size of 2.4 μm. Are shown respectively.

As can be seen from FIGS. 4 and 5, the PMLG spherical particles prepared by the membrane emulsification method using the SPG tube have a narrow particle size distribution and high uniformity as compared with the conventional method. It was confirmed that the dispersibility was excellent. In other words, this indicates that the classification operation of the prepared particles is almost unnecessary (that is, the yield is high).

Example 3 This example is for investigating the relationship between the average pore size of SPG tubes and the average particle size of PMLG spherical particles.

Average pore size is 2.4 μm, 4.2 μm, 5.7 μm
m, 7.5 μm and 11 μm SPG tubes,
PMLG spherical particles were prepared by the method of Example 1.

The relationship between the average particle size of the particles and the average pore size of the SPG tube used is shown in FIG.

From this figure, it was found that the average particle size of the PMLG spherical particles prepared by the method of the present invention corresponds to the pore size of the SPG tube used. That is, it was confirmed that the particle size of PMLG can be easily controlled according to the present invention.

Example 4 This example is for investigating the concentration effect of PVA as a viscosity modifier (dispersion stabilizer) in forming PMLG into spherical particles.

FIG. 7 shows the results of studying the concentration effect of the PVA aqueous solution as the dispersion stabilizer in the formation of spherical particles of PMLG (using the same apparatus as in Example 1 and using an SPG tube having an average pore size of 2.4 μm). 1 wt% PML for oil phase liquid
A G / EDC solution was used.

As can be seen from this figure, in order to monodisperse the O / W emulsion, the concentration of PVA as the dispersion stabilizer should be 0.5 wt% or more. That is, when the concentration of PVA, which is a dispersion stabilizer, is low, the solubility of the oil phase in the aqueous phase is large, and the O / W emulsion tends to be unstable and large in its formation. However, when the concentration of PVA exceeds a certain value, the O / W emulsion stabilizes,
It is considered that the PMLG spherical particles have a constant particle size.

Example 5 (Cellulose, Batch Type) Spherical particles of cellulose triacetate (TAC) were formed by using the apparatus shown in FIG. An SPG tube having an average pore diameter of 4.2 μm was used, and degassing was performed in the same manner as in Example 1.

In the aqueous phase, 2400 ml of a 1 wt% PVA aqueous solution was prepared in the same manner as in the same example.

The oil phase contains 5.06 g of TAC and methylene chloride.
Add 400 ml to a beaker and stir well for about 2 hours, then add 5 more
TAC1 filtered through a ~ 9μm glass filter
Used as a wt% methylene chloride solution.

The membrane emulsification operation was carried out for about 4 hours in the same manner as in the same example, but a Teflon tube was used as the connecting tube.

The particles were formed by removing the solvent by evaporation at 30 ° C. for about 24 hours to prepare TAC spherical particles.

The obtained particles were stored in distilled water.

The particle size distribution and optical micrograph of TAC spherical particles thus prepared using the SPG tube were compared and examined with those of commercially available cellulose, and it was prepared using the SPG tube. TAC
It was confirmed that the spherical particles had a narrower particle size distribution than the commercially available cellulose particles.

[0063]

EFFECTS OF THE INVENTION According to the present invention, as described above, the characteristics in the formation of spherical fine particles of hydrophobic polyamino acid and hydrophobic cellulose through membrane emulsification using a microporous glass tube are 1) It is possible to obtain particles having a narrow particle size distribution and high monodispersity by using such a tube, 2) the particle size can be easily controlled by the pore size of such a tube, and 3) continuous particles. Is possible.

[Brief description of drawings]

FIG. 1 shows an outline of an apparatus for producing microsphere particles used in Example 1.

FIG. 2 shows an outline of a continuous microsphere particle forming device used in Example 2.

FIG. 3 shows an outline of an apparatus for producing microsphere particles used in Comparative Example 1.

FIG. 4 shows a comparison of the particle size distribution between the microsphere particles obtained by the method of the present invention and that obtained by the conventional method.

FIG. 5 shows another comparison of particle size distribution between microsphere particles obtained by the method of the present invention and those obtained by a conventional method.

FIG. 6 shows the relationship between the pore size of a microporous glass tube and the average particle size of microsphere particles obtained by using the tube.

FIG. 7 shows the effect of viscosity modifier concentration on microsphere particle size.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hirotaka Ihara 3-21-9 Takahira, Kumamoto-shi, Kumamoto Prefecture (72) Inventor Makoto Iwatsuki 1-15-1 Kyobashi, Chuo-ku, Tokyo Ajinomoto Co., Inc.

Claims (2)

[Claims] 1. A solution of a hydrophobic polyamino acid or a hydrophobic cellulose in an organic solvent (oil phase, dispersed phase) and an aqueous medium (aqueous phase, continuous phase) are used as materials and subjected to membrane emulsification with a microporous glass tube. To form an O / W emulsion, from which the organic solvent is removed by evaporation to obtain a dispersion of the polyamino acid or the cellulose microspheres in the aqueous medium, and optionally the microspheres. A method for producing monodisperse microsphere particles, characterized in that 2. The organic solvent solution is incompatible with the polyamino acid or the cellulose, compatible with the organic solvent, insoluble in the aqueous medium, and more than the organic solvent and the aqueous medium. The method for producing monodisperse microsphere particles according to claim 1, wherein an additive having a high boiling point (additive for porosity) is also added.