KR20140095470A - Apparatus for preparing fine particles - Google Patents

Abstract

(1) for supplying a fluid, a mixing means (2) for mixing a substance in the fluid, and a nozzle (11) for adiabatically expanding the fluid mixed with the substance. The apparatus for producing fine particles according to claim 1, (3). The inner surface of the nozzle 11 is formed of a dielectric material.

Description

[0001] APPARATUS FOR PREPARING FINE PARTICLES [0002]

The present invention relates to a process for producing fine particles comprising feeding means for feeding a fluid, mixing means for mixing the material in the fluid, and injection means for injecting the fluid mixed with the material through the nozzle for adiabatic expansion thereof To a fine particle production apparatus.

Many substances such as drugs, natural substances, etc. are hardly water-soluble. In particular, about 40% of drugs are poorly water-soluble. It is required to improve the solubility of these drugs by increasing their specific surface area by atomizing them.

As a conventional apparatus for producing fine particles of a substance, various apparatuses are known which perform techniques such as a supercritical fluid method (RESS method), a micelle forming method and a micronization (pulverization) method (see, for example, Patent Document 1 and Non-Patent Document 1).

Patent Document 1: International Patent Application Publication No. 2006/046670

Non-Patent Document 1: Satoshi, NISHIKINO "Drug Delivery System" 24-5, 2009, p. 492-498

However, by means of an apparatus based on any one of the above-mentioned techniques, fine particles of a size smaller than 100 nm in diameter (hereinafter referred to as "nanoparticles" Is not yet possible due to the following reasons. Even if the nanoparticles are once formed, the formed nanoparticles can not maintain their dispersion state, and these nanoparticles re-agglomerate. Incidentally, in order to prevent such re-agglomeration, for example, the surface of the nanoparticles may be coated with an additive such as a surfactant. However, if these additives have adverse effects on the human body, these nanoparticles can not be used in the manufacture of medicines or foods.

An object of the present invention is to provide a fine particle manufacturing apparatus capable of manufacturing nanoparticles of a size smaller than 100 nm in diameter in a stable and reliable manner.

According to a first aspect of a particulate production apparatus for producing particulates related to the present invention, the particulate production apparatus comprises a supply means for supplying a fluid, a mixing means for mixing the substance in the fluid, And injecting means for injecting the air through the nozzle for its adiabatic expansion; The inner surface of the nozzle is formed of a dielectric material.

(Action and effect)

With the features described above, as the material passes through the passageway within the nozzle, the material becomes electrostatic due to friction with the inner surface of the nozzle, and the nanoparticles also become static. Because these nanoparticles have the same sign (same polarity) of static charge, the nanoparticles repel each other by electrostatic force (repulsion) and prevent their re-agglomeration. Therefore, re-agglomeration can be prevented without using any additive such as a surfactant. As a result, nanoparticles having an average particle size smaller than 100 nm in diameter can be manufactured in a stable and reliable manner.

According to the second aspect of the present invention, the nozzle has a length of 20 mm to 600 mm.

(Action and effect)

With the above-described feature that the nozzle has a length of 20 mm to 600 mm, friction between the material and the inner surface of the nozzle is promoted so that the material becomes electrostatically charged in a more reliable manner.

According to a third aspect of the present invention, the fluid comprises liquefied carbon dioxide.

Liquefied carbon dioxide is denser than carbon dioxide under gaseous conditions, including supercritical conditions, so that larger amounts of material can be dispersed, mixed, or dissolved therein. Thus, efficient production of nanoparticles is possible. Moreover, liquefied carbon dioxide is harmless and does not adversely affect the human body even though it is absorbed by the human body. Thus, it is advantageous in manufacturing medicines or foods. In addition, since liquefied carbon dioxide can be maintained at a low temperature, for example, at a temperature lower than room temperature, it can also be used when using nanoparticles in the manufacture of medicines or foods that are susceptible to high temperatures.

According to the fourth aspect of the present invention, the fine particle manufacturing apparatus further includes a heating means for warming the nozzle.

(Action and effect)

When the fluid is injected through the nozzle for its adiabatic expansion, a drop in the temperature of the nozzle occurs, which also causes dew condensation in the nozzle. When this condensation is frozen, the passage in the nozzle can be closed. However, according to the above-described feature of the present invention, it is possible to prevent the temperature drop of the nozzle as the nozzle is warmed by the heating means, thereby suppressing the occurrence of such condensation condensation. As a result, clogging of the nozzle passage due to condensation condensation can be effectively prevented.

Fig. 1 is a view conceptually showing an apparatus for producing fine particles according to the present invention.
2 is a view conceptually showing a fine particle production apparatus according to another embodiment of the present invention.
FIG. 3 shows scanning electron microscopy (SEM) of nanoparticles of sesamin prepared using the apparatus of the present invention.
Figure 4 shows scanning electron microscopy (SEM) of raw materials of sesamin prior to formation of nanoparticles.
Figure 5 shows an electron micrograph (SEM) of nanoparticles of naproxen prepared using the apparatus of the present invention.
6 is a diagram showing an analysis pattern of powder X-ray analysis (PXRD) of nanoparticles and raw materials of sesamin.
Fig. 7 is a diagram showing dissolution patterns of nanoparticles and raw materials of sesamin. Fig.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, an embodiment of a particulate production apparatus according to the present invention will be described with reference to the accompanying drawings.

(Embodiments)

As shown in Fig. 1, the apparatus for producing fine particles according to the present invention comprises a supply means for supplying a fluid, a mixing means for mixing a substance in the fluid, a fluid mixing means for injecting the fluid mixed with the substance through a nozzle And collecting means for collecting the produced fine particles.

(Supply means)

The feeding means 1 includes a fluid storage vessel 5 for storing a predetermined amount of fluid therein, a feed pump 6 for feeding the fluid to the mixing means 2, and a primary valve 7). The fluid storage vessel 5 and the mixing means 2, which will be described later, are connected to each other via a pipe 8. In the middle of the extension of the pipe 8, a feed pump 6 and a primary valve 7 are provided. When the primary valve 7 is opened, the fluid in the fluid storage vessel 5 is fed by the feed pump 6 inside the pipe 8 and supplied to the pressure vessel (not shown) of the mixing means 2.

The fluid usable in the present invention is not particularly limited as long as the fluid can disperse, mix or dissolve the substance. Also, preferably, the fluid has a high density and little effect on the human body to improve dispersion, mixing, or dissolution of the material. Some non-limiting examples of such fluids include, for example, supercritical fluids such as supercritical carbon dioxide, liquefied carbon dioxide, and the like; Of these, liquefied carbon dioxide is particularly preferable.

(Mixing means)

The mixing means 2 comprises a pressure vessel (not shown) for dispersing, mixing or dissolving the substance in the fluid at a predetermined pressure and a filter (not shown) for filtering the final fluid containing the dispersed, Non-urban). The material may be dispersed, mixed, or dissolved in the fluid in a pressure-resistant vessel. Here, even if a part thereof remains dispersed, mixed or not dissolved therein, such a residual material is removed by the filter so that the passage of the pipe 12 and the nozzle 11 disposed on the downstream side, which will be described later, , Or is not likely to be obstructed by undissolved material.

(Injection means)

The injection means 3 includes a secondary valve 10 for controlling the flow rate and a nozzle 11 for injecting the filtered fluid. The mixing means 2 and the nozzles 11 are connected to each other via a pipe 12 and the pipe 12 includes a secondary valve 10. When the secondary valve 10 is opened, a predetermined amount of fluid filtered by a filter (not shown) of the mixing means 2 is transferred inside the pipe 12 and supplied to the nozzle 11. [

In the inside of the nozzle 11, a not-shown passage through which the fluid flows is formed. The material forming the nozzle 11 itself is not particularly limited, but the essential requirement is that at least the inner surface (passage) of the nozzle 11 is formed of a dielectric material. Some non-limiting examples of such a dielectric material usable on the inner surface of the nozzle 1 include glass, synthetic resin, and the like. Incidentally, as the synthetic resin, polyether ether ketone (PEEK) having high mechanical strength and excellent processability is particularly preferable.

Furthermore, the inner diameter of the inner surface of the nozzle 11 may be in the range of 20 탆 to 100 탆, preferably 25 탆 to 65 탆, and more preferably 40 탆 to 60 탆. The length of the nozzle 11 may be in the range of 20 mm to 600 mm, preferably 30 mm to 400 mm, more preferably 50 mm to 200 mm.

(Recovery means)

The recovery means (4) includes a recovery chamber (13) surrounding the front periphery of the nozzle (11); In this recovery chamber 13, for example, a glass bottle 14 for containing manufactured nanoparticles, a substrate formed of a mica for attaching nanoparticles as shown in FIG. 2, And a substrate 15 for a substrate can be disposed. Furthermore, the recovery chamber 13 can be configured to be hermetically closed, so that a predetermined amount of an inert gas such as nitrogen can be filled therein, if necessary.

(Heating means)

Spraying fluid from the nozzle 11 for adiabatic expansion causes a temperature drop of the nozzle 11 which also causes condensation to form and this condensation may freeze and eventually block the passage. To prevent this, heating (or heating) means (not shown) such as a heater for heating or heating the tip of the nozzle 11 may be provided. By providing such heating means, the particulate production apparatus can be used even at a position where a large amount of water vapor exists in the atmosphere. Further, if the spraying is continued for a long time, the temperature of the nozzle 11 is excessively lowered, and the resultant dry ice tends to adhere to the periphery of the nozzle 11. [ If left untreated without any treatment, it may cause occlusion of the passage. Thus, by heating the nozzle 11 by the heating means, it is possible to prevent such a temperature drop of the nozzle 11, thereby preventing the adhesion of the dry ice and ultimately preventing the occlusion of the passage of the nozzle 11. [

On the other hand, the heating means may be configured to heat / heat the entire injection means 3 or the mixing means 2 as well as the nozzles 11.

(Manufacturing method of nanoparticles)

The production of nanoparticles by using the fine particle production apparatus constructed as described above is carried out as follows.

First, a predetermined amount of material is charged into a pressure-resistant container (not shown) of the mixing means 2; Thereafter, the primary valve 7 is opened to supply the fluid until a predetermined pressure (for example, 10 MPa) is reached, thereby dispersing, mixing, or dissolving the substance therein.

Thereafter, the secondary valve 10 is opened, and the fluid containing the substance dispersed, mixed, or dissolved therein is injected from the nozzle 11 into the recovery chamber 13. Here, the fluid ejected from the nozzle 11 experiences a sudden and rapid volume expansion, and a sudden temperature drop due to the joule-Thomson effect occurs. This causes a sharp drop in the dissolution rate of the material to the fluid, so that a certain amount of material precipitates inside. Since this precipitation process takes place in a very short time, nanoparticles with narrow particle size distribution range can be obtained.

The nanoparticles thus obtained are recovered in a glass bottle 14 or the like provided in advance in the recovery chamber 13, for example.

In the present invention, when the material passes through the passage in the nozzle 11, electrostatic charge is generated inside the nozzle due to the friction generated between the inner surface of the nozzle and the nanoparticles. Since these nanoparticles have the same sign (same polarity) of static charge, the nanoparticles repel each other due to the electrostatic force (repulsive force), effectively preventing their re-aggregation. Thus, according to the present invention, it is possible to effectively prevent re-agglomeration of nanoparticles without using additives such as surfactants. As a result, nanoparticles having an average particle size smaller than 100 nm (100 nm or less) can be produced in a stable manner.

(Example)

The nanoparticles were prepared from two kinds of compounds, sesamin and naproxen.

6.4 mg of sesamin were measured and then charged into a sample folder (pressure vessel sealed with a filter having a pore diameter of 10 [mu] m) having an internal volume of 1 ml: and as a fluid, liquefied carbon dioxide was introduced at room temperature under a pressure of 10 MPa , And the sesamin was dissolved therein.

Thereafter, the secondary valve was opened to form a PEEK shielded glass nozzle having an inner diameter of 50 mu m and a passage length of 100 mm (i.e., an inner portion forming the passage was formed of PEEK, and an outer peripheral portion of the inner portion thereof was made of glass Was sprayed into the recovery chamber for adiabatic expansion of the liquefied carbon dioxide in which the sesamin was dissolved to prepare fine particles. Similarly, 6.0 mg of naproxen was measured and these microparticles were prepared by the same procedure as above.

Then, the thus-prepared fine particles of sesamin and naproxen were adhered to a substrate formed of mica, and then coated with platinum (Pt) by sputtering. Incidentally, this coating by this sputtering method may be carried out when necessary or when necessary.

For each of these particulates of platinum coated sesamin and naproxen, their particle diameters were investigated using a scanning electron microscope (SEM). Furthermore, for the fine particles of sesamin, their primary particle size and crystal state were studied by powder X-ray diffraction (PXRD).

As shown in Figs. 3 (a) and 3 (b), nanoparticles having an average particle diameter of 50 nm or less were prepared for sesamin. Furthermore, as shown in Figs. 5 (a) and 5 (b), nanoparticles having an average particle size of about 50 nm were also prepared for naproxen. It was found that none of these nanoparticles were aggregated, and thus nanoparticles in a dispersed state were produced.

Next, powder X-ray analysis (PXRD) was performed to investigate the crystal state of the prepared sesamin nanoparticles. Incidentally, as a comparative example, a powder X-ray analysis (PXRD) was also performed on the sesamin raw material.

As shown in Fig. 6, in the powder X-ray analysis of the sesamin raw material (0.4 mg), a sharp peak was clearly observed at around 15 degrees. On the other hand, powder X-ray analysis of the sesamin nanoparticles (0.4 mg) showed no such clear peak. This suggests that most of the sesamin nanoparticles are in amorphous (amorphous) form, different from the sesamin source.

Incidentally, using the Scherrer equation from the obtained peak of PXRD, the calculation of the primary particle size of the sesamin raw material was given as an output value of 190 nm to 370 nm.

The dissolution test was then performed on the sesamin nanoparticles and their raw materials.

0.5 mg of each of the sesamin nanoparticles and the raw materials were charged in a glass bottle, and 5 ml of water was added to each of them, and the light absorbance thereof was measured at 285 nm.

As shown in Figure 7, in the case of the sesamin nanoparticles, all the particles quickly dissolved after the water was injected. On the other hand, in the case of sesamin raw materials, all the materials required at least several hours to dissolve. That is, it has been found that the sesamin in the form of nanoparticles can be dissolved in water at a much higher rate than its raw material.

Thus, with the present invention, regardless of the crystal state of the particles, the dissolution rate of the drug that should be water-insoluble is significantly improved through the increase of the specific surface area per unit weight of the drug due to their formation into the nanoparticles .

(Industrial applicability)

The apparatus for producing microparticles according to the present invention can be used for producing nanoparticles of various materials such as natural products, drugs and the like.

1: Supply means
2: mixing means
3: injection means
4: collecting means
5: Fluid storage container
6: Feed pump
7: Primary valve
8: Piping
10: Secondary valve
11: Nozzle
12: Piping
13: Collection room
14: Glass bottles
13: substrate

Claims (5)

A fine particle manufacturing apparatus for producing fine particles,
A supply means for supplying fluid,
Mixing means for mixing the material in the fluid, and
And injection means for injecting the fluid mixed with the material through a nozzle for adiabatic expansion thereof,
Wherein the inner surface of the nozzle is formed of a dielectric material. The method according to claim 1,
Wherein the nozzle has a length of 20 mm to 600 mm. 3. The method according to claim 1 or 2,
Wherein the fluid comprises liquefied carbon dioxide. 3. The method according to claim 1 or 2,
And heating means for warming the nozzle. The method of claim 3,
And heating means for warming the nozzle.

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