JPH0389938A - Preparation of ultrafine particle - Google Patents

Abstract

PURPOSE:To produce new kind of ultrafine particles by introducing the inert gas atmosphere into a reaction chamber and evaporating the aimed substance from a main crucible in this reaction chamber and simultaneously evaporating the allowable additive from an auxiliary crucible and depositing the mixture of both on a substrate as the ultrafine particles. CONSTITUTION:A main crucible 11 and an auxiliary crucible 12 which can be independently heated and controlled are prepared in a reaction chamber 1. The inert gas atmosphere is introduced into this reaction chamber 1 and both the crucible 11 and the crucible 12 are heated at the prescribed temp. respectively. The aimed substance is evaporated from the main crucible 11 and simultaneously the allowable additive is evaporated form the auxiliary crucible 12. The mixture of both is deposited on a substrate 5 as ultrafine particles. As a result, the ultrafine particles in which the required amount of the additive is admixed with the aimed substance can be produced. Further the ultrafine particles high in amorphousness whose crystallinity is controlled can be produced by admixing the impurity having crystallization controlling effect. The ultrafine particles having amorphousness show excellent solubility and dispersibility.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a method for producing ultrafine particles, and particularly to a method for producing ultrafine particles that have excellent solubility and dispersibility in solvents such as aqueous solvents. .

[Prior Art] A method for producing ultrafine particles according to the prior art will be described with reference to FIG.

A reaction chamber 1 formed by a vacuum vessel is connected to an exhaust system 2 and an inert gas source 3 via valves 7 and 8. A crucible 4 for evaporating raw materials is disposed inside the reaction vessel 1, and a substrate 5 is disposed above the crucible 4 for adhering produced ultrafine particles. The substrate 5 is cooled by a cooling system (not shown) such as a liquid nitrogen system.

In producing ultrafine particles, first, raw materials of a predetermined composition such as organic compounds are charged into a crucible 4, and the reaction chamber 1 is hermetically sealed.

The exhaust system 2 exhausts the inside of the reaction chamber 1 via the valve 7, e.g.
After evacuation to a high vacuum of about 6 Torr, helium (He
), an inert gas such as argon (Ar) is introduced from an inert gas source 3 through a valve 8 to maintain a predetermined inert gas pressure.

Thereafter, the substrate 5 is cooled, and the crucible 4 in which raw materials have been charged in advance is gradually heated, and the temperature is raised to the evaporation temperature.6 The heated raw materials are liquefied and vaporized from the surface. Note that some raw materials do not liquefy and sublimate directly from the solid phase to the gas phase.

The raw material gas molecules heated and evaporated in the crucible 4 collide with inert gas molecules in the atmosphere, are cooled, and gradually coagulate to form ultrafine particles. The generated ultrafine particles are placed above the crucible 4, attached to a cooled substrate 5, and collected.

The advantages of ultrafine organic particles over bulk particles include a change in surface charge as the particle size decreases and an improvement in dissolution rate or dispersibility in solvents.

Particle size and particle crystallinity are important parameters that determine the dissolution rate, degree of supersaturation, and dispersibility of a substance in a solvent. Ultrafine organic particles have significantly smaller particle sizes than bulk materials and exhibit poor solubility (dissolution rate, supersaturation degree) and dispersibility.

On the other hand, it is also well known that amorphous substances exhibit superior solubility and dispersibility compared to crystalline substances.

Conventionally, poorly soluble drugs are made by mixing bulk raw materials and drug additives (lactose, methylcellulose, etc.), pulverizing them in a ball mill, etc., and mixing them to form ultra-fine particles and impart amorphous properties to improve solubility. It was increasing.

[Problems to be Solved by the Invention] As described above, conventionally, certain organic substances have been made into ultrafine particles using a ball mill or the like in order to improve their solubility and dispersibility in solvents.

However, in certain organic substances, Super II! Even when it is made into one particle, the crystallinity of the ultrafine particles to be purified is high, and the expected effect of improving the dissolution rate in the solvent and the solubility (or dispersibility) of supersaturation degree may not be obtained.

An object of the present invention is to provide a method for producing a new type of ultrafine particles.

Another object of the present invention is to provide a method for producing ultrafine amorphous organic particles with improved solubility and dispersibility in solvents.

[Means for solving the problem] Prepare a main crucible and an auxiliary crucible that can be heated independently in a reaction chamber, introduce an inert gas atmosphere into the reaction chamber, and heat the main crucible and auxiliary crucible to a predetermined temperature. Then, the target substance is simultaneously evaporated from the main crucible and the acceptable additive is evaporated from the auxiliary crucible, and a mixture of both is deposited as ultrafine particles on the substrate.

Even if the target substance and additives are initially loaded in each crucible,
The reservoir may be supplied in small quantities.

If the target substance is an organic substance, an impurity that prevents the crystallization of the target substance is used as an additive, and the evaporated substance is captured on the substrate.
It is possible to obtain ultrafine particles of amorphous organic material.

[Function] Production of ultrafine particles G, in order to inhibit the crystallization that is carried out by evaporating the ultrafine particle raw material from the crucible and colliding it with an inert atmosphere gas, impurities etc. are added to the target substance. When additives are put into a crucible together with the target substance, selective evaporation occurs when they are heated and evaporated in the crucible, and the resulting ultrafine particles often do not have the desired concentration of additives.

By providing an auxiliary crucible that can be heated independently from the main crucible and evaporating the target substance from the main crucible and the additive from the auxiliary crucible, it becomes possible to independently control the amount of evaporation of each. In this way, evaporation is performed simultaneously from two or more types of evaporation sources in the reaction chamber, and ultrafine particles of a mixture of the target substance and a desired amount of additive can be deposited on the substrate.

If you have a target substance or an organic substance and want to add impurities that inhibit crystallization to improve its solubility and dispersibility, supply the additive to the auxiliary crucible and separate it from the main crucible in an inert gas atmosphere. By simultaneously evaporating from a crucible and capturing ultrafine particles on a cooled substrate,
It becomes possible to obtain amorphous ultrafine particles with excellent solubility and dispersibility.

In the first place, there are two general methods for obtaining an amorphous substance: (1) rapid cooling of the substance to quickly granulate it, and (2) a method of mixing impurities into the target substance to suppress crystal growth. The method (2) involves evaporating and mixing additives from an auxiliary crucible in parallel with the evaporation of the target substance. In this way, amorphous ultrafine particles with low crystallinity can be obtained.

Amorphous ultrafine particles have excellent solubility and dispersibility due to their small particle size, and are expected to further improve solubility and dispersibility due to their amorphous nature.

[Example] Hereinafter, the present invention will be described in detail with reference to the drawings.

FIG. 1 shows an apparatus for producing ultrafine particles.

The reaction chamber 1 is connected via a valve 7 to an exhaust system 2 and via a further valve 8 to an inert gas source 3.

The reaction chamber 1 is constructed, for example, by placing a stainless steel or glass Pel jar on a stainless steel base. The exhaust system 2 is configured, for example, by a combination of a rotary pump and a diffusion pump.

The inert gas source 3 supplies an inert gas such as a group Ⅰ gas such as J(e, Ar, etc.) or an inert gas such as N2 gas which can be considered inert to a predetermined raw material.

A main crucible 11 and an auxiliary crucible 12 are arranged within the reaction chamber 1. Each router is connected to an independently controllable power source.

A coolable substrate 5 is disposed above the crucible 11, 12. The substrate 5 can be cooled to near liquid nitrogen temperature by a liquid nitrogen system (not shown).

The main crucible 1J and the auxiliary crucible 12 are, for example, containers made of high melting point metals such as W and Mo that also serve as heaters, respectively.
It consists of a container made of quartz, alumina, etc. placed on top of the quartz container, and a container made of quartz, alumina, etc. with a heater embedded in it.

The procedure for producing ultrafine particles will be explained below.

A desired amount of a raw material for a desired target substance such as an organic compound is charged into the main crucible 11, and a desired amount of a crystallization inhibiting impurity is charged into the auxiliary crucible 12. The substrate 5 is placed and the reaction chamber 1 is hermetically sealed. The inside of the reaction chamber 1 is evacuated to a high vacuum (for example, a vacuum of 10' Torr or more), and H is supplied into the reaction chamber 1 from the inert gas source 3.
e, an inert gas such as Ar is introduced. The inert gas is adjusted to a predetermined pressure (for example, 0.1 to 10 Torr) to create an inert gas atmosphere. The inert gas atmosphere may be allowed to flow.

The main crucible 11 and the auxiliary crucible 12 are heated to a temperature suitable for the evaporation temperature (or sublimation temperature) of each raw material, and the target substance is transferred from the main crucible 11 to the auxiliary crucible 12.
The crystallization-inhibiting impurities are simultaneously evaporated.

The molecules (or atoms) of the target substance and the crystallization inhibiting substance that evaporated at the same time repeatedly collide with the inert gas molecules of the atmospheric gas, cool, grow, and mix, and form the ultrafine particles of the mixture. and is deposited on the substrate 5. The ultrafine particles become amorphous because they are rapidly cooled by collision with inert gas molecules and contain a crystallization inhibiting substance. Also, since the substrate 5 is cooled, it grows, and the substrate 5
For example, the target substance is an organic substance such as a poorly soluble drug, and the crystallization inhibiting substance is lactose, methylcellulose, etc.

Introduce tle gas into the vacuum container and increase the degree of vacuum to I Tor.
After adjusting to r, the main crucible containing 1 g of the target substance and the auxiliary crucible containing L-leucine Ig, which is an additive, are heated. 2 main crucibles and 2 auxiliary crucibles each
If you adjust the temperature to 70℃ and 200℃ and evaporate, it will become a melting pot.
The mixed ultrafine particles adhere to the glass substrate installed in the second part. The mixing ratio of the target substance and additive in the produced superimitation particles was 1:1.

In the above-mentioned method for producing ultrafine particles, various heating methods can be used, such as resistance heating, optical heating using a halogen lamp or laser beam, and induction heating.

Also, patent application Hei 1. As proposed in No. 85149, the reaction chamber may further include a raw material storage section and a plurality of conveying tools for transporting the raw materials from the raw material storage section to each crucible.

The EC material storage section stores raw materials and allows them to be taken out as appropriate, and is made up of, for example, a stainless steel shelf, a container with an outlet at the bottom that can be opened and closed, and the like.

The conveyance tool is composed of a spoon member or the like driven by a drive means such as a gear.

In the case of such top formation, each crucible can be heated to the desired pfr temperature without initially charging the raw material into each crucible.

After each crucible reaches a predetermined temperature, a small amount of raw material is intermittently or continuously introduced into each crucible from the raw material storage section. ■In addition to the method of reciprocating the spoon member, etc. that plays the role of transporting raw materials between the raw material storage section and the crucible using boots or gears, ■The method of installing a bell 1 conveyor from the raw material storage section above the crucible , A method of dropping raw materials little by little onto a belt conveyor from the raw material storage section and transporting them onto the crucible.■ A conveyance path is formed from the raw material storage section to the top of the crucible, and an opening is made in the lower part of one storage section in the original stage to transport the raw materials. The material is introduced into the conveyor path little by little by vibration, etc.
There are methods for transporting the raw materials to the crucible along the conveyance path, ■a combination of these methods, and any method can be adopted.

By intermittently or continuously introducing the raw material into the crucible in small quantities from the raw material storage section, the raw material can be evaporated or vaporized within a short period of time. Since it evaporates within a short time, the composition of the raw material is unlikely to change due to selective evaporation.

2 Although the case where one auxiliary crucible is used has been described, the number of auxiliary crucibles may be plural. 6 The additive may be a stable organic compound that does not cause any inconvenience in the use of the target substance.

The type is not limited to one.

By the method described above, ultrafine particles are created in which the target substance is mixed with an acceptable amount of additives as impurities. The composition ratio of the target substance and additive in the ultrafine particles can be controlled by independently controlling the evaporation amount of each.

[Effects of the Invention] As described above, according to the present invention, ultrafine particles in which a desired amount of additives are mixed into a target substance can be produced.

By adding impurities that have the effect of suppressing crystallization,
Highly amorphous ultrafine particles with suppressed crystallinity can be obtained.

Amorphous ultrafine particles exhibit excellent solubility and dispersibility.

9

[Brief explanation of drawings]

FIG. 1 is a sectional view of an ultrafine particle manufacturing apparatus used in an embodiment of the present invention, and FIG. 2 is a sectional view of an ultrafine particle manufacturing apparatus according to the prior art. In the figure, 8 1 2 Reaction chamber exhaust system Inert gas source Crucible valve Main crucible Auxiliary crucible

Claims (2)

[Claims] (1) A step of preparing a main crucible and an auxiliary crucible that can be heated independently in the reaction chamber, and a step of introducing an inert gas atmosphere into the reaction chamber and heating the main crucible and the auxiliary crucible to a predetermined temperature, respectively. A method for producing ultrafine particles, comprising simultaneously evaporating a target substance from a main crucible and an acceptable additive from an auxiliary crucible, and depositing a mixture of both as ultrafine particles on a substrate. (2) The target substance is an organic substance, the additive is an impurity that prevents crystallization of the target substance, the substrate is cooled, and the ultrafine particles are amorphous. Method for producing ultrafine particles.