JP2005205264A - Method and apparatus for redispersing fine particle and vessel containing liquid to be treated - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method and an apparatus for redispersing a fine particle, by each of which flocculated fine particles in a solvent can efficiently dispersed again in the solvent as primary fine particles and to provide a vessel containing the liquid to be treated. <P>SOLUTION: This apparatus 1A for redispersing the fine particle is composed of: a treatment chamber 3 for housing a liquid 2 which is to be treated and contains the solvent 4 and substance-flocculated fine particles 5; a magnet stick 11 and a magnet stirrer 12 for coarsely dispersing the flocculated fine particles 5 in the solvent 4 by agitation; a pressure control unit 35 for generating bubbles of an inert gas 6 in the solvent 4 by decompressing the liquid 2 to be treated in a chamber 30 and; an ultrasonic transducer 20. The flocculated fine particles 5 is dispersed again as primary fine particles of a substance by irradiating the liquid 2 which is to be treated and in which the flocculated fine particles 5 are dispersed coarsely, with ultrasonic waves from the ultrasonic transducer 20 and decompressing the the liquid 2 to be treated by the pressure control unit 35. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a redispersion method of fine particles made of a substance such as an organic compound, a redispersion apparatus, and a container containing a liquid to be used for redispersion of fine particles.

  Micronization of the material results in an extreme surface area increase. For this reason, there exists an advantage that the property intrinsic | native to a substance becomes easy to appear by atomizing a substance. In addition, in the case of a hardly soluble or insoluble substance, the fine particles are solubilized in a solvent such as water by the micronization (the fine particles are suspended in the solvent, but light scattering is small) Therefore, it may be in a state where it seems to be pseudo-solubilized).

As an example of such a micronization method, there is a method disclosed in Patent Document 1 (Japanese Patent Laid-Open No. 2001-113159). Here, a method for producing fine particles of an organic pigment or an aromatic condensed polycyclic compound in a solvent by irradiating a laser beam is disclosed.
JP 2001-113159 A Japanese Patent Laid-Open No. 4-300645 JP 2002-105212 A JP-A-5-106093

  If the above-described micronization technique is used, there is a possibility that a new raw material preparation method can be provided, and application in a wide range of fields is expected. For example, new materials based on microparticles are developed in the material field, and in the drug discovery field, for example, ADME tests (absorption, distribution, metabolism, excretion) of drug candidates that are hardly soluble or insoluble due to microparticulation. Test).

  Here, generally, fine particles of a substance have a property of aggregating in a solvent such as water. For this reason, when fine particles of a material are produced by a fine particle formation method such as the above-described method using the light crushing action by laser light irradiation, a good dispersion state of fine particles in a solvent is impaired by aggregation and precipitation of the fine particles. There is a problem.

  As a method for preventing such agglomeration of fine particles in a solvent, a surfactant is added to the liquid to be treated containing fine particles of the substance in the solvent to stabilize the pseudo solubilized state of the fine particles. There is a way to make it. On the other hand, for example, in the case of producing drug fine particles in the field of drug discovery, since the drug fine particles are to be introduced into the body, it is necessary to suppress the addition amount of the surfactant. However, when the amount of the surfactant added is small, it is difficult to maintain the pseudo-solubilized state of the fine particles over a long period (for example, about 3 years), and the aggregated fine particles are precipitated. In such a case, it is necessary to re-disperse the aggregated fine particles in the solvent into primary fine particles before actually using the fine particles.

  Conventionally, methods described in Patent Documents 2 to 4 are known as methods for dispersing the aggregated fine particles. For example, in Patent Document 2, liquefied gas is used as a medium, and fine particles are dispersed by utilizing the rapid vaporization. However, this method requires an operation of re-adding the fine particles separated from the liquefied gas into the solvent, and there is a problem that the liquid to be treated containing the aggregated fine particles cannot be redispersed while being in a liquid state. . In Patent Document 3, fine particles are dispersed using a powdered medium and a rotating stirrer while air is introduced into the liquid to be treated. In such a method, the powdery medium is introduced into the liquid to be treated. For this reason, there is a possibility that foreign substances other than the fine particles are mixed. Moreover, the process of isolate | separating the disperse | distributed microparticles | fine-particles and powdered media is needed. Further, in Patent Document 4, after degassing with a suction device while bubbling inactive nitrogen gas in the plating solution to replace dissolved gas with nitrogen gas, ultrasonic vibration is applied to disperse the fine particles. Is going. However, even with such a method, it cannot be said that the efficiency of redispersion of fine particles by gas replacement is sufficiently improved.

  The present invention has been made to solve the above problems, and a fine particle redispersion method, a redispersion device, and fine particles capable of efficiently redispersing aggregated fine particles in a solvent into primary fine particles. It aims at providing the container containing the to-be-processed liquid used for the redispersion process of this.

  In order to achieve such an object, the fine particle redispersion method according to the present invention includes (1) a first dispersion in which aggregated fine particles are coarsely dispersed in a solvent with respect to a liquid to be treated containing aggregated fine particles of the substance in the solvent. (2) A bubble of dissolved gas is generated in the solvent of the liquid to be treated by depressurization to adhere around the aggregated fine particles, and the liquid to be treated is vibrated to re-disperse the aggregated fine particles into the substance fine particles. And a second dispersion step.

  The fine particle redispersion device according to the present invention includes (a) a processing chamber for storing a liquid to be processed containing aggregated fine particles of a substance in a solvent, and (b) bubbles of dissolved gas in the solvent of the liquid to be processed by decompression. And (c) a vibration applying means for re-dispersing the agglomerated fine particles into substance fine particles by applying vibration to the liquid to be treated.

  According to the fine particle redispersion method and redispersion apparatus described above, bubbles of dissolved gas generated by decompression are adhered to the surroundings of the aggregated fine particles that are roughly dispersed in a solvent by stirring or the like. By applying vibration to the liquid to be treated in such a state, the vibration of the aggregated fine particles becomes larger due to the attached bubbles. Therefore, the aggregated fine particles in the solvent can be efficiently redispersed into primary fine particles.

  Here, regarding the method of applying vibration to the liquid to be treated, the fine particle redispersion method preferably applies vibration by irradiating the liquid to be treated with ultrasonic waves in the second dispersion step. Similarly, in the redispersion device, it is preferable that the vibration applying unit is an ultrasonic irradiation unit that applies vibration by irradiating the liquid to be processed with ultrasonic waves. Thereby, vibration can be effectively applied to the liquid to be treated. As for the coarse dispersion of the aggregated fine particles, the redispersion device may include a coarse dispersion means for roughly dispersing the aggregated fine particles in the solvent of the liquid to be treated.

  The fine particle redispersion method preferably includes a pressurization step between the first dispersion step and the second dispersion step by dissolving a predetermined gas in the solvent of the liquid to be treated by pressurization to form a dissolved gas. . Similarly, the redispersion device preferably includes a pressurizing means for dissolving a predetermined gas in the solvent of the liquid to be treated by pressurization to obtain a dissolved gas. As a result, it is possible to reliably generate bubbles of dissolved gas in the solvent due to reduced pressure and to adhere the aggregated fine particles to the periphery, and the efficiency of the redispersion process of the fine particles is improved.

  In addition, each process including the first dispersion process and the second dispersion process may be performed from outside the sealed processing chamber while containing the liquid to be processed. In this case, the processing chamber is preferably configured to have a variable volume so that the internal pressure is adjusted with respect to the outside. Further, in the second dispersion step, the pressure may be reduced by opening a predetermined part of the sealed processing chamber.

  In the redispersion method and the redispersion apparatus, the dissolved gas in the solvent of the liquid to be treated is preferably nitrogen gas or a rare gas that is an inert gas having low reactivity. Alternatively, other gas such as air may be used as the dissolved gas. When redispersing fine drug particles, it is preferable to use a rare gas such as argon, krypton, or xenon as the dissolved gas for the purpose of preventing oxidation by dissolved oxygen and generation of nitrous acid by dissolved nitrogen.

  A container containing a liquid to be processed according to the present invention includes a liquid to be processed containing aggregated fine particles of a substance in a solvent, a liquid to be processed, and a predetermined gas that is partly dissolved in the solvent of the liquid to be processed and becomes a dissolved gas. And a container configured to be able to be depressurized by opening a predetermined portion thereof while being sealed in a state in which the inside is pressurized. The container containing the liquid to be processed having such a configuration can be suitably applied to the redispersion processing of the fine particles described above.

  According to the present invention, after the aggregated fine particles are roughly dispersed in the solvent, the liquid to be treated is vibrated in a state where the bubbles of the dissolved gas are attached to the periphery of the aggregated fine particles by reducing the pressure, thereby the aggregated fine particles in the solvent. Can be efficiently re-dispersed into primary fine particles.

  Hereinafter, preferred embodiments of a fine particle redispersion method, a redispersion device, and a container containing a liquid to be treated according to the present invention will be described in detail with reference to the drawings. In the description of the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. Further, the dimensional ratios in the drawings do not necessarily match those described.

  FIG. 1 is a block diagram schematically showing a first embodiment of a fine particle redispersion device according to the present invention. The fine particle redispersion device 1A is a device for redispersing fine particles with respect to a liquid to be treated containing aggregated fine particles of a substance in a solvent. The liquid 2 to be treated that is subject to redispersion treatment is composed of a solvent 4 such as liquid phase water and aggregated fine particles 5 contained in the solvent 4. Here, the agglomerated fine particles 5 are obtained by aggregating the primary fine particles of the substance in the solvent 4 and are usually precipitated in the solvent 4. However, the liquid to be treated 2 does not have to be aggregated all, and is subject to redispersion processing including the case where some of the fine particles having aggregability are aggregated. In addition, examples of the fine particles of the substance include those prepared by a microparticulation method using a light crushing action by laser light irradiation, but there are no particular limitations on the method of manufacturing the fine particles to be subjected to redispersion processing. .

  As shown in FIG. 1, the fine particle redispersion device 1 </ b> A includes a processing chamber 3 for storing a liquid 2 to be processed. The upper portion of the liquid 2 to be processed in the processing chamber 3 is filled with a predetermined gas 6 in a gas phase. As this gas 6, nitrogen gas or a rare gas which is an inert gas is preferably used. Further, a part of the gas 6 is dissolved in the solvent 4 of the liquid 2 to be treated, and becomes the dissolved gas.

  A magnetic stick 11 is accommodated in the processing chamber 3 together with the liquid 2 to be processed. The magnetic stick 11 and the magnetic stirrer 12 agitate the solvent 4 and the aggregated fine particles 5 of the liquid 2 to be processed in the processing chamber 3 to disperse (coarsely) the aggregated fine particles 5 in the solvent 4 as a whole. The coarse dispersion means.

  An ultrasonic transducer 20 and an ultrasonic transducer driving device 25 that drives and controls the ultrasonic transducer 20 are installed at predetermined positions outside the processing chamber 3. The ultrasonic transducer 20 is an ultrasonic irradiation means for redispersing the aggregated fine particles 5 into primary fine particles of the substance by irradiating the liquid 2 to be processed with ultrasonic waves. In the present embodiment, the ultrasonic transducer 20 is disposed in close contact with one side surface of the processing chamber 3. Here, with respect to the ultrasonic transducer 20, the processing chamber 3 is preferably configured to be able to irradiate the liquid 2 to be processed using ultrasonic vibration. . In addition, a monitoring means for monitoring the vibration amplitude of the processing chamber 3 by ultrasonic irradiation may be provided.

  In order to control the pressure in the processing chamber 3 in which the liquid 2 to be processed is stored, a pressure control chamber 30 is provided so as to surround the processing chamber 3. The chamber 30 is filled with the inert gas 6 described above. In addition, a pressure control device 35 for controlling the pressure in the chamber 30 is connected to the chamber 30. Further, an inert gas cylinder 36 for supplying the inert gas 6 into the chamber 30 is connected to the pressure control device 35.

  The pressure control device 35 has a function as a depressurizing unit for depressurizing the liquid 2 to be processed in the chamber 30 and a function as a pressurizing unit for performing pressurization. Further, a pressure monitor 37 is connected to the pressure control chamber 30 together with the pressure control device 35, and the pressure in the chamber 30 is monitored by the pressure monitor 37.

  In addition, a dispersion state monitoring device 13 is installed for the liquid 2 to be processed stored in the processing chamber 3. The dispersion state monitoring device 13 is a monitoring means for monitoring the dispersion state of the aggregated fine particles 5 and the redispersed fine particles in the solvent 4 of the liquid 2 to be treated. The monitoring of the dispersion state of the fine particles is performed by, for example, a method of irradiating the liquid 2 to be processed and measuring the transmittance. Specifically, the dispersion state of fine particles in the solvent 4 is measured by measuring light scattering, absorbance, and the like in the liquid 2 to be processed in the processing chamber 3 using a light source and a light detector installed across the processing chamber 3. There is a configuration to monitor. In FIG. 1, the distributed state monitoring device 13 is schematically illustrated.

  The magnet stirrer 12, the ultrasonic transducer driving device 25, and the pressure control device 35 are connected to a control device 15 including a computer or the like. In the present embodiment, the control device 15 is also connected to the distributed state monitoring device 13 and the pressure monitor 37. The control device 15 controls the redispersion processing of the fine particles by controlling the operation of each part of the redispersion device 1A.

  Next, the fine particle redispersion method according to the present invention using the fine particle redispersion device 1A shown in FIG. 1 will be described with reference to the flowchart shown in FIG. 2 and the pressure control timing chart shown in FIG. Here, in the timing chart of FIG. 3, the horizontal axis indicates the elapsed time from the start of the redispersion process, and the vertical axis indicates the pressure in the pressure control chamber 30.

  First, the liquid 2 to be processed containing the aggregated fine particles 5 of the substance in the solvent 4 is accommodated in the processing chamber 3 and installed in the pressure control chamber 30. Then, an operation instruction signal is sent from the control device 15 to the magnetic stirrer 12, and the liquid 2 to be treated is stirred by the magnetic stick 11 under atmospheric pressure conditions to disperse the aggregated fine particles 5 in the solvent 4. As a result, the aggregated fine particles 5 are roughly dispersed in the entire solvent 4 (step S101, first dispersion step).

  Next, a pressure command signal is sent from the control device 15 to the pressure control device 35, and the inert gas 6 is supplied from the gas cylinder 36, thereby pressurizing the pressure control chamber 30 to a predetermined pressure. Thereby, the liquid 2 to be processed in the processing chamber 3 is pressurized, and the inert gas 6 is dissolved in the solvent 4 of the liquid 2 to be processed to become a dissolved gas (S102, pressurizing step).

  When the inert gas 6 is sufficiently dissolved in the solvent 4, a pressure reduction instruction signal is sent from the control device 15 to the pressure control device 35, and the pressures of the liquid 2 and the inert gas 6 in the chamber 30 are gradually reduced. . At the same time, the ultrasonic vibrator 20 is driven by the vibrator driving device 25 to irradiate the liquid to be processed 2 in the processing chamber 3 with ultrasonic waves (S103, second dispersion step). At this time, due to the reduced pressure in the chamber 30, the dissolved gas of the inert gas 6 reaches saturation in the solvent 4 of the liquid 2 to be processed, and bubbles of the dissolved gas are generated. The generated dissolved gas bubbles adhere around the aggregated fine particles 5 that are roughly dispersed throughout the solvent 4. In this state, when the ultrasonic wave is applied to the liquid 2 to be processed by the ultrasonic vibrator 20, the aggregated fine particles 5 around the bubbles greatly vibrate and are redispersed with high efficiency into the primary fine particles of the substance.

  Subsequently, the dispersion state of the aggregated fine particles 5 and the redispersed fine particles in the solvent 4 is monitored from the outside of the processing chamber 3 by the dispersion state monitoring device (evaluation device) 13 (S104). Then, it is confirmed whether or not an overall good dispersion state is obtained in the liquid to be treated 2 (S105). If such a dispersion state is not obtained, the redispersion process is continued. If a good dispersion state is obtained, an instruction signal for returning the pressure to the atmospheric pressure is sent from the control device 15 to the pressure control device 35, and the pressure in the chamber 30 is reduced to a pressure lower than the atmospheric pressure. (S106). In the process of returning to the atmospheric pressure, the fine bubbles of the dissolved gas generated in the solvent 4 are dissolved again, and finally the liquid 2 to be treated in which the primary fine particles are well redispersed is obtained.

  The effects of the fine particle redispersion method and redispersion device according to the above embodiment will be described.

  According to the fine particle redispersion method and redispersion device shown in FIGS. 1 to 3, it occurs when the pressure inside the chamber 30 is reduced by the pressure control device 35 with respect to the aggregated fine particles 5 roughly dispersed in the solvent 4. The bubbles of the dissolved gas of the inert gas 6 are adhered around the aggregated fine particles 5. By irradiating the liquid 2 to be processed with the ultrasonic vibrator 20 in such a state, the vibration of the aggregated fine particles 5 due to the ultrasonic waves becomes larger due to the attached bubbles. Therefore, it is possible to efficiently re-disperse the aggregated fine particles 5 in the solvent 4 into primary fine particles including the case where the fine particles to be redispersed are submicron order fine particles.

  Further, in the above embodiment, after the aggregated fine particles 5 are roughly dispersed in the solvent 4 and before pressure reduction and ultrasonic irradiation are performed on the liquid 2 to be processed, the pressure is increased in the solvent 4 of the liquid 2 to be processed. The inert gas 6 is dissolved to form a dissolved gas. As a result, it is possible to reliably generate bubbles of dissolved gas in the solvent 4 due to reduced pressure and adhere to the surroundings of the aggregated fine particles 5 with a sufficient amount of dissolved gas in the solvent 4. Therefore, the efficiency of the fine particle redispersion treatment is improved. However, such pressurization treatment to the liquid to be treated 2 may not be performed when there is a sufficient amount of dissolved gas in the solvent 4 in advance.

  Further, as the dissolved gas dissolved in the solvent 4, it is preferable to use nitrogen gas or rare gas (helium, argon, xenon, etc.) as the inert gas having low reactivity as described above. Alternatively, other gas such as air may be used as the dissolved gas. Further, the vibration frequency of the ultrasonic wave applied to the liquid to be treated 2 is not particularly limited, but generally a frequency of 20 kHz to 100 kHz is used.

  As a means for redispersing the agglomerated fine particles 5 into primary fine particles, in the above-described embodiment, vibration is applied by irradiating the liquid to be treated 2 with ultrasonic waves using the ultrasonic vibrator 20. In general, in the second dispersion step, fine particles may be redispersed by applying vibration to the liquid to be treated using a vibration applying unit. However, it is preferable to use ultrasonic irradiation means such as the ultrasonic vibrator 20 as the vibration applying means in order to effectively apply vibration to the liquid to be processed.

  The type of fine particles of the substance to be redispersed by the above-described method and apparatus is not particularly limited, but the primary fine particles having a particle size of 10 nm to 1000 nm can sufficiently obtain the effect of redispersion. Is preferable. Moreover, the fine particles and the aggregated fine particles 5 to be redispersed may be organic compounds. Examples of the organic compound include organic pigments, aromatic condensed polycyclic compounds, drugs (drugs, pharmaceutical-related substances), and the like.

  Specific examples of the organic compound to be subjected to the fine particle redispersion treatment include, for example, poorly soluble drugs such as clobetasone butyrate and carbamazepine, which are drugs, and insoluble drugs. The fine particle redispersion method and apparatus described above can be applied to drug candidate substances (natural products, compound libraries, etc.), quasi-drugs, cosmetics, etc., in addition to the drug substances.

  When an organic compound such as a drug is a target, water is preferably used as the solvent, and some alcohols, saccharides, and salts may be contained. Alternatively, a solvent other than water may be used. Examples of such solvents include ethyl alcohol which is a monohydric alcohol, glycols which are a dihydric alcohol (propylene glycol, polyethylene glycol, etc.), and glycerol which is a trihydric alcohol. In addition, soybean oil, corn oil, sesame oil, peanut oil and the like, which are vegetable oils, can also be used as a solvent. These solvents are suitably used as organic solvents for non-aqueous injections when used as injections.

  In the redispersion method and redispersion device of the above-described embodiment, the aggregated fine particles can be suitably redispersed under the conditions of no addition of a surfactant or addition of a surfactant at a low concentration. This has a great merit in application to pharmaceuticals in which the kind and concentration of additives are strictly limited.

  Next, the content of the present invention will be described more specifically by way of examples. However, the present invention is not limited to the following examples.

(Example 1)
In this example, an attempt was made to redisperse aggregated fine particles of FePc (iron phthalocyanine) as a fine particle substance to be redispersed. FePc is a substance that is highly cohesive and difficult to redisperse. Moreover, water was used as the solvent. FIG. 4 is a graph showing the particle size distribution of FePc. In this graph, the horizontal axis indicates the particle diameter (μm) of FePc, and the vertical axis indicates the relative particle amount in terms of volume. Further, the particle size distribution of FePc was measured by a laser diffraction type particle size distribution measuring apparatus (SALD7000, Shimadzu Corporation).

In the graph of FIG. 4, a graph A1 shows a particle size distribution in a state in which FePc fine particles are aggregated. In this graph, the particle size is approximately 7 μm to 35 μm. Graph A2 shows the particle size distribution when a surfactant (Igapal CA-630: molecular weight 602) is added to the liquid to be treated at a concentration of 5 × 10 ⁻³ mol / l. In this state, the cohesiveness of the fine particles is eliminated, so that the primary fine particles are dispersed. From the graph, it can be seen that the particle size distribution of the primary fine particles is 250 nm to 800 nm.

  Next, graph A3 shows a particle size distribution when only the ultrasonic irradiation is performed on the aggregated fine particles shown in graph A1. Here, ultrasonic irradiation performed irradiation for 10 minutes using the ultrasonic cleaner (Shimadzu Rika Instruments SUS-103). The vibration frequency of the ultrasonic wave is 45 kHz. In this graph A3, it can be seen that the particle size distribution is shifted in a direction smaller than that in the graph A1 due to ultrasonic irradiation, and the dispersion state of the fine particles is somewhat improved. However, the particle diameter of the primary fine particles is far from 250 nm to 800 nm, and the aggregated fine particles are not sufficiently redispersed.

  Graph A4 shows the particle size distribution when only the pressurization / decompression treatment is performed on the aggregated fine particles. Here, in the pressurizing / depressurizing process, after pressurizing to 5 atm using air as a base, a process of gradually depressurizing from 5 atm to 0.2 atm for 20 seconds was performed. In this graph A4, redispersion of the aggregated fine particles was not observed.

  On the other hand, graph A5 shows the particle size distribution when the aggregated fine particles are subjected to ultrasonic irradiation and pressurization / decompression treatment by the method of the present invention. Here, after pressurizing to 5 atm using air as a base, the ultrasonic irradiation was performed and the pressure was gradually reduced from 5 atm to 0.2 atm for 20 seconds. Comparing the graph A5 with the graphs A1 to A4, the average particle size is smaller than the graph A3 with only ultrasonic irradiation and the graph A4 with only pressurization / decompression treatment, and a graph of a complete dispersion state using a surfactant. It can be seen that primary particles similar to A2 having a particle diameter of 250 nm to 800 nm are obtained in a large amount in a short time. From the above, it was confirmed that a fine dispersion state of fine particles can be obtained by the fine particle redispersion method of the present invention.

(Example 2)
In this example, redispersion of aggregated fine particles of clobetasone butyrate (synthetic corticosteroid for external use), which is a poorly soluble drug, was attempted as a fine particle substance to be redispersed. As the liquid 2 to be treated, water was used as the solvent 4, clobetasone butyrate 0.5 mg / ml, and surfactant Tween 80 were mixed with water at a concentration of 0.02 mg / ml. This surfactant concentration is insufficient to prevent the aggregation of clobetasone butyrate microparticles, and the microparticles are allowed to settle to the bottom of the processing chamber as aggregated microparticles. FIG. 5 is a graph showing the particle size distribution of clobetasone butyrate. In this graph, the horizontal axis represents the particle size (μm) of clobetasone butyrate, and the vertical axis represents the relative particle amount in terms of volume. Further, the measurement of the particle size distribution is the same as in FIG.

  In the graph of FIG. 5, a graph B1 shows a particle size distribution when only coarse dispersion of the aggregated fine particles by stirring is performed. In this graph, although a small amount of fine particles having a particle diameter of about 100 nm, which are primary fine particles, are present, a large amount of aggregated fine particles having a particle diameter of about 1 μm to 20 μm are contained. Graph B2 shows the particle size distribution when only the ultrasonic irradiation is performed on the aggregated fine particles. Also in this graph, it can be seen that agglomerated fine particles having a particle diameter of 1 μm to 20 μm remain to some extent, and the redispersion treatment is insufficient.

  On the other hand, graph B3 shows the particle size distribution when redispersion processing is performed by the method of the present invention. In this graph, the primary fine particles in the vicinity of the particle diameter of 100 nm are greatly increased, and conversely, the aggregated fine particles in the vicinity of the particle diameter of 1 μm to 20 μm are greatly decreased as compared with the graph B1 of only the coarse dispersion and the graph B2 of only the ultrasonic irradiation. . From the above, it was confirmed that even when drug fine particles, which are pharmaceuticals, are targeted, according to the fine particle redispersion method of the present invention, a good dispersion state of the fine particles can be obtained.

  The fine particle redispersion method and redispersion device according to the present invention will be further described. In the following embodiments, illustration and description of coarse dispersion means for roughly dispersing aggregated fine particles, pressurization / decompression means for performing pressure / decompression treatment, and ultrasonic irradiation means for performing ultrasonic irradiation are omitted. doing.

  FIG. 6 is a diagram showing the configuration of the second embodiment of the fine particle redispersion device under conditions of (a) atmospheric pressure, (b) high pressure, and (c) low pressure. In the present embodiment, a hermetically sealed processing chamber 3a is used as a processing chamber for storing the liquid to be processed 2 containing a solvent and aggregated fine particles.

  The processing chamber 3a is a stretchable chamber and has a structure that can change its internal volume. Thereby, the internal pressure of the processing chamber 3a is adjusted to be equal to the external pressure. The processing chamber 3a is disposed in the pressure control chamber 30a. In such a configuration, when the pressure in the chamber 30a is changed from the atmospheric pressure state shown in FIG. 6A to a high pressure and a low pressure, as shown in FIGS. 6B and 6C, the processing chamber 3a itself Expands and contracts with external pressure changes. At this time, the liquid 2 and the inert gas 6 in the sealed processing chamber 3a are pressurized and depressurized without contact with the outside.

  By using the processing chamber 3a thus sealed as a processing chamber and performing each step necessary for the redispersion processing from the outside of the processing chamber 3a, the liquid to be processed is contaminated from the outside in the redispersion processing step. Is prevented. Further, since the work such as replacement of the liquid 2 to be processed into the processing chamber 3a is not necessary, it is suitable for quick redispersion processing. These are particularly useful in the redispersion treatment of drug fine particles used as pharmaceuticals. Moreover, as a material of the stretchable processing chamber 3a, for example, rubber can be used.

  FIG. 7 is a diagram showing the configuration of the third embodiment of the fine particle redispersion device under conditions of (a) atmospheric pressure, (b) high pressure, and (c) low pressure. In the present embodiment, a sealed piston 3b composed of a piston outer container 3c and an inner container 3d is used as a processing chamber for storing the liquid to be processed 2 containing a solvent and aggregated fine particles.

  Similar to the processing chamber 3a shown in FIG. 6, the piston 3b is configured such that its internal volume is variable by moving the inner container 3d relative to the outer container 3c, and the internal pressure can be changed. It has become. Also with such a piston 3b, it is possible to perform the redispersion process in a state where the liquid 2 to be processed is sealed. In this case, a chamber 30b surrounding the piston 3b may be installed so that the piston inner container 3d automatically moves according to the pressure in the chamber 30b.

  FIG. 8 is a diagram showing the configuration of the fourth embodiment of the fine particle redispersion device in (a) an initial state, (b) a coarse dispersion state, (c) a reduced pressure state, and (d) a redispersion state. In the present embodiment, the fine particle redispersion treatment is performed using the container containing the liquid to be treated according to the present invention.

As shown in FIG. 8A, the container with the liquid to be processed according to the present embodiment contains the liquid 2 to be processed containing the aggregated fine particles 5 of the substance in the solvent 4 and the liquid 2 to be processed in a sealed state. And the container 3e. The vessel 3e, together with the treatment solution 2, a predetermined gas 6 as a dissolved gas is dissolved is partially in the solvent 4 in the to-be-treated liquid 2 is higher than the external pressure (e.g. atmospheric pressure) P ₀ It is sealed while being pressurized to a predetermined pressure P ₁ (P ₁ > P ₀ ). The container 3e is a container that becomes a processing chamber when performing the redispersion process, and is configured to be able to depressurize the liquid 2 to be processed by opening a predetermined portion thereof.

In the redispersion process of fine particles using the container with the liquid to be processed having such a configuration, first, the inside of the container 3e is stirred with respect to the liquid 2 to be processed in the initial state shown in FIG. As shown in b), the aggregated fine particles 5 are roughly dispersed in the solvent 4 as a whole. In this state, as shown in FIG. 8 (c), the treatment liquid 2 is irradiated with ultrasonic waves, and the container 3 e is opened by opening a hole 3 f in a part thereof. Is reduced to a pressure P ₀ equal to the outside. At this time, bubbles of the inert gas 6 are generated in the solvent 4 of the liquid 2 to be treated and adhere to the periphery of the aggregated fine particles 5. When the treatment liquid 2 is irradiated with ultrasonic waves in this state, the aggregated fine particles 5 vibrate greatly and are redispersed into the primary fine particles 5a as shown in FIG. 8 (d).

By performing each process necessary for the redispersion process using the container for liquid to be processed having such a configuration, the redispersion process can be completed easily in a short time. The container 3e serving as a processing chamber, it is sufficient withstand inclusion of the treatment liquid 2 and inert gas 6 at high pressure P _1, stretchability not required. Specific examples of the material include Teflon (registered trademark), nylon, and vinyl. In addition, such a container containing a liquid to be treated can be used as an ampoule containing a liquid to be treated containing, for example, drug fine particles that are drugs.

  In the above-mentioned container containing the liquid to be treated, if an excessive amount of gas is dissolved in the solvent, it becomes difficult to selectively attach bubbles of the generated dissolved gas around the aggregated fine particles. It is preferable to enclose a gas such as an inert gas by pressurizing at a pressure of 1.1 atm to 1.5 atm. Moreover, it is preferable to use argon (saturated dissolution amount 5.3 cc / l) as the gas to be sealed. Argon gas is also useful in that it is inexpensive. In addition to argon gas, gas such as xenon (saturated dissolution amount 108 cc / l), krypton (saturated dissolution amount 59.8 cc / l) may be used.

  The fine particle redispersion method, redispersion device, and container to be treated according to the present invention are not limited to the above-described embodiments and examples, and various modifications are possible. For example, the coarse dispersion of the aggregated fine particles 5 in the solvent 4 of the liquid 2 to be treated is roughly dispersed using the magnetic stick 11 and the magnetic stirrer 12 in FIG. 1, but the processing chamber 3 is rotated and deformed. Alternatively, coarse dispersion may be performed using other means such as shuffling the processing chamber 3. Further, it is not essential to provide the coarse dispersion means in the chamber 30 as shown in FIG. For example, before the processing chamber 3 is placed in the chamber 30, the processing chamber 3 is coarsely dispersed in advance using a stirrer, for example, vortex, or the processing chamber 3 is flipped with a finger to perform rough dispersion. A method is also conceivable. Moreover, you may use structures other than the above about the ultrasonic irradiation means with respect to the to-be-processed liquid 2, or a vibration application means.

  INDUSTRIAL APPLICABILITY The present invention can be used as a fine particle redispersion method, a redispersion apparatus, and a container containing a liquid to be used for fine particle redispersion processing, which can efficiently redisperse aggregated fine particles in a solvent into primary fine particles. It is.

1 is a configuration diagram schematically illustrating a first embodiment of a fine particle redispersion device. FIG. 2 is a flowchart showing an example of a fine particle redispersion method using the redispersion device shown in FIG. 1. 3 is a timing chart showing pressure control in a chamber in the redispersion method shown in FIG. It is a graph which shows the particle diameter distribution of FePc. It is a graph which shows the particle diameter distribution of clobetasone butyrate. It is a figure which shows the structure of 2nd Embodiment of the redispersion apparatus of microparticles | fine-particles in the state of the conditions of (a) atmospheric pressure, (b) high pressure, and (c) low pressure, respectively. It is a figure which shows the structure of 3rd Embodiment of the redispersion apparatus of microparticles | fine-particles in the state of the conditions of (a) atmospheric pressure, (b) high pressure, and (c) low pressure, respectively. It is a figure which shows the structure of 4th Embodiment of the redispersion apparatus of microparticles | fine-particles in (a) initial state, (b) rough dispersion state, (c) pressure reduction state, and (d) redispersion state, respectively.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 1A ... Fine particle redispersion device, 2 ... Liquid to be processed, 3 ... Processing chamber, 4 ... Solvent, 5 ... Aggregated fine particle, 6 ... Inert gas, 11 ... Magnet stick, 12 ... Magnet stirrer, 13 ... Dispersion state monitoring device DESCRIPTION OF SYMBOLS 15 ... Control apparatus, 20 ... Ultrasonic transducer, 25 ... Ultrasonic transducer drive apparatus, 30 ... Pressure control chamber, 35 ... Pressure control apparatus, 36 ... Inert gas cylinder, 37 ... Pressure monitor.

Claims (13)

A first dispersion step of roughly dispersing the aggregated fine particles in the solvent with respect to a liquid to be treated containing the aggregated fine particles of the substance in the solvent;
A bubble of dissolved gas is generated in the solvent of the liquid to be treated by depressurization to adhere to the periphery of the aggregated fine particles, and the aggregated fine particles are redispersed into fine particles of the substance by applying vibration to the liquid to be treated. A redispersion method of the fine particles.   The redispersion method according to claim 1, wherein in the second dispersion step, vibration is applied by irradiating the liquid to be treated with ultrasonic waves.   A pressurization step is provided between the first dispersion step and the second dispersion step, wherein a predetermined gas is dissolved in the solvent of the liquid to be treated by pressurization to form the dissolved gas. The redispersion method according to claim 1 or 2.   4. Each of the steps including the first dispersion step and the second dispersion step is performed from outside a processing chamber that contains the liquid to be processed and is sealed. Redistribution method.   The re-dispersion method according to claim 4, wherein the processing chamber is configured to have a variable volume so that an internal pressure is adjusted with respect to the outside.   6. The redispersion method according to claim 4 or 5, wherein, in the second dispersion step, pressure reduction is performed by opening a predetermined portion of the sealed processing chamber.   The re-dispersion method according to claim 1, wherein the dissolved gas is nitrogen gas or rare gas. A processing chamber containing a liquid to be processed containing aggregated fine particles of a substance in a solvent;
Decompression means for generating bubbles of dissolved gas in the solvent of the liquid to be treated by decompression;
A fine particle redispersing device comprising vibration applying means for applying vibration to the liquid to be treated to redisperse the aggregated fine particles into fine particles of the substance.   9. The redispersion device according to claim 8, wherein the vibration applying unit is an ultrasonic irradiation unit that applies vibration by irradiating the liquid to be treated with ultrasonic waves.   The redispersion device according to claim 8 or 9, further comprising a pressurizing means for dissolving a predetermined gas in the solvent of the liquid to be treated to form the dissolved gas by pressurization.   The re-dispersion device according to any one of claims 8 to 10, wherein the processing chamber is configured to have a variable volume so that an internal pressure is adjusted with respect to the outside.   The re-dispersion device according to any one of claims 8 to 11, wherein the dissolved gas is nitrogen gas or a rare gas. A liquid to be treated containing aggregated fine particles of a substance in a solvent;
The liquid to be treated and a predetermined gas that is partly dissolved in the solvent of the liquid to be treated to form a dissolved gas are contained and sealed in a pressurized state, and the predetermined part is opened. And a container configured to be able to be depressurized by doing so.

Images