JP4398280B2 - Method for producing fine particles - Google Patents

Description

  The present invention relates to fine particles of a substance such as an organic compound, a method for producing fine particles, and a production apparatus.

  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 such a fine particle forming 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 by irradiating a laser beam is disclosed. Non-patent documents 1 to 3 also describe the formation of fine particles of an organic compound by laser light irradiation.
JP 2001-113159 A Y. Tamaki et al., "Tailoring nanoparticles of aromatic and dye molecules by excimer laser irradiation", Applied Surface Science Vol. 168, p.85-88 (2000) Y. Tamaki et al., "Nanoparticle Formation of Vanadyl Phthalocyanine by Laser Ablation of Its Crystalline Powder in a Poor Solvent", J. Phys. Chem. A 2002, 106, p.2135-2139 (2002) B. Li et al., "Enhancement of organic nanoparticle preparation by laser ablation in aqueous solution using surfactants", Applied Surface Science Vol. 210, p.171-176 (2003)

  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 materials field, and in the drug discovery field, ADME tests (absorption, distribution, metabolism, excretion tests) of drug candidates that are insoluble or insoluble due to micronization Etc. could be implemented.

  However, when performing the micronization process on the liquid to be processed in which the substance to be micronized and the solvent are mixed as described above, the light crushing action by the laser light irradiation is performed when the laser light is irradiated in the solvent. It occurs only in particles of material that have passed through a certain position. For this reason, in the method described above, the efficiency of atomization may become a problem when it is desired to perform the atomization process in a short time.

  The present invention has been made to solve the above-described problems, and provides a fine particle production method, a production apparatus, and fine particles capable of efficiently performing fine particle formation of a substance by laser light irradiation. Objective.

In order to achieve such an object, the method for producing fine particles according to the present invention is a production method for producing fine particles by photodisrupting a substance in a solvent of a liquid to be treated. And (2) a large particle capturing step for selectively capturing large particles to be micronized at a predetermined processing position among particles of a substance in a solvent. If, (3) by irradiation with light crushing laser beam with respect to the liquid to be treated processing position, the substance in the solvent and a laser beam irradiation step of fine particles, the large particles trapped step, processing position By irradiating the liquid to be treated with laser light for light capture having a wavelength of 900 nm or more, large particles are captured, and light is emitted before starting irradiation of the light crushing laser light in the laser light irradiation step. Laser for capture Stops the irradiation, it characterized that you resume the irradiation of the light trapping laser beam after finishing the irradiation of the light crushing laser beam.

  The fine particle production apparatus according to the present invention is a production apparatus for producing fine particles by photodisrupting a substance in a solvent of a liquid to be treated, and (a) a liquid to be treated in which the substance and the solvent are mixed. (B) selectively capturing large particles to be micronized at a predetermined processing position among particles of a substance in the solvent of the liquid to be processed stored in the storage unit; It is characterized by comprising a large particle capturing means and (c) a laser light source for irradiating a liquid to be processed at a processing position with a laser beam for light crushing to make a substance in a solvent into fine particles.

  According to the fine particle manufacturing method and apparatus described above, in the liquid to be processed containing the substance to be micronized, among the particles of the substance in the solvent, large particles exceeding a predetermined particle diameter are captured at the processing position. Then, the light crushing process by laser light irradiation is performed on the liquid to be processed at the processing position. As a result, the micronization process is selectively performed on large particles that are not sufficiently micronized. Therefore, it becomes possible to efficiently atomize the substance by laser light irradiation.

  Here, regarding the method for capturing large particles of a substance, the manufacturing method preferably captures the large particles by restricting the flow path of the liquid to be treated at the processing position in the large particle capturing step. Similarly, in the manufacturing apparatus, it is preferable that the large particle capturing means includes a flow path restricting means for restricting the flow path of the liquid to be processed in the storage means at the processing position. Examples of such flow path limiting means include a filter, a capillary, and a minute gap.

  Or it is preferable that a manufacturing method capture | acquires a large particle by irradiating the laser beam for light capture with respect to the to-be-processed liquid of a process position in a large particle capture | acquisition step. Similarly, in the manufacturing apparatus, it is preferable that the large particle capturing unit includes a light capturing laser light source that irradiates the processing target liquid with light capturing laser light.

  As described above, in the case of using light capture by laser light for capturing large particles, the manufacturing method uses light before starting irradiation of the light crushing laser light in the laser light irradiation step in the large particle capturing step. It is preferable that the irradiation of the capturing laser beam is stopped and the irradiation of the capturing laser beam is resumed after the irradiation of the light crushing laser beam is finished. The manufacturing apparatus preferably includes a control unit that controls the irradiation timing of the light crushing laser light by the laser light source and the irradiation timing of the light capturing laser light by the light capturing laser light source. By controlling the irradiation timing of the light crushing laser light and the light capturing laser light in this way, it is possible to irradiate the light crushing laser light in a state where the binding of the large particle group due to the laser light capturing is instantaneously released, The generated fine particles are easily separated from the large particle group. Thereby, the efficiency of the micronization process can be improved.

  In addition, the wavelength of the light capturing laser beam is preferably 900 nm or more. Thereby, generation | occurrence | production of a photochemical reaction can be prevented in substances, such as an organic compound, in the solvent of a to-be-processed liquid.

  Further, the manufacturing method may use interference fringes of laser light in the irradiation of the laser light for capturing light to the liquid to be processed at the processing position. Similarly, the manufacturing apparatus may include an interference optical system for using the interference fringes of the laser light in the irradiation of the light capturing laser light onto the liquid to be processed at the processing position.

  As described above, when the interference fringes are used, the optical system including the two optical slits is an interference optical system, and the interference fringes of the laser light are formed by the laser light passing through the two optical slits. There is a configuration using interference fringes. Alternatively, there is a configuration in which an optical system configured with two optical paths is an interference optical system, and interference fringes formed by laser light emitted from each of the two optical paths are used as the interference fringes of the laser light.

  Further, the substance to be finely divided may be an organic compound. Examples of organic compounds include drugs and the like in addition to organic pigments and aromatic condensed polycyclic compounds. In the case of a drug, the photochemical reaction in the drug due to laser light irradiation can be sufficiently prevented, and the fine particles can be produced without losing the drug efficacy. Moreover, the fine particle of the drug increases the surface area of the drug, and the drug fine particle can be obtained with improved absorbability to living tissue.

  The fine particles according to the present invention are fine particles produced by the above-described fine particle production method. According to such fine particles, fine particles of a substance that is efficiently manufactured and in a good state can be obtained.

  According to the present invention, among the particles of the substance in the solvent of the liquid to be treated, the large particles having a predetermined particle diameter are selectively captured, and the laser light for atomizing the captured large particles By performing irradiation, it becomes possible to efficiently atomize the substance.

  Hereinafter, preferred embodiments of a fine particle production method, production apparatus, and fine particles according to the present invention will be described 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 the apparatus for producing fine particles according to the present invention. The fine particle production apparatus 1A is an apparatus for producing fine particles by photo-crushing a substance in a solvent of a liquid to be treated. The liquid to be treated 2 is composed of a solvent 4 such as liquid phase water, and raw material particles 5 of a substance to be atomized contained in the solvent 4. In addition, it is preferable that the to-be-processed liquid 2 is made into low temperature from a viewpoint of improving the microparticulation effect | action and preventing the thermal deterioration by laser beam irradiation. In this case, although not shown in FIG. 1, it is good also as a structure further equipped with the cooling means for cooling the to-be-processed liquid 2. FIG.

  As shown in FIG. 1, the fine particle manufacturing apparatus 1 </ b> A includes a storage member 3 for storing a liquid 2 to be treated in which raw material particles 5 of a substance and a solvent 4 are mixed. In the present embodiment, the housing member 3 is connected to the circulation pump 40 via the flow paths 41 and 42 schematically shown in the figure, and the liquid 2 to be treated is connected together with the flow paths 41 and 42. It is a channel member which constitutes a circulation channel.

  The flow path restriction member 20 is installed at a predetermined position corresponding to the processing position 30 for performing the material micronization process on the flow path member 3. The flow path restriction member 20 restricts the flow path of the liquid 2 to be treated from the particles 6 of the substance in the solvent 4 of the liquid 2 to be treated flowing in the flow path member 3. This is a large particle capturing means for selectively capturing at the processing position 30. The restricting member 20 is configured to capture, as large particles 6, particles that exceed a predetermined particle size, which is a guide for atomization, due to the restricting configuration of the flow path. The large particles 6 to be captured include raw material particles 5 themselves and particles that are not sufficiently finely divided.

  Further, the manufacturing apparatus 1 </ b> A includes a high-power laser light source 10 that irradiates the liquid 2 to be processed stored in the flow path member 3 with a laser beam for light crushing with a predetermined wavelength. The laser light source 10 supplies laser light having a wavelength suitable for making large particles 6 such as raw material particles 5 of the substance in the solvent 4 of the liquid 2 to be processed into fine particles.

  As the laser light source 10, a fixed wavelength laser light source can be used when the wavelength to be set in the laser light is known in advance. Alternatively, a wavelength tunable laser light source may be used as the laser light source 10. In this case, laser light with an appropriate wavelength can be appropriately set and irradiated based on the light absorption characteristics of the substance or solvent. Moreover, you may provide optical intensity adjustment means, such as an attenuation | damping filter and an optical attenuator, with respect to the laser light source 10 as needed.

  The laser light source 10 is connected to a control device 15 composed of a computer or the like. The control device 15 controls the irradiation timing, irradiation intensity, and the like of the light crushing laser light from the laser light source 10. In the present embodiment, the control device 15 is also connected to the circulation pump 40 and the like. The control device 15 controls the production of fine particles in this device by controlling the operation of each part of the production device 1A.

  Next, a method for producing fine particles according to the present invention using the fine particle production apparatus 1A shown in FIG. 1 will be described.

  First, a solvent 4 such as water and raw material particles 5 of a substance to be microparticulated are mixed to prepare a liquid 2 to be treated, and includes a flow path member 3, flow paths 41 and 42, and a circulation pump 40. Then, the liquid 2 to be treated is introduced into the flow path that functions as the accommodating means (preparation step). At this time, the raw material particles 5 are contained in the solvent 4 in the state of a dissolved substance or an insoluble substance. Subsequently, the circulation pump 40 is operated so that the upstream flow path 41, the flow path member 3 in which the flow path restriction member 20 is installed, and the circulation flow path of the downstream flow path 42 are processed at a predetermined flow rate. Circulate liquid 2. At this time, among the particles of the substance in the solvent 4 of the liquid 2 to be processed that passes through the flow path restriction member 20, the large particles 6 such as the raw material particles 5 to be subjected to the fine particle treatment are processed by the restriction member 20. 30 is selectively captured (large particle capture step).

  Next, the laser light source 10 is controlled by the control device 15 in a state where the large particles 6 are captured at the processing position 30 as described above. Then, light crushing laser light having a wavelength set according to the light absorption characteristics of the substance to be atomized is applied from the laser light source 10 to the liquid to be processed 2 at the processing position 30 in the flow path member 3. Irradiate the treatment liquid 2. By this laser light irradiation, in the liquid 2 to be processed in the flow path member 3, the large particles 6 of the substance in the solvent 4 and captured by the restricting member 20 are atomized by the light crushing action, and the fine particles 7 are generated. (Laser beam irradiation step). When the generated fine particles 7 reach a predetermined particle size, they are released from the capturing state by the restricting member 20 and flow out to the downstream flow path 42. By performing such a step while circulating the liquid 2 to be processed by the circulation pump 40, the micronization process for the substance in the solvent 4 of the liquid 2 to be processed is performed.

  The effects of the fine particle production method and production apparatus according to the present embodiment will be described.

  According to the fine particle manufacturing apparatus 1A and the manufacturing method shown in FIG. 1, in the liquid 2 to be processed containing the substance to be atomized, large particles exceeding a predetermined particle size among the particles of the substance in the solvent 4 6 is captured at the processing position 30, and only fine particles can pass through the processing position 30. And the optical crushing process by irradiating the laser beam for optical crushing from the laser light source 10 with respect to the to-be-processed liquid 2 in the process position 30 is performed. Thereby, the micronization process is selectively performed on the large particles 6 that are not sufficiently micronized such as the raw material particles 5. Therefore, it becomes possible to efficiently atomize the substance by laser light irradiation.

  In the above configuration, the flow path member 3 is used as a storage member that stores the liquid 2 to be processed, and the large particles 6 are captured by the flow path restriction member 20. Thereby, the large particles 6 of the substance to be atomized can be suitably captured at the processing position 30. Further, by installing the circulation pump 40 and circulating the liquid 2 to be treated, efficient capture of the large particles 6 by the flow path restriction member 20 is realized.

  In FIG. 1, the flow path member 3 is shown as the storage means for storing the liquid 2 to be treated. However, the flow path member 3 is combined with the flow paths 41 and 42 to form one flow path member (accommodation). Member) or a combination of a plurality of flow path members. Further, the flow path restriction member 20 provided for the flow path member 3 may have a configuration in which a part or all of the flow path member 3 is used as the flow path restriction member 20 or a flow prepared as a separate member. The path restriction member 20 may be attached to the flow path member 3.

  Moreover, about the accommodation of the to-be-processed liquid 2, it is good also as a structure which does not circulate the to-be-processed liquid 2. FIG. In this case, the connection between the circulation pump 40 and the flow path 42 may be cut off, and the fine particles that have passed through the flow path restriction member 20 are considered to have completed the atomization process.

  Here, it is preferable to use a pulse laser light source as the laser light source 10. In particular, in order to perform micronization with sufficient efficiency while suppressing the occurrence of excessive photochemical reaction and thermal decomposition in the liquid 2 to be treated, if the light intensity threshold value causing the light fragmentation phenomenon is exceeded, 1 It is preferable to use a pulse laser light source having a low irradiation energy per pulse and a high repetition frequency.

  Further, the substance to be atomized by laser light irradiation may be an organic compound. Examples of the organic compound include organic pigments, aromatic condensed polycyclic compounds, drugs (drugs, pharmaceutical-related substances), and the like. In these cases, it is preferable that the wavelength of the light crushing laser light irradiated from the laser light source 10 to the liquid 2 to be processed is longer than the absorption band due to the electronic transition of the substance to be atomized. In particular, in the case of a substance that needs to avoid photodegradation (photochemical reaction), the wavelength is preferably in the infrared region, and more preferably 900 nm or more. Thereby, the fine particle formation of the substance by laser light irradiation can be suitably realized while reducing quality deterioration. In the case of a drug, the fine particles can be produced without losing the medicinal effect of the drug by efficiently performing the fine particle formation by the above method.

  In detail, organic compounds used as drugs often contain relatively weak chemical bonds in their molecular structure, but when such organic compounds are irradiated with light such as ultraviolet light, fine particles are partially generated. At the same time, some of the photochemical reaction of the organic compound may occur through the electronically excited state to generate impurities. In particular, in the case of a drug (medicine) in which an organic compound is administered into the body, such an impurity causes a side effect and may adversely affect the living body. Therefore, such a situation should be avoided as much as possible. On the other hand, the production of impurities can be sufficiently suppressed by producing fine particles of an organic compound by the production method described above that can improve the efficiency of the fine particle treatment and suppress the occurrence of a photochemical reaction. It becomes possible.

  In addition, as described above, by realizing the microparticulation of the drug while maintaining its medicinal properties without losing its medicinal effect, search for, and determination of candidate compounds such as physicochemical research and screening that could not be evaluated in the form before microparticulation , ADME test, general toxicity in animal preclinical test, general pharmacology, pharmacology, biochemical research, clinical test, etc. In addition, by the above-described production method, drugs that can be administered to a very wide variety of living bodies can be obtained. For this reason, the range of drug selection can be dramatically expanded. In addition, since the surface area of the drug is increased by making the drug fine particles and the absorbability to living tissue is improved, effective drug fine particles can be obtained in a small amount. Such a micronization treatment is also effective for organic compounds other than drugs.

  Specific examples of organic compounds to be microparticulated include poorly soluble or insoluble drugs such as clobetasone butyrate and carbamazepine which are drugs. Further, the above-described method and apparatus for producing fine particles can be applied to drug candidate substances (natural products, compound libraries, etc.), quasi-drugs, cosmetics and the like in addition to the drug substances.

  Further, as described above, water is preferably used as a solvent for organic compounds such as drugs, 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 can be suitably used as organic solvents for non-aqueous injections when used as injections.

  In the fine particle manufacturing apparatus 1A shown in FIG. 1, the laser beam intensity and time required for the micronization process in advance are used to stop laser light irradiation on the liquid 2 to be processed at the processing position 30 at the time of manufacturing the fine particles. Thus, it is possible to control the laser beam irradiation based on the processing time. Alternatively, monitoring means for monitoring the state of fine particles of the substance in the liquid 2 to be processed may be installed at the processing position 30 and controlled according to the monitoring result.

  Moreover, as the flow path restricting member 20 that captures the large particles 6 by restricting the flow path of the liquid 2 to be treated at the processing position 30, as shown in FIGS. Various configurations can be used.

  FIG. 2 is a view showing an example of a flow path restricting member used in the manufacturing apparatus shown in FIG. In the configuration shown in FIG. 2, a filter 21 that captures large particles 6 exceeding a predetermined particle size is installed as a flow channel limiting member in a flow channel member 3 that constitutes a part of the circulation flow channel using the circulation pump 40. is doing. At this time, the inside of the flow path member 3 is divided into a pre-treatment liquid chamber 31 on the upstream side of the filter 21 and a post-treatment liquid chamber 32 on the downstream side, and the position on the upstream side of the filter 21 is a large particle. 6 is the processing position 30 where it is captured. A light passage window 11 made of, for example, quartz is provided on the surface of the flow path member 3 facing the processing position 30 on the filter 21 on the upstream side.

  According to such a configuration, it is possible to selectively capture the large particles 6 of the substance to be atomized by the filter 21 and efficiently atomize the substance by laser light irradiation. As such a filter 21, a filter having high resistance to laser light irradiation, such as a filter made of a material such as glass wool, is used in order to receive irradiation of the laser beam for light fragmentation from the laser light source 10. Is preferred. Further, when the filter 21 has a certain degree of light transmittance, it is preferable to improve the efficiency of the micronization process because the light crushing process can be performed on the particles of the substance that has entered the filter 21.

  Further, in the configuration in which the filter is installed in the flow path of the liquid to be treated as described above, the configuration is such that a plurality of filters are installed so that the particle size of the substance that can be captured gradually decreases from the upstream side toward the downstream side. Also good. In this case, it is preferable to install a plurality of laser light sources so as to correspond to each of the plurality of stages of filters. According to such a configuration, the efficiency of atomization can be further improved.

  FIG. 3 is a view showing another example of the flow path limiting member used in the manufacturing apparatus shown in FIG. Here, a capillary member 23 shown in FIG. 3A is used as a flow path limiting member for the circulation flow path of the liquid 2 to be treated. The capillary member 23 is a capillary array in which a plurality of capillaries 22 having a conical or tapered inner space whose inner diameter decreases from the upstream side toward the downstream side are bundled. Alternatively, it is possible to use a single capillary as the flow path restricting member instead of the capillary array.

  In this configuration example, as shown in FIG. 3B, the capillary 22 described above is installed as a flow path limiting member at a predetermined position of the circulation flow path using the circulation pump 40. At this time, the large particles 6 exceeding a predetermined particle diameter are captured in the internal space of the capillary 22, and the laser light source 10 irradiates the large particles 6 with the laser light for light crushing. According to such a configuration, the large particles 6 of the substance can be selectively captured by the capillary 22, and the substance can be efficiently atomized by laser light irradiation.

  FIG. 4 is a view showing another example of the flow path limiting member used in the manufacturing apparatus shown in FIG. Here, the flow path restriction member 24 shown in FIG. 4A is used as the flow path restriction member for the circulation flow path of the liquid 2 to be treated. The flow path restricting member 24 includes two side plates 24a and a spacer 24b that integrally supports the side plates 24a so that the inner width decreases from the upstream side toward the downstream side.

  In this configuration example, as shown in FIG. 4B, the above-described flow path restriction member 24 is installed as a flow path restriction member at a predetermined position of the circulation flow path using the circulation pump 40. At this time, large particles 6 exceeding a predetermined particle diameter are captured in a minute gap sandwiched between the side plates 24a of the flow path restriction member 24, and the laser light source 10 irradiates the large particles 6 with laser light for light crushing. Is done. According to such a configuration, the large particles 6 of the substance can be selectively captured by the flow path restriction member 24, and the substance can be efficiently atomized by laser light irradiation. In such a configuration, the non-parallelism of the side plate 24a in the flow path restriction member 24 is determined by the shape of the spacer 24b.

  As shown in FIGS. 2 to 4 above, as the flow path restricting member 20 in the configuration shown in FIG. 1, various configurations such as a configuration using a filter, a capillary, and a minute gap can be used. is there.

  FIG. 5 is a block diagram schematically showing a second embodiment of the apparatus for producing fine particles according to the present invention. In this manufacturing apparatus 1B, a circulation pump 40 connected to the flow path member 3 via the flow path member 3, the flow paths 41, 42 containing the liquid 2 to be treated in which the raw material particles 5 of the substance and the solvent 4 are mixed, The configuration of the laser light source 10 that irradiates the liquid 2 to be processed with the light crushing laser light is the same as that shown in FIG.

  In the present embodiment, a light capturing laser light source 25 for irradiating the processing target liquid 2 at the processing position 30 for performing the fine particle processing of the substance with respect to the flow path member 3 is installed. Has been. The light capturing laser light source 25 irradiates the large particle 6 to be atomized with the light capturing laser light among the particles of the substance in the solvent 4 of the liquid 2 to be processed flowing in the flow path member 3. This is a large particle capturing means that selectively captures light at the processing position 30. The laser light source 25 is configured to capture particles larger than a predetermined particle size, which is a guide for atomization, as large particles 6 according to the laser light power, the laser spot shape, and the like.

  In the configuration shown in FIG. 5, the light crushing laser light source 10 and the light capturing laser light source 25 are arranged at positions where the flow path member 3 is sandwiched so that both have the same optical axis. Further, light passage windows 36 and 37 made of, for example, quartz are provided on the surface of the flow path member 3 facing the laser light sources 10 and 25, respectively. Although not shown in FIG. 5, in this apparatus 1 </ b> B, in the vicinity of the processing position 30 so that the irradiation laser light from the light crushing laser light source 10 does not damage the facing light capturing laser light source 25. It is preferable to provide an optical system for forming a focal point.

  The light crushing laser light source 10 and the light capturing laser light source 25 are connected to a control device 15 including a computer. The control device 15 controls the irradiation timing of the light crushing laser light from the laser light source 10 and the irradiation timing of the light capturing laser light from the laser light source 25. In the present embodiment, the control device 15 is also connected to the circulation pump 40 and the like. The control device 15 controls the production of the fine particles in this device by controlling the operation of each part of the production device 1B described above.

  Next, a method for producing fine particles according to the present invention using the fine particle production apparatus 1B shown in FIG. 5 will be described.

  First, the liquid 2 to be processed in which the solvent 4 and the raw material particles 5 of the substance are mixed is prepared, and the liquid 2 to be processed is introduced into the flow path (preparation step). Subsequently, the circulation pump 40 is operated to circulate the liquid 2 to be treated at a predetermined flow rate in the circulation channels 41, the channel member 3, and the channel 42. Further, the laser light for light capture is irradiated from the laser light source 25 through the light passage window 37 to the liquid 2 to be processed at the processing position 30 in the flow path member 3. At this time, among the particles of the substance in the solvent 4 of the liquid 2 to be processed that passes through the flow path member 3, large particles 6 such as the raw material particles 5 are selectively collected near the optical axis of the light capturing laser beam. And light trapped (large particle trapping step).

  Next, the laser light source 10 is controlled by the control device 15 in a state where the large particles 6 are captured at the processing position 30 as described above. Then, with respect to the liquid 2 to be processed at the processing position 30 in the flow path member 3, light crushing laser light having a predetermined wavelength is transmitted from the laser light source 10 to the liquid 2 to be processed through the light passage window 36. Irradiated by the same optical axis as the capturing laser beam. By this laser light irradiation, in the liquid 2 to be processed in the flow path member 3, the large particles 6 of the substance that are in the solvent 4 and are light-captured on the optical axis by the light-capturing laser light are atomized by the light crushing action. Then, the fine particles 7 are generated (laser light irradiation step). When the generated fine particle 7 reaches a predetermined particle size, it exits the light capturing state by the light capturing laser beam and flows out to the flow path 42 on the downstream side. By performing such a step while circulating the liquid 2 to be processed by the circulation pump 40, the micronization process for the substance in the solvent 4 of the liquid 2 to be processed is performed.

  The effects of the fine particle production method and production apparatus according to the present embodiment will be described.

  According to the fine particle production apparatus 1B and the production method shown in FIG. 5, among the particles of the substance in the solvent 4 of the liquid 2 to be treated, the large particles 6 exceeding a predetermined particle size are captured at the treatment position 30. The light crushing process is performed by irradiating the processing target liquid 2 at the processing position 30 with the light crushing laser beam. As a result, the large particles 6 are selectively subjected to the fine particle treatment, and the material fine particles can be efficiently formed by laser light irradiation.

  In the above configuration, the large particles 6 are captured by light capture using laser light emitted from the light capturing laser light source 25. Thereby, the large particles 6 of the substance to be atomized can be suitably captured at the processing position 30. Further, in such a configuration, the wavelength of the light capturing laser light irradiated from the laser light source 25 to the liquid to be treated 2 is to avoid the occurrence of a photochemical reaction and the deterioration of the substance (for example, deterioration of drug quality). Similarly to the laser beam for photodisruption, the wavelength is preferably 900 nm or more.

  Regarding the control conditions of the irradiation timing of the laser light at the laser light sources 10 and 25 by the control device 15, in the capture of the large particles 6 by irradiating the light capturing laser light, the light crushing laser light from the laser light source 10 is captured. It is preferable to stop the irradiation of the light capturing laser beam from the laser light source 25 before starting the irradiation, and restart the irradiation of the light capturing laser beam after the irradiation of the light crushing laser beam is finished. Thus, by stopping the light capture while the laser light for light crushing is irradiated on the liquid 2 to be processed, the generated fine particles 7 in which the large particles 6 are photocrushed at the processing position 30 are efficiently separated. In addition, the efficiency of atomization can be improved.

  Here, the capture conditions (light capture force) such as the particle size of the large particles 6 captured by the laser light from the light capture laser light source 25 are the wavelength of the light capture laser light, the refractive index of the substance particles and the solvent. Depends greatly on the diameter of the substance particles to be captured, the intensity of the irradiated laser beam, the numerical aperture (squeezing angle) of the laser beam for capturing light, the spot diameter, and the like. For example, the wavelength is 1064 nm, the solvent is water (n = 1.33), the substance to be captured is a drug (n = 1.6), the numerical aperture is 0.35 (10 times the objective lens), and the irradiation laser light intensity is 2.8 mW. In addition, it is possible to perform three-dimensional light capture under the condition that the spot diameter is 1.4 μm and the diameter of the particles to be captured is 10 μm.

  In addition, various configurations may be used as a specific irradiation configuration of the light capturing laser beam to the liquid 2 to be processed. For example, from the viewpoint of forming a plurality of light capturing spots on the liquid 2 to be processed, light capturing laser light may be irradiated using interference fringes of laser light. In this case, an interference optical system for forming interference fringes of laser light is used. As a configuration example of such an interference optical system, as schematically shown in FIG. 6, interference fringes formed by laser light from a light capturing laser light source 25 that has passed through each of two optical slits 51 a and 51 b. There is a configuration using 52. Alternatively, as schematically shown in FIG. 7, there is a configuration in which interference fringes 54 formed by laser light from the light-capturing laser light sources 25a and 25b irradiated on the two optical paths 53a and 53b are used.

  The fine particle production method, production apparatus, and fine particles according to the present invention are not limited to the above-described embodiments and examples, and various modifications are possible. For example, as a capturing means for capturing large particles of a substance at a processing position, other means capable of capturing large particles may be used in addition to the above-described filter, capillary, minute gap, and laser light source for capturing light.

  INDUSTRIAL APPLICABILITY The present invention can be used as a fine particle manufacturing method, a manufacturing apparatus, and a fine particle capable of efficiently performing fine particle formation by laser light irradiation.

It is a block diagram which shows schematically 1st Embodiment of the manufacturing apparatus of microparticles | fine-particles. It is a figure which shows an example of the flow-path restriction member used for the manufacturing apparatus shown in FIG. It is a figure which shows the other example of the flow-path restriction member used for the manufacturing apparatus shown in FIG. It is a figure which shows the other example of the flow-path restriction member used for the manufacturing apparatus shown in FIG. It is a block diagram which shows schematically 2nd Embodiment of the manufacturing apparatus of microparticles | fine-particles. It is a figure which shows the structural example of the interference optical system used for irradiation of the laser beam for light capture. It is a figure which shows the structural example of the interference optical system used for irradiation of the laser beam for light capture.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 1A, 1B ... Manufacturing apparatus of microparticles | fine-particles, 2 ... Liquid to be processed, 3 ... Flow path member (accommodating member), 4 ... Solvent, 5 ... Raw material particles of substance, 6 ... Large particles, 7 ... Fine particles, 10 ... For light crushing Laser light source, 11 ... light passage window, 15 ... control device, 20 ... channel restriction member, 21 ... filter, 22 ... capillary, 23 ... capillary member, 24 ... channel restriction member, 25 ... laser light source for light capture, 30 ... processing position, 31 ... pre-treatment liquid chamber, 32 ... post-treatment liquid chamber, 36, 37 ... light passage window, 40 ... circulation pump, 41, 42 ... flow path.

Claims (4)

A method for producing fine particles by photocrushing a substance in a solvent of a liquid to be treated,
A preparation step of preparing a liquid to be treated in which a substance and a solvent are mixed;
Among the particles of the substance in the solvent, a large particle capturing step for selectively capturing large particles to be micronized at a predetermined processing position;
A laser beam irradiation step of pulverizing the substance in the solvent by irradiating the processing liquid at the processing position with a laser beam for photodisruption ,
In the large particle capturing step, the large particle is captured by irradiating the liquid to be treated at the processing position with a light capturing laser beam having a wavelength of 900 nm or more,
Before starting the irradiation of the light crushing laser light in the laser light irradiation step, the irradiation of the light capturing laser light is stopped, and after the irradiation of the light crushing laser light is finished, the light capturing laser the method of manufacturing fine particles, characterized that you resume the irradiation of the light. In the irradiation of the light trapping laser beam with respect to the liquid to be treated in the processing position, method according to claim 1, wherein utilizing the interference fringes of the laser beam. The manufacturing method according to claim 2 , wherein an interference fringe formed by the laser light that has passed through each of the two optical slits is used as the interference fringe of the laser light. 3. The manufacturing method according to claim 2 , wherein an interference fringe formed by laser light emitted from each of two optical paths is used as the interference fringe of the laser light.

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