JP4593144B2 - Method and apparatus for determining atomization conditions, and method and apparatus for producing fine particles - Google Patents

Description

  The present invention relates to a method and apparatus for determining the conditions for atomization when a substance such as an organic compound is atomized, and a method and apparatus for producing fine particles using the same.

  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, it is difficult to determine the presence or absence of actual micronization by laser light irradiation in a method of performing micronization processing by light crushing on a liquid to be processed in which a substance to be micronized and a solvent are mixed. For this reason, there exists a problem that it cannot be judged easily whether the irradiation conditions of the laser beam with respect to a to-be-processed liquid are set suitably.

  For example, when a microparticulation process is performed by irradiating a laser beam under a certain irradiation condition, the presence or absence of microparticulation actually occurring in the liquid to be treated at that time is determined by the degree of coloring of the solvent accompanying the microparticulation or the electron Judgment is possible by the measurement result of the particle size by a microscopic image (SEM). However, in any of these methods, the presence or absence of atomization can be determined only after the atomization process has been performed to some extent.

  The present invention has been made to solve the above-described problems, and it is possible to appropriately control the laser light irradiation conditions for the liquid to be processed by determining the presence or absence of atomization by laser light irradiation. It is an object of the present invention to provide a method and apparatus for determining the atomization conditions, and a method and apparatus for manufacturing particles using the same.

  The inventor of the present application investigated a wide variety of substances with respect to the above-described laser light irradiation conditions and the presence or absence of fine particle formation by laser light irradiation. As a result, it was found that the optimum laser light irradiation conditions differ greatly depending on the substance to be atomized. This indicates that it is necessary to optimize the irradiation condition of the laser beam by some method when executing the processing in order to realize the rapid micronization processing for each substance.

  Furthermore, the inventor of the present application examined a method for optimizing the laser light irradiation conditions based on the above findings. As a result, in the micronization process performed by irradiating the raw material particles of the substance with laser light, it was found that light emission occurs under irradiation conditions that enable micronization, and the present invention has been achieved.

That is, the method for determining the micronization conditions according to the present invention is as follows. (1) The liquid in the solvent is micronized by irradiating the liquid to be treated containing the substance to be micronized in the solvent with a laser beam of a predetermined wavelength. And a luminescence measurement step for measuring luminescence accompanying the atomization generated under irradiation conditions capable of atomization, and (2) pulverization in the liquid to be processed obtained from the luminescence measurement result in the luminescence measurement step. And a condition determining step for determining the irradiation condition of the laser beam on the liquid to be treated based on the light emission characteristics reflecting the situation, and the light emission measured in the light emission measuring step is in the irradiation condition capable of micronization, particulates from the raw material particles of a substance in a liquid solvent and wherein the light emitting der Rukoto by cavitation of the solvent when it is released.

The apparatus for determining atomization conditions according to the present invention includes (a) a processing chamber for storing a processing liquid containing a substance to be atomized in a solvent, and (b) a processing liquid stored in the processing chamber. On the other hand, a luminescence measuring means for measuring luminescence accompanying the atomization that occurs when irradiation with a laser beam having a predetermined wavelength for atomizing a substance in a solvent and that occurs under irradiation conditions capable of atomization; c) Condition determining means for determining the irradiation condition of the laser light on the liquid to be processed based on the light emission characteristics that are obtained from the measurement result of the light emission by the light emission measuring means and reflect the state of the fine particles in the liquid to be processed. the provided, luminescence is measured in the luminescence measuring device, the irradiation conditions can be micronized, Ru emission der cavitation of the solvent when the fine particles from the raw material particles of a substance in a liquid solvent is released And wherein the door.

  According to the above-described method and apparatus for determining the atomization conditions, when laser light is irradiated to the liquid to be processed containing the substance to be atomized, the luminescence generated with the atomization is measured in the liquid to be processed. The laser light irradiation conditions are determined with reference to the light emission characteristics. In this way, by performing emission measurement when executing the micronization process, it is possible to determine the micronization status such as the presence or absence of micronization by laser light irradiation and the processing speed during the process. Then, by determining the irradiation condition of the laser beam based on the light emission characteristics reflecting the micronization state in the processing liquid, the irradiation condition is optimized so as to increase the processing speed. It becomes possible to control the laser light irradiation conditions quickly and reliably. In particular, in the method using luminescence measurement, it is possible to easily determine the state of atomization and determine the laser light irradiation conditions.

  Here, in the method for determining the atomization condition, it is preferable to obtain a characteristic regarding the emission intensity as the emission characteristic in the condition determining step. Similarly, in the determining apparatus, it is preferable that the condition determining unit obtains a characteristic regarding the emission intensity as the emission characteristic.

  As a specific method for determining the irradiation condition in this case, in the condition determining step, the relationship between the emission intensity and the laser beam irradiation time is obtained as the light emission characteristic, and the laser beam irradiation time as the irradiation condition is determined from the obtained relationship. Can be used.

  In the light emission measurement step, the laser light wavelength is changed and the light emission is measured a plurality of times. In the condition determination step, the relationship between the light emission intensity and the laser light wavelength is obtained as the light emission characteristics, and the irradiation is performed from the obtained relationship. A method of determining the laser beam wavelength as a condition can be used.

  In the light emission measurement step, the laser light intensity is changed and the light emission is measured multiple times. In the condition determination step, the relationship between the light emission intensity and the laser light intensity is obtained as the light emission characteristic, and the irradiation is performed from the obtained relationship. A method of determining the laser beam intensity as a condition can be used.

  Alternatively, in the light emission measurement step, the laser light pulse waveform is changed and the light emission is measured a plurality of times, and in the condition determination step, the relationship between the light emission intensity and the laser light waveform is obtained as the light emission characteristics, and from the obtained relationship A method of determining the laser beam waveform as the irradiation condition may be used. As conditions for the laser beam waveform in this case, for example, there are waveform conditions such as the rise time, fall time, and pulse width of the pulse waveform of the laser beam.

  In the method for determining the atomization condition, it is preferable to obtain a characteristic regarding the light emission timing as the light emission characteristic in the condition determining step. Similarly, in the determination apparatus, it is preferable that the condition determination unit obtains a characteristic regarding the light emission timing as the light emission characteristic.

  As a specific method for determining the irradiation condition in this case, in the condition determining step, the light emission start timing with respect to the laser light irradiation timing is obtained as the light emission characteristic, and the pulse of the laser light necessary for atomization is obtained from the obtained start timing. A method of calculating the lower limit value of the width and determining the laser light pulse width as the irradiation condition with reference to the lower limit value can be used.

  Further, in the condition determining step, the light emission end timing with respect to the laser light irradiation timing is obtained as the light emission characteristics, the upper limit value of the pulse width of the laser light necessary for micronization is calculated from the obtained end timing, and the upper limit value is set. A method of determining a laser beam pulse width as an irradiation condition can be used as a reference.

  In general, as the laser light irradiation condition determined based on the measured emission characteristics, at least one of a laser light irradiation time, a laser light wavelength, a laser light intensity, and a laser light waveform is determined. preferable. Alternatively, irradiation conditions other than these may be determined.

  In addition, the method for determining the atomization conditions is to measure the emission spectrum in the emission measurement step, and to separate the emission associated with atomization and the emission of the particle itself in the condition determination step with reference to the emission spectrum. Is preferred. Similarly, in the determination apparatus, it is preferable that the light emission measuring unit measures the light emission spectrum, and the condition determining unit refers to the light emission spectrum and separates the light emission accompanying the atomization and the light emission of the fine particle itself. According to such a configuration, it is possible to suitably determine the laser light irradiation condition based on the light emission characteristics.

  Further, the determination apparatus may include an irradiation light measurement unit that performs measurement on the laser light irradiated to the liquid to be processed. Thereby, the light emission characteristics can be suitably obtained with reference to the measurement result of laser light and the measurement result of light emission.

  The method for producing fine particles according to the present invention is a production method for producing fine particles by photocrushing a substance in a solvent of a liquid to be treated, and includes the method for determining the fine particle formation condition described above, wherein the substance and the solvent are mixed. Laser light for atomizing a substance in the solvent by irradiating the liquid to be treated with laser light based on the preparation step for preparing the liquid to be treated and the irradiation conditions determined in the condition determining step An irradiation step.

  A fine particle production apparatus according to the present invention is a production apparatus for producing fine particles by photo-disrupting a substance in a solvent of a liquid to be treated. On the other hand, a laser light source that irradiates a laser beam for atomizing a substance in a solvent, and a control unit that controls the irradiation condition of the laser beam by the laser light source based on the irradiation condition determined by the condition determining unit; It is characterized by providing.

  According to the fine particle manufacturing method and apparatus described above, the micronization process is executed with reference to the irradiation condition of the laser beam determined based on the light emission characteristics reflecting the micronization state in the liquid to be processed. . Thereby, it is possible to suitably execute the atomization process by laser light irradiation on the material to be atomized included in the liquid to be processed.

  According to the present invention, the emission measurement is performed when the atomization process is performed, and the irradiation condition of the laser beam is determined based on the emission characteristics reflecting the state of atomization in the liquid to be processed. It becomes possible to quickly and reliably control the irradiation condition of the laser beam to the treatment liquid.

  DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of a fine particle formation condition determining method, a determining apparatus, a fine particle manufacturing method, and a manufacturing apparatus according to the present invention will be described below 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 an embodiment of a device for determining the atomization conditions according to the present invention and a device for producing fine particles using the device. 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.

  The fine particle manufacturing apparatus 1A includes a determination apparatus 10 that determines a fine particle condition for performing a fine particle process by light crushing on a raw material particle 5 of a substance in a solvent 4, and a laser light source that supplies laser light having a predetermined wavelength. 20 and a control device 25 for controlling the micronization process.

  First, the configuration of the atomization condition determining apparatus 10 will be described. As shown in FIG. 1, the determination apparatus 10 includes a processing chamber 3 for storing the liquid 2 to be processed. The processing chamber 3 is made of, for example, a material such as quartz through which a laser beam for atomization processing or light emitted from the liquid to be processed 2 described later is transmitted. In addition, with respect to the processing chamber 3 and the liquid 2 to be processed, a magnetic stick and a magnetic stirrer for dispersing the raw material particles 5 in the solvent 4 by stirring the liquid 2 to be processed, and the processing chamber 3 at a predetermined temperature. You may install the thermostat etc. to hold | maintain.

  In the determination method of the atomization conditions by the determination apparatus 10, first, a laser beam having a predetermined wavelength used for light crushing is applied to the liquid 2 to be processed that contains the raw material particles 5 of the substance to be atomized in the solvent 4. Then, the substance in the solvent 4 is atomized. At the same time, the luminescence generated in the liquid 2 to be treated as the particles are made is measured. And based on the light emission characteristic calculated | required from the measurement result of this light emission, the irradiation conditions of the laser beam with respect to the to-be-processed liquid 2 are determined. As described above, such a method for determining the atomization condition is based on the light emission phenomenon associated with the atomization treatment by laser light irradiation found by the present inventors.

  In the configuration shown in FIG. 1, a luminescence measuring device 11 is installed at a predetermined position with respect to a processing chamber 3 in which a processing target liquid 2 to be irradiated with laser light is stored. The luminescence measuring device 11 is for measuring light emitted from the processing chamber 3 and, in particular, for measuring luminescence accompanying micronization that occurs when the processing target liquid 2 is irradiated with laser light for light crushing. is there.

  A half mirror 13 is disposed between the processing chamber 3 and the light emission measuring device 11 as light branching means. Further, an irradiation light measuring device 12 for monitoring the light irradiated to the liquid 2 to be processed is installed at a position where the light from the processing chamber 3 branched by the half mirror 13 enters. This irradiation light measuring device 12 detects the light component reflected and scattered by the processing liquid 2 or the processing chamber 3 out of the laser light for light crushing irradiated to the processing liquid 2, so that the processing liquid 2 is monitored.

  The measurement signal from the luminescence measurement device 11 and the measurement signal from the irradiation light measurement device 12 are input to the analysis device 15. The analysis device 15 is a condition determination unit that determines the irradiation condition of the laser light to the liquid 2 to be processed based on the light emission characteristics obtained from the light emission measurement result by the light emission measurement device 11.

  Specifically, the analysis device 15 acquires information about the light emission from the liquid to be treated 2 based on the measurement signal from the light emission measurement device 11. Further, the analysis device 15 acquires information about the laser light irradiated on the liquid 2 to be processed by the measurement signal from the irradiation light measurement device 12. And from the measurement result which these information shows, the light emission characteristic of the light emission which has arisen in the to-be-processed liquid 2 with micronization is calculated | required. The light emission characteristics required here reflect the state of micronization in the liquid 2 to be treated, such as the presence or absence of micronization by laser light irradiation and the processing speed. The analysis device 15 refers to the light emission characteristics and determines the irradiation condition of the laser light to the liquid 2 to be processed in consideration of the processing conditions such as a desired processing speed.

  Next, the structure of the fine particle manufacturing apparatus 1A having the fine particle formation condition determining apparatus 10 having the above structure will be described.

  In addition to the determining device 10, the manufacturing apparatus 1 </ b> A includes a high-power laser light source 20 that irradiates the processing target liquid 2 accommodated in the processing chamber 3 with laser light for light fragmentation with a predetermined wavelength. The laser light source 20 supplies a laser beam having a wavelength suitable for making the 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 20, 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 tunable laser light source may be used as the laser light source 20. In this case, laser light having an appropriate wavelength can be set appropriately and irradiated based on the light absorption characteristics of the substance. 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 20 as needed.

  In particular, in the configuration for determining the irradiation condition of the laser beam for photodisruption in the determination device 10 as shown in FIG. 1, it is preferable to use a laser light source that can easily adjust the laser beam intensity. When adjustment is necessary, it is preferable to use a wavelength tunable laser light source. Alternatively, a laser light source group including a plurality of wavelength-fixed laser light sources having different laser light wavelengths may be used. Such a configuration is useful in that the determination apparatus 10 can determine the laser beam intensity dependency and laser beam wavelength dependency of micronization even when determining suitable irradiation conditions of the laser beam.

  The laser light source 20 and the analysis device 15 of the determination device 10 are connected to a control device 25 including a computer. The control device 25 controls the production of fine particles by controlling the operation of each part of the production device 1A including the determination device 10 described above. In particular, in the present embodiment, the control device 25 actually irradiates the liquid 2 to be processed by the laser light source 20 based on the suitable irradiation condition of the laser light determined by the analysis device 15 that is the condition determining means. Control the laser light irradiation conditions. Although specific laser light irradiation conditions controlled by the control device 25 depend on the configuration of the laser light source 20, conditions such as the intensity of laser light to be irradiated and the laser light wavelength are controlled.

  A display device 26 is connected to the control device 25. The control device 25 displays on the display device 26 a screen necessary for determining the atomization conditions by the determination device 10 or a screen relating to the atomization processing in the manufacturing apparatus 1A.

  Next, a method for determining the atomization conditions and 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, water 4 as a solvent and raw material particles 5 of a substance to be atomized are mixed to prepare the liquid 2 to be processed, and the liquid 2 to be processed is introduced into the processing chamber 3 (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. Next, the laser light source 20 is controlled by the control device 25, and the laser light for light crushing having a predetermined wavelength is irradiated from the laser light source 20 to the liquid 2 to be processed. By this laser light irradiation, the raw material particles 5 in the solvent 4 are atomized in the liquid 2 to be processed in the processing chamber 3 (laser light irradiation step).

  On the other hand, the luminescence measuring device 11 measures the luminescence from the liquid 2 to be treated as it is atomized by laser light irradiation (luminescence measurement step). Further, the irradiation light measuring device 12 monitors the laser light applied to the liquid 2 to be processed. The analysis device 15 obtains a light emission characteristic from the light emission measurement result by the light emission measurement device 11, and determines a suitable irradiation condition of the laser beam based on the light emission characteristic (condition determination step). And the control apparatus 25 controls the irradiation conditions of the laser beam to the to-be-processed liquid 2 by the laser light source 20 based on the irradiation conditions determined by the analysis apparatus 15. FIG. Thereby, in the liquid 2 to be processed, the raw material particles 5 of the substance in the solvent 4 are subjected to a micronization process under a desired condition (laser light irradiation step).

  The effects of the method and apparatus for determining the atomization conditions, the method for manufacturing particles, and the apparatus for manufacturing according to the present embodiment will be described.

  According to the apparatus and method for determining the atomization conditions shown in FIG. 1, when the liquid 2 to be processed including the raw material particles 5 of the substance to be atomized is irradiated with laser light, The light emission generated with the fine particles is measured, and the laser light irradiation conditions are determined with reference to the light emission characteristics. In this way, by performing luminescence measurement using the luminescence measuring device 11 when performing the pulverization process, the state of pulverization such as the presence or absence of pulverization by the laser light irradiation and the processing speed is determined during the execution of the process. be able to.

  Then, the irradiation condition of the laser beam is determined by the analyzer 15 based on the light emission characteristics reflecting the state of atomization in the liquid 2 to be processed, so that the irradiation condition is optimized so as to increase the processing speed. It becomes possible to quickly and surely control the irradiation condition of the laser light to the liquid 2 to be processed by the laser light source 20. In particular, in the above method using luminescence measurement by the luminescence measuring device 11, the determination of the state of fine particles and the determination of the irradiation condition of the laser beam can be executed easily and in real time.

  Further, according to the fine particle production apparatus 1A and the production method using the fine particle condition determination device 10 and the determination method, the determination is based on the light emission characteristics reflecting the state of fine particle formation in the liquid 2 to be processed. By performing the atomization process with reference to the irradiation condition of the laser beam, the atomization process by the laser beam irradiation is suitably performed on the raw material particles 5 of the substance to be atomized contained in the liquid 2 to be processed. It becomes possible to execute. In addition, the light emission phenomenon which arises with micronization is specifically mentioned later.

  Here, regarding the light emission characteristics obtained in the analysis device 15 and used for determining the irradiation condition of the laser light, specifically, it is preferable to obtain the characteristics regarding the light emission intensity. Or it is preferable to obtain | require the characteristic regarding light emission timing. Further, a time waveform of light emission due to a change in light emission intensity with time may be obtained. By referring to these light emission characteristics, the state of fine particles in the liquid to be treated 2 can be suitably evaluated.

  In this case, as the luminescence measuring device 11, it is preferable to select and use a device capable of measuring a necessary luminescence parameter according to the luminescence characteristics used in the analysis device 15 for evaluating the micronization state. Examples of the light emission parameter measured by the light emission measuring device 11 include light emission intensity, light emission timing, time waveform due to time change of light emission, and the like.

  Moreover, when calculating | requiring the characteristic about light emission wavelength as a light emission characteristic, it is preferable to use what can measure a light emission wavelength as the light emission measuring device 11. FIG. As such a configuration, there is a configuration in which only a light emitting component in a specific wavelength band is measured by installing a wavelength filter. Alternatively, a device capable of measuring an emission spectrum may be used as the light emission measuring device 11. This makes it possible to evaluate various characteristics of light emission associated with micronization.

  Further, in the configuration in which the emission spectrum is measured in the luminescence measuring device 11, it is possible to separate the luminescence accompanying the atomization and the luminescence of the fine particles themselves with reference to the measured emission spectrum in the analysis device 15. . Thereby, the light emission phenomenon accompanying microparticulation can be selectively measured, and the microparticulation state can be more accurately evaluated. For example, if the material of the raw material particles 5 to be micronized originally emits light, an emission spectrum is obtained in advance in a state where no light emission due to micronization has occurred, and the emission spectrum is used for micronization. It is preferable to selectively separate the accompanying luminescence.

  As a specific configuration of the luminescence measuring apparatus 11 in such a case, for example, a spectrum analyzer using a photodetector used for measuring luminescence intensity, luminescence timing, etc., and a multi-detector used for measuring luminescence spectrum. A combination of these can be used. Also, other configurations may be used.

  Further, the irradiation light measuring device 12 for monitoring the laser light irradiated from the laser light source 20 to the liquid 2 to be processed has a certain sensitivity to the wavelength of the irradiated laser light, and the laser light irradiation. It is preferable to use a photodetector that can measure the timing and the time waveform due to the time change of the laser beam.

  Further, it is preferable to determine at least one of the laser beam irradiation time, the laser beam wavelength, the laser beam intensity, and the laser beam waveform as the laser beam irradiation condition determined by the analyzer 15 as the condition determining unit. It is also possible to control the irradiation conditions by other parameters.

  In addition, about the substance of the raw material particle | grains 5 used as the object of atomization by laser beam irradiation, various substances are good. Examples of such substances include organic compounds. Examples of the organic compound include organic pigments, aromatic condensed polycyclic compounds, drugs (drugs, pharmaceutical-related substances), and the like. In the case of a drug, the photochemical reaction in the drug due to laser light irradiation can be sufficiently prevented by appropriately setting the irradiation condition of the laser light and efficiently performing fine particle formation. Therefore, the fine particles can be produced without losing the drug efficacy. For the photochemical reaction, the wavelength of the laser light irradiated to the liquid 2 to be treated is suitably selected (for example, an infrared wavelength that can avoid photodegradation due to the photochemical reaction, or a wavelength of 900 nm or more). By doing so, it is possible to further suppress the occurrence of a photochemical reaction.

  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 above-described production method capable of efficiently performing the fine particle treatment and suppressing 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. In addition to the above pharmaceutical substances, the method and apparatus for determining the microparticulation conditions described above and the method and apparatus for producing fine particles can be used for drug candidate substances (natural products, compound libraries, etc.), quasi drugs, cosmetics, etc. Is also applicable.

  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.

  The determination of the emission characteristics used for the evaluation of the state of atomization in the liquid 2 to be processed and the irradiation conditions of the laser light will be described more specifically. In the following, the description will be given focusing on the measurement of the light emission characteristics and the determination of the irradiation condition of the laser beam, but in general, such a measurement / determination operation is performed as a pre-stage of the micronization process. Alternatively, it may be performed together with the fine particle treatment.

  First, a method using the relationship between the emission intensity and the laser beam wavelength as the emission characteristic will be described. FIG. 2 is a graph showing the relationship between the emission intensity and the laser beam wavelength. In this case, the wavelength range of the laser beam to be measured is limited, and the laser beam intensity at which light emission associated with the atomization is obtained in the wavelength range is set. Next, while the light intensity is fixed by the control device 25, only the laser light wavelength is changed, and the laser light is irradiated from the laser light source 20 to the liquid 2 to be processed. Then, the change in the emission intensity with respect to the wavelength is measured by the light emission measuring device 11 and the analysis device 15, and the measurement result illustrated in the graph of FIG. 2 is acquired as the light emission characteristic. By referring to such light emission characteristics, it is possible to suitably determine the laser light wavelength as the laser light irradiation condition for the liquid 2 to be treated.

  Next, a method using the relationship between the emission intensity and the laser beam intensity as the emission characteristics will be described. FIG. 3 is a graph showing the relationship between the emission intensity and the laser beam intensity. In this case, the laser beam wavelength to be measured is set. Next, while the wavelength is fixed by the control device 25, only the laser light intensity is changed, and the laser light is irradiated from the laser light source 20 to the liquid 2 to be processed. And the change of the emitted light intensity with respect to light intensity is measured by the light emission measuring device 11 and the analyzer 15, and the measurement result illustrated in the graph of FIG. 3 is acquired as a light emission characteristic. By referring to such light emission characteristics, it is possible to suitably determine the laser light intensity as the irradiation condition of the laser light to the liquid 2 to be processed.

  Next, a method using the relationship between the emission intensity and the laser beam waveform as the emission characteristics will be described. In this case, the laser light wavelength and light intensity to be measured are set. Next, while the wavelength and light intensity are fixed by the control device 25, only the pulse waveform of the pulse laser light is changed, and the laser light is irradiated from the laser light source 20 to the liquid 2 to be processed. And the change of the emitted light intensity with respect to an optical waveform is measured by the light emission measuring device 11 and the analyzer 15, and a measurement result is acquired as a light emission characteristic. By referring to such light emission characteristics, it is possible to suitably determine the laser beam waveform as the irradiation condition of the laser beam to the liquid 2 to be processed.

  In such a case, the conditions for the laser light waveform include, for example, waveform conditions such as the rise time, fall time, and pulse width of the pulse waveform of the laser light. In addition, when measuring the light emission characteristics and controlling the irradiation condition of the laser light with respect to such a waveform condition, it is necessary to use a laser light source having a variable laser light waveform as the laser light source 20. In each of the above-described methods, for light emission measurement by the light emission measuring device 11, it is necessary to measure light emission a plurality of times by changing the wavelength, intensity, and pulse waveform of the laser light.

  Next, a method using the relationship between the emission intensity and the laser beam irradiation time as the emission characteristic will be described. FIG. 4 is a graph showing the relationship between the emission intensity and the laser beam irradiation time. In this case, the laser light wavelength and light intensity to be measured are set. Next, laser light is irradiated from the laser light source 20 to the liquid 2 to be processed while the wavelength and light intensity are fixed by the control device 25. Then, the temporal change of the emission intensity due to the laser light irradiation time is measured by the light emission measuring device 11 and the analysis device 15, and the measurement result illustrated in the graph of FIG. 4 is acquired as the light emission characteristics.

  According to the examination result by the inventors of the present application, as described above, light emission occurs with the atomization by light crushing under the irradiation condition that enables the atomization. In addition, it was found that the emission intensity decreased as the atomization process progressed, and no light emission occurred in the sample where the atomization was completed to such an extent that the atomization hardly progressed. Therefore, by referring to the time variation of the light emission intensity as shown in FIG. 4 as the light emission characteristics, the laser light irradiation time as the laser light irradiation condition for the liquid 2 to be processed is determined by the time T until the light emission is stopped. It can be suitably determined.

  Here, as a specific method for determining the laser light irradiation time T, for example, a threshold value is set for the light emission intensity, and the laser light irradiation time T depends on the time until the light emission intensity changes and becomes equal to or less than the threshold value. There is a way to determine. Alternatively, there is a method in which a threshold is set for the rate of change of the emission intensity with time, and the laser light irradiation time T is determined by the time until the rate of change of the emission intensity becomes equal to or less than the threshold. Moreover, you may use methods other than these.

  Next, a method using light emission timing as the light emission characteristic will be described.

  As a method of determining the laser light irradiation condition with reference to the light emission timing, there is a method of referring to the light emission start timing with respect to the laser light irradiation timing as the light emission characteristics. This start timing corresponds to a delay time of light emission with respect to laser light irradiation. In this case, it is preferable to calculate the lower limit value of the pulse width of the laser beam necessary for atomization from the obtained start timing, and determine the laser beam pulse width as the irradiation condition with reference to the lower limit value.

  Further, there is a method of referring to the light emission end timing with respect to the laser light irradiation timing as the light emission characteristics. This end timing corresponds to the duration of light emission with respect to laser light irradiation. In this case, it is preferable to calculate the upper limit value of the pulse width of the laser beam necessary for atomization from the obtained end timing, and determine the laser beam pulse width as the irradiation condition with reference to the upper limit value.

  A specific example of the method for determining the irradiation condition of the laser beam using the light emission timing will be described. FIG. 5 is a graph showing temporal changes in laser light intensity and light emission intensity. Here, the fine particle processing is performed by irradiating a pulse laser beam having a wide pulse width, and the timing of the irradiated laser beam and light emission at this time is measured by the light emission measuring device 11, the irradiation light measuring device 12, and the analyzing device 15. Measure and analyze.

In the example shown in FIG. 5, the light emission starts at the start timing delayed by the time t _{1 with} respect to the laser light irradiation timing, and the light emission ends at the end timing of the time t ₂ . This indicates that fine particles are generated between times t _{1 and} t ₂ with respect to laser beam irradiation. At this time, it is preferable to set the light emission start timing t ₁ as the lower limit value, the end timing t ₂ as the upper limit value, and set the pulse width w of the laser light within a range of t ₁ <w ≦ t ₂ . Thereby, the micronization process by laser beam irradiation can be performed efficiently. Note that the pulse width of the laser beam may be set to some extent wider pulse width than the upper limit value t _2.

  Next, the contents of the present invention will be described more specifically with specific data.

  First, emission spectra and emission time waveforms when various substances are targeted for atomization will be described. Here, graphite, carbon nanotubes, Si, VOPc (vanadyl phthalocyanine: pigment), clobetasone butyrate (pharmaceutical), carbamazepine (pharmaceutical), ibuprofen (pharmaceutical), and econazole nitrate (pharmaceutical) are used as samples to be micronized. I chose. Then, a suspension (processed liquid) of each sample is prepared at a concentration of 1 mg / ml in water as the solvent 4, and 3 ml of the processed liquid is placed in a quartz square cell (10 mm × 10 mm × 40 mm) as the processing chamber 3. 2 was applied and laser light irradiation for light crushing was performed.

  A YAG pulse laser was used as the laser light source 20. The light irradiation conditions are a wavelength of 1064 nm, a repetition frequency of 10 Hz, FWHM 4.85 ns, and the energy per pulse is 300 mJ / pulse. Moreover, the adjustment of the irradiation laser beam intensity for causing the light emission phenomenon in each sample was performed by varying the spot diameter using a lens. For observation of light emission, a high-speed response type photodetector (DET210 manufactured by THORLABS: response speed of 1 ns or less), a high-speed response type oscilloscope (Agilent infinite: 2.25 GHz, 8GSa / s), and a multi-channel type The spectroscope (manufactured by Hamamatsu Photonics Co., PMA11) was used.

  First, the emission spectrum generated with the micronization of the sample was investigated. 6A to 6D are graphs showing the wavelength dependence of the obtained emission intensity. In each graph, the horizontal axis indicates the emission wavelength (nm), and the vertical axis indicates the emission intensity (A.U.). Also, graph A1 in FIG. 6A is VOPc, A2 is Si, graph B1 in (b) is graphite, B2 is carbon nanotube, graph C1 in (c) is carbamazepine, graph D1 in (d) is clobetasone butyrate, D2 shows the emission spectrum of ibuprofen, and D3 shows the emission spectrum of econazole nitrate.

In addition, the intensity of the irradiated laser beam from which the light emission phenomenon can be observed varies depending on the sample. For this reason, in this example, the VOPc and Si particles in FIG. 6 (a) have a light irradiation intensity of 450 mJ / cm ² · pulse, and the graphite and carbon nanotubes in (b) have a light irradiation intensity of 200 mJ / cm ² · pulse, (c). The carbamazepine of (d) and clobetasone butyrate / ibuprofen / econazole nitrate of (d) were subjected to spectral analysis under the condition of 3000 mJ / cm ² · pulse.

  As can be seen from these graphs in FIG. 6, emission spectra having almost the same tendency were obtained from any of the samples. From this result, it is considered that the luminescence phenomenon is not caused by the physical properties of the sample but is caused by the solvent (in this case, water). The reason for this light emission phenomenon is that high-speed fine particles are released from the surface of the raw material particles into the water when irradiated with laser light, so that light is emitted by cavitation of the solvent. Can be considered. That is, light emission is observed when the fine particles are released from the raw material particles into the solvent liquid at high speed, and the light emission characteristics are considered to be useful for monitoring the production of fine particles. In this case, for example, considering the optimization of the necessary laser light irradiation conditions for the material to be atomized, an efficient atomization process can be realized by obtaining irradiation conditions that increase the emission intensity. be able to.

  FIGS. 7A to 7F are graphs showing laser light to be irradiated and temporal timing of light emission accompanying micronization, and a time waveform. In each graph, the dotted line indicates the laser light, and the solid line indicates the light emission accompanying the atomization. The horizontal axis indicates time (5 ns / div), and the vertical axis indicates the detection signal intensity corresponding to the emission intensity. 7 (a) shows graphite, (b) shows carbon nanotubes, (c) shows VOPc, (d) shows carbamazepine, (e) shows ibuprofen, and (f) shows the time waveform of light emission of clobetasone butyrate. Yes.

  According to these graphs of FIG. 7, light emission occurs without delay in the rise of the irradiation laser light in (a) graphite, (b) carbon nanotube, and (c) VOPc. That is, in these samples, it is presumed that fine particles are ejected from the surface of the raw material particles into the water almost in synchronization with the irradiation under these irradiation conditions. On the other hand, the samples (d) to (f), which are pharmaceuticals, emit light with a delay of about 1 ns with respect to the irradiation laser beam, unlike the above samples. That is, under this irradiation condition, it is considered that a pulse width of 1 ns or more is necessary at least for micronization of pharmaceuticals.

  As described above, by comparing the timings of laser light and light emission, the lower limit laser light pulse width necessary for atomization can be obtained. Conversely, in the case where the pulse width of the laser beam is long and the time width of the light emission associated with the micronization is shorter than that of the laser beam, it is assumed that the portion of the pulse laser beam that does not emit light does not contribute to the micronization Is done. In this case, the upper limit value of the pulse width necessary for atomization can also be obtained.

  Next, the relationship between the emission intensity and the laser beam intensity will be described. Here, using VOPc as a sample, the relationship between the intensity of the irradiated laser beam and the intensity of the emission generated as a result of fine particle formation by laser beam irradiation was determined. The light irradiation conditions are a wavelength of 1064 nm, a repetition frequency of 10 Hz, FWHM 4.85 ns, and the energy per pulse is 300 mJ / pulse. Further, the adjustment of the irradiation laser light intensity was performed by changing the spot diameter using a lens. For the liquid to be treated, VOPc raw material particles were suspended in water at a concentration of 1 mg / ml, and 3 ml was suspended in a quartz square cell for fine particle treatment.

FIG. 8 is a graph showing the relationship between the obtained emission intensity and the laser beam intensity. In this graph, the horizontal axis represents the laser light intensity (mJ / cm ² · pulse), and the vertical axis represents the light emission intensity (signal intensity corresponding to the maximum value of light emission, mV). In the case of this VOPc, the light emission phenomenon was observed from the irradiation laser light intensity of about 300 mJ / cm ² · pulse, and the light emission intensity tended to increase as the light intensity increased. That is, it can be seen that in the micronization of VOPc, the micronization process can be suitably executed by setting the irradiation conditions with the laser beam irradiation intensity of 300 mJ / cm ² · pulse or more.

  For the laser light wavelength, a suitable irradiation condition can be similarly set according to the relationship between the emission intensity and the laser light wavelength. For example, in the relationship between the emission intensity and the laser beam wavelength, the optimum laser beam wavelength for the fine particle treatment can be determined by obtaining the wavelength at which the emission intensity is maximized. Further, by obtaining a wavelength range in which light emission can be obtained, a wavelength width that can be selected by micronization can be obtained.

Next, the relationship between the light emission characteristics and the laser beam irradiation time will be described. Here, using VOPc as a sample, the relationship between the laser beam irradiation time and the emission intensity (maximum value of emission) was determined. The light irradiation conditions are a wavelength of 1064 nm, a repetition frequency of 10 Hz, a FWHM of 4.85 ns, a spot size of 3.5 mmφ, and an irradiation laser light intensity of 600 mJ / cm ² · pulse. For the liquid to be treated, VOPc raw material particles were suspended in water at a concentration of 1 mg / ml, and 3 ml was suspended in a quartz square cell for fine particle treatment.

  In this experiment, a surfactant (Igapal CA-630: molecular weight 602) was added at a concentration of 0.29 mmol / l for the purpose of preventing aggregation of the generated fine particles. The laser light irradiation time is 0.5 minutes, 3 minutes, 6 minutes, and 9 minutes before the treatment (0 minutes), and the emission intensity at each irradiation time and DMS (particle size distribution measuring apparatus: SALD7000 manufactured by Shimadzu Corporation). The particle size distribution of the sample was also obtained.

  FIG. 9 is a graph showing the particle size distribution of VOPc in the liquid to be treated at each irradiation time. In this graph, the horizontal axis indicates the particle diameter (μm), and the vertical axis indicates the relative particle amount. From this graph, the raw material particles of VOPc before the treatment are distributed in a particle size range of about 15 to 70 μm. On the other hand, when the treatment time for atomization by laser light irradiation is extended, there is almost no difference between 6 minutes and 9 minutes, and it can be seen that finely divided VOPc is obtained in the vicinity of a particle diameter of 200 nm.

  FIG. 10 is a graph showing the relationship between the emission intensity and the laser beam irradiation time. In this graph, the horizontal axis indicates the laser beam irradiation time (minutes), and the vertical axis indicates the emission intensity (mV). In this graph, the emission intensity is greatest immediately after laser light irradiation, and gradually decreases as the atomization proceeds. Then, after 6 minutes of irradiation, the emission intensity was reduced to about 1/10 of the initial value, and after 9 minutes of irradiation, the emission was not observable.

  This result corresponds to the micronization state shown in the graph of FIG. That is, it is presumed that high-speed fine particles that cause cavitation in the solvent disappeared after 9 minutes. As described above, by monitoring the light emission phenomenon that accompanies micronization, information for determining the progress of micronization and the completion of micronization can be obtained. Further, by determining the laser light irradiation conditions based on such light emission characteristic information, the fine particle treatment can be suitably controlled.

  The method for determining atomization conditions, the determining apparatus, the method for manufacturing fine particles, and the manufacturing apparatus according to the present invention are not limited to the above-described embodiments and examples, and various modifications can be made. For example, with respect to the monitoring of the laser light for light fragmentation, the laser light intensity and the irradiation timing of the laser light are referred to with reference to a signal from the laser light source 20 or a control signal sent from the control device 25 to the laser light source 20. It is also possible to adopt a configuration for monitoring irradiation conditions such as. In this case, the irradiation light measuring device 12 shown in FIG. 1 is unnecessary.

  Further, the analysis device 15 and the control device 25 may be configured by separate computers, or may be configured by a single computer having both the analysis function and the control function. Further, the display device 26 used for displaying the light emission characteristics or the like may be omitted if unnecessary. Further, when the laser beam wavelength to be irradiated overlaps with the emission spectrum band, the laser beam wavelength may be set outside the emission spectrum band if it is necessary to prioritize the monitoring of the state of fine particles.

  The present invention uses a determination method, a determination apparatus, and a determination method for atomization that can determine the presence or absence of atomization by laser light irradiation and suitably control the irradiation condition of the laser light to the liquid to be processed. It can be used as a production method and production apparatus for fine particles.

It is a block diagram which shows roughly one Embodiment of the determination apparatus of microparticulation conditions, and the manufacturing apparatus of microparticles | fine-particles using the same. It is a graph which shows the relationship between emitted light intensity and a laser beam wavelength. It is a graph which shows the relationship between emitted light intensity and laser beam intensity. It is a graph which shows the relationship between emitted light intensity and laser beam irradiation time. It is a graph which shows the time change of a laser beam intensity and light emission intensity. It is a graph which shows the wavelength dependence of emitted light intensity. It is a graph which shows the time waveform of a laser beam and light emission. It is a graph which shows the relationship between emitted light intensity and laser beam intensity. It is a graph which shows the particle diameter distribution of VOPc. It is a graph which shows the relationship between emitted light intensity and laser beam irradiation time.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 1A ... Fine particle manufacturing apparatus, 2 ... Liquid to be processed, 3 ... Processing chamber, 4 ... Solvent, 5 ... Raw material particles (substance), 10 ... Fine particle condition determination device, 11 ... Luminescence measuring device, 12 ... Irradiation light measurement Device: 13 ... half mirror, 15 ... analysis device, 20 ... laser light source, 25 ... control device, 26 ... display device.

Claims (16)

Microparticles that are generated under irradiation conditions that enable the atomization of the substance in the solvent by irradiating the liquid to be treated containing the substance to be atomized in the solvent with laser light of a predetermined wavelength. A luminescence measuring step for measuring luminescence accompanying the conversion;
The irradiation condition of the laser light on the liquid to be processed is determined based on the light emission characteristics that are obtained from the measurement result of the light emission in the light emission measurement step and reflect the state of atomization in the liquid to be processed. A condition determining step ,
Wherein the said light emission measured in luminescence measuring step, the irradiation condition can be the fine particles is, Ru emission der cavitation of the solvent when the particles are released from the raw material particles of the substance in the liquid of the solvent A method for determining a micronization condition characterized by the above.   The determination method according to claim 1, wherein, in the condition determination step, a characteristic regarding emission intensity is obtained as the emission characteristic.   The laser light irradiation time as the irradiation condition is determined from the obtained relationship in the condition determining step by obtaining a relationship between the light emission intensity and the laser light irradiation time as the light emission characteristics. How to determine. In the light emission measurement step, while measuring the light emission a plurality of times by changing the wavelength of the laser light,
3. The determination according to claim 2, wherein, in the condition determining step, a relationship between the emission intensity and the laser beam wavelength is obtained as the emission characteristic, and the laser beam wavelength as the irradiation condition is determined from the obtained relationship. Method. In the light emission measurement step, while measuring the light emission a plurality of times by changing the intensity of the laser beam,
3. The determination according to claim 2, wherein, in the condition determining step, a relationship between the emission intensity and the laser beam intensity is obtained as the emission characteristic, and the laser beam intensity as the irradiation condition is determined from the obtained relationship. Method. In the light emission measurement step, while measuring the light emission a plurality of times by changing the pulse waveform of the laser light,
3. The determination according to claim 2, wherein, in the condition determining step, a relationship between the emission intensity and the laser beam waveform is obtained as the emission characteristic, and the laser beam waveform as the irradiation condition is determined from the obtained relationship. Method.   The determination method according to claim 1, wherein in the condition determination step, a characteristic regarding a light emission timing is obtained as the light emission characteristic.   In the condition determining step, a light emission start timing relative to the laser light irradiation timing is obtained as the light emission characteristic, and a lower limit value of the pulse width of the laser light necessary for atomization is calculated from the obtained start timing. 8. The determination method according to claim 7, wherein a laser light pulse width as the irradiation condition is determined with reference to a value.   In the condition determining step, an end timing of light emission with respect to the irradiation timing of the laser beam is obtained as the emission characteristic, and an upper limit value of the pulse width of the laser beam necessary for atomization is calculated from the obtained end timing, and the upper limit is calculated. 8. The determination method according to claim 7, wherein a laser light pulse width as the irradiation condition is determined with reference to a value. A method for producing fine particles by photocrushing a substance in a solvent of a liquid to be treated,
A method for determining the micronization condition according to any one of claims 1 to 9 ,
A preparation step of preparing the liquid to be treated in which the substance and the solvent are mixed;
And a laser light irradiation step of pulverizing the substance in the solvent by irradiating the liquid to be treated with the laser light based on the irradiation conditions determined in the condition determining step. A method for producing fine particles characterized by the above. A processing chamber containing a liquid to be processed containing a substance to be atomized in a solvent;
Occurs under irradiation conditions that enable micronization that occurs when the liquid to be processed contained in the processing chamber is irradiated with laser light having a predetermined wavelength for micronizing the substance in the solvent. A luminescence measuring means for measuring luminescence accompanying the microparticulation,
Conditions for determining the irradiation condition of the laser light on the liquid to be processed based on the light emission characteristics that are obtained from the measurement result of the light emission by the light emission measuring means and reflect the state of micronization in the liquid to be processed A determination means ,
Said emission is measured in the luminescence measuring device, the irradiation condition can be the fine particles is, Ru emission der cavitation of the solvent when the particles are released from the raw material particles of the substance in the liquid of the solvent An apparatus for determining the atomization condition, characterized in that: 12. The determination apparatus according to claim 11 , wherein the condition determining unit obtains a characteristic regarding the light emission intensity as the light emission characteristic. 13. The determination apparatus according to claim 11 or 12 , wherein the condition determination unit obtains a characteristic regarding light emission timing as the light emission characteristic. The said condition determination means determines at least 1 of a laser beam irradiation time, a laser beam wavelength, a laser beam intensity | strength, and a laser beam waveform as said irradiation conditions, The any one of Claims 11-13 characterized by the above-mentioned. The determination device described. The determination apparatus according to claim 11 , further comprising an irradiation light measurement unit that performs measurement on the laser light irradiated to the liquid to be processed. It is a manufacturing apparatus that photocrushes a substance in a solvent of a liquid to be processed to produce fine particles,
The apparatus for determining microparticle formation conditions according to any one of claims 11 to 15 ,
A laser light source for irradiating the liquid to be treated with the laser light for atomizing the substance in the solvent;
An apparatus for producing fine particles, comprising: control means for controlling an irradiation condition of the laser beam by the laser light source based on the irradiation condition determined by the condition determining means.

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