JP4101812B2 - Molecular structure compound identification system - Google Patents

Description

  The present invention relates to a molecular structure composite identification apparatus that performs physical property evaluation on a molecular state of a pharmaceutical crystal or the like by any of X-ray diffraction and infrared light / visible light / ultraviolet light.

  “PHARM TECH JAPAN ● Vol.18 No.10 (2002) pp.81-96) is known for“ physical property evaluation on molecular state of pharmaceutical crystals (12) ”. On page 92, “A sample crystallized in 96 wells as shown in FIG. 7 automatically moves to Birefringence Station, and determines whether it is crystalline or amorphous based on the birefringence sign. For the samples whose crystals were confirmed on 96 wells, each sample on the wells was automatically aligned at the XRD Station shown in FIG. For example, the X-ray diffraction pattern of phenylbutazone as shown in Fig. 9 is confirmed as Well C8, Well B8, Well A9. Similarly, Raman spectrum is measured at Raman Station, Fig. 10 shows the spectrum of phenylbutazone shown in Fig. 9 and is shown as Well A8, Well D5, Well F5, Well G11, and at Melting Point Station, the phase transition of crystals with temperature, etc. Is also automatically measured "

  Moreover, as a chemical reaction processing apparatus provided with the X-ray diffraction apparatus, it is known by Unexamined-Japanese-Patent No. 2001-219052.

  An apparatus and method for characterizing a library of different substances using X-ray diffraction is known from US 6,371,640 B1.

PHARM TECH JAPAN Vol.18 No.10 (2002) pp.81-96 JP 2001-219052 A US 6,371,640 B1

  As described above, in Non-Patent Document 1, an X-ray diffraction pattern is measured at XRD Station, similarly, a Raman spectrum is measured at Raman Station, and a temperature-dependent crystal is measured at Melting Point Station. It is described that the phase transfer and the like are automatically measured. As described in Non-Patent Document 1, X-ray diffraction pattern measurement, Raman spectrum measurement, and crystal phase transfer measurement by temperature are performed at different stations. ) And the number of measurements, the number of data increases and the data management becomes very complicated, and it is necessary to repeatedly control the positioning of Well at each station and the positioning control is very complicated.

  As described above, in both Non-Patent Document 1 and Patent Documents 1 and 2, the test sample mounting plate on which a large number of test samples are formed continuously or in positions is held on the stage. Reduce the number of measurements by performing X-ray diffraction analysis, Raman scattering analysis, reflected infrared analysis, reflected ultraviolet analysis, and sample reflection image analysis on the above sample simultaneously or continuously. However, it has not been considered to reduce the number of data, simplify the inspection / test path by nondestructive inspection, and perform it reliably and at high speed.

  The object of the present invention is to solve the above-mentioned problems, in a state where a test sample mounting plate on which a large number of test samples are formed on a stage is held on a stage. X-ray diffraction analysis, sample reflection image, Raman scattering analysis, reflected infrared analysis, and reflected ultraviolet analysis can be performed simultaneously or sequentially to shorten the inspection path by nondestructive inspection, for example, drug development An object of the present invention is to provide a molecular structure composite identification apparatus and method for shortening the period, and stabilizing production and quality.

  In order to achieve the above object, the present invention provides an X-ray beam limited to a diameter of 0.5 mm or less and infrared / visible / ultraviolet light with respect to the same test sample placed on the test sample mounting plate. An irradiation optical system for irradiating any one or a plurality of wavelength beams, and an X-ray diffraction pattern obtained from the test sample and a detection optical system for detecting reflected light or scattered light emitted from the test sample A molecular structure composite identification apparatus characterized in that at least X-ray diffraction pattern data and reflection optical image data are acquired simultaneously or successively from the test sample.

  The present invention also provides a test sample mounting plate on which a plurality of test samples are mounted, a sample holding mechanism for holding the position of the test sample mounting plate in an adjustable manner, and an X-ray beam X A ray generator, a shutter device that controls irradiation / non-irradiation of an X-ray beam generated from the X-ray generator, an illumination light source that emits a wavelength beam of visible light, and an X-ray beam emitted through the shutter device The X-ray optical element that irradiates the test sample with a diameter of 0.5 mm or less and the test sample that irradiates the visible light wavelength beam emitted from the illumination light source with the X-ray optical element. A condensing optical system that irradiates and collects reflected or scattered light emitted from the test sample, and is placed opposite to the X-ray optical element with the test sample sandwiched therebetween. An X-ray detector for detecting X-ray diffraction from the specimen and the condensing optical system A detection optical system including a light receiving device that receives the reflected or scattered light and detects it as a signal, obtains data of an X-ray diffraction pattern from a sample to be detected from the X-ray detector, and performs the detection A molecular structure composite identification apparatus characterized in that data of a reflected optical image from a test sample is acquired simultaneously or successively with the acquisition of data of the X-ray diffraction pattern from a light receiving device of an optical system.

  The present invention also provides a test sample mounting plate on which a plurality of test samples are mounted, a sample holding mechanism for holding the position of the test sample mounting plate in an adjustable manner, and an X-ray beam X A ray generator, a shutter device that controls irradiation / non-irradiation of the X-ray beam generated from the X-ray generator, and an illumination light source that emits one or a plurality of wavelength beams of infrared rays, visible light, and ultraviolet rays An X-ray optical element that irradiates a test sample with an X-ray beam irradiated through the shutter device limited to a diameter of 0.5 mm or less, and the one or more wavelength beams emitted from the illumination light source. A condensing optical system for condensing and irradiating the test sample irradiated by the X-ray optical element and collecting reflected light or scattered light emitted from the test sample, and the test sample sandwiched between The test sample is installed opposite to the X-ray optical element, An X-ray detector for detecting X-ray diffraction from the above and a detection optical system including a light receiving device that receives reflected light or scattered light collected by the condensing optical system and detects it as a signal. X-ray diffraction pattern data from the test sample is acquired from the line detector, and any one of the reflected optical image, Raman scattering spectrum, reflected infrared spectrum, and reflected ultraviolet spectrum from the test sample from the light receiving device of the detection optical system The molecular structure composite identification apparatus is characterized in that one or a plurality of data is acquired simultaneously or continuously with data acquisition of the X-ray diffraction pattern.

  In the molecular structure composite identification apparatus, the present invention further comprises means for measuring the solubility (dissolution point) of each test sample placed on the test sample placing plate. It is characterized by obtaining solubility data of a test sample.

In the molecular structure composite identification apparatus, the present invention further includes a moving device that moves the position coordinates of the test sample placed on the test sample placing plate by controlling the position coordinates continuously or discretely. It is characterized by having.
In the molecular structure composite identification apparatus, the present invention is characterized in that the X-ray optical element is formed of a tubular reflective X-ray capillary having an inner diameter of 0.5 mm or less.
In the molecular structure composite identification apparatus according to the present invention, the X-ray optical element may be constituted by an X-ray reflecting mirror having a surface shape so that reflected X-rays converge on the test sample. Features.
Further, the present invention is characterized in that, in the molecular structure composite identification apparatus, the condensing optical system is configured by a reflecting mirror provided with a hole for allowing an X-ray beam to pass therethrough.
Further, the present invention is characterized in that, in the molecular structure composite identification apparatus, the condensing optical system is constituted by an optical lens provided with a hole for allowing an X-ray beam to pass therethrough.
In the molecular structure composite identification apparatus according to the present invention, the test sample mounting plate is configured by mounting a large number of test samples on a continuous or positional basis.

Further, the present invention provides the molecular structure composite identification apparatus, in addition to the measurement of the X-ray diffraction pattern and the reflection optical image of the test sample, the measurement of the Raman scattering spectrum, the measurement of the reflected infrared spectrum, and the reflected infrared spectrum. When the measurement is performed, the measurement unit is switched so that data of a specific spectrum or a plurality of spectra can be acquired by exchanging the measurement unit.
In the molecular structure composite identification apparatus, the present invention may be configured such that the X-ray detector includes an X-ray detection device having a detectable region having a diameter of 20 mm to 80 mm, and a test sample on the sample side of the X-ray detection device. A circular slit installed around the position on the extended line of the X-ray beam, and a linear movement type position adjusting mechanism for transmitting only a specific diffraction line so as to irradiate the X-ray detection device. It is characterized by being configured.
In the molecular structure composite identification apparatus according to the present invention, a two-dimensional X-ray detector is used as the X-ray detector, and an annular shape centering on a position on an extended line of the X-ray beam that irradiates the test sample is used. The X-ray diffraction pattern data of the test sample is obtained by obtaining a numerical value integrated for each region.

Further, the present invention provides the molecular structure composite identification apparatus, wherein at least the individual identification code or information is assigned to the test sample mounting plate, and the assigned individual identification code or information is mechanically A reading device is provided that reads by any one of a plurality of methods such as optics, electromagnetic waves, and magnetism.
Further, the present invention provides the molecular structure composite identification apparatus, wherein the individual identification code or information given to the test sample mounting plate and the position coordinates or position information of each test sample on the test sample mounting plate Are managed in correspondence with data acquired from each test sample.
In the molecular structure composite identification apparatus, the present invention stores identification information of each test sample placed on the test sample placement plate in correspondence with data acquired from each test sample. A storage device is provided.
Further, in the molecular structure composite identification apparatus, the present invention acquires the identification information of each test sample placed on the test sample mounting plate and the formation conditions of each test sample from each test sample. And a storage device that stores data corresponding to the data.

  In the molecular structure composite identification apparatus, the present invention provides a storage sample holder for storing a plurality of test sample mounting plates, and the test sample between the storage sample holder and the sample holding mechanism. An exchange device for automatically exchanging the placement plate, and each time the measurement for one test sample placement plate is completed, the test device placement plate in the storage sample holder is moved by the exchange device. It is characterized in that the sample holding mechanism is exchanged sequentially or in a designated order.

  In the molecular structure composite identification apparatus, the present invention may be any one or more of an X-ray diffraction pattern, a Raman scattering spectrum, a reflected infrared spectrum, a reflected ultraviolet spectrum, and a reflected optical image as data acquired from each test sample. It is the data of this.

  According to the present invention, errors occur when X-ray diffraction and one or more of infrared light, visible light, ultraviolet light, and Raman scattering are performed simultaneously or sequentially on a large number of test samples. It is possible to perform complex identification of the molecular structure accurately and efficiently.

  Embodiments of a molecular structure composite identification apparatus and method according to the present invention will be described with reference to the drawings.

[First Embodiment]
First, a first embodiment of a molecular structure composite identification apparatus according to the present invention will be described with reference to FIGS. Reference numeral 16 denotes a test sample on which a large number of test samples 17 are placed (formed) as cells or wells continuously or at a distance, and an individual identification code or information (for example, an ID number) 18 is given. A plate (test sample cell or sample plate with well) is held in a horizontal direction by a sample holding mechanism (sample mounting stage) 13. As a result, the test sample mounting plate 16 is moved by the moving device (stage) 14 via the sample holding mechanism 13 so that the predetermined test sample 17 is aligned with the beam axis. As a large number of test samples 17, samples obtained by recrystallizing medicinal components under recrystallization conditions (solvent composition, solvent concentration, solvent temperature, temperature history, atmosphere, etc.) can be considered. In this case, the integrated nondestructive inspection 21 performed by the molecular structure composite identification apparatus 20 according to the present invention shown in FIG. 2 includes crystal morphology, polymorph analysis, and bond analysis. Crystal forms (needle crystals, plate crystals, and other bulk crystals) can be inspected by an optical image of visible light. Polymorphic analysis (crystal analysis of polymorphs having different regular atomic arrangement structures) can be examined by an X-ray diffraction spectrum. The bond analysis (basic structure analysis about the size of a functional group) can be inspected by Raman scattering / infrared / ultraviolet spectrum (mainly Raman scattering spectrum).

  Further, an individual identification code or information (for example, an ID number) 18 assigned to the test sample mounting plate 16 is wired to the overall control unit 15 by any one of mechanical, optical, electromagnetic wave, magnetic, or a plurality of methods. Alternatively, the overall control unit 15 is read from the code or information read by the wirelessly connected reading device 19 and the position (position coordinates) on the test sample mounting plate 16 detected from the moving device (stage) 14. The test sample 17 is configured to be identified.

  By the way, the individual identification code or information (for example, ID number) given to the test sample mounting plate in advance, the position coordinates or position information of the test sample on the test sample mounting plate, and the test sample The formed test sample forming conditions are input using an input means (including a recording medium and a network) and stored in the storage device 15c.

  The molecular structure composite identification apparatus 30 is configured to display an X-ray generation unit 1 installed on the upper part of the apparatus so as to irradiate X-rays toward the bottom surface of the apparatus housing, a visible light illumination light source 2 of the sample, and an optical image of visible light. A sample observation camera 3 to be acquired, an objective mirror (Cassegrain reflection optical system) 11a as a condensing optical system 11 for condensing scattered light and reflected light from the test sample 17, a laser light source 22 for Raman excitation of the sample, The half mirrors 4a and 4c, the total reflection mirror 4b, the mount 4 for holding the mirrors 4a to 4c, the objective mirror 11a, etc., the Raman (infrared / ultraviolet) light receiving device 5, and the X-ray beam. An X-ray blocking device (X-ray shutter device) 6 for irradiating / non-irradiating the test sample 17 and an X-ray optical element 12 for limiting the X-ray beam irradiated to the test sample to a diameter of about 0.5 mm or less. X-ray capillary (inner diameter is 0. a tubular total reflection X-ray capillary) 12a, which is approximately equal to or less than mm and adjusted to a surface state capable of almost totally reflecting X-rays, a Raman (infrared / ultraviolet) light spectroscopic device 7, and a power supply device for an X-ray generation unit 8, an X-ray detector 9 having a ring shutter 10, the position of which can be adjusted in the X-ray beam axis direction, an overall control unit 15 having a data processing unit 15 a, and a display device 15 b connected to the overall control unit 15. A storage device 15c for storing integrated nondestructive inspection results corresponding to a large number of test samples 17 placed as cells or wells on the test sample mounting plate 16, and a test sample mounting plate 16 And a reading device 19 that reads an individual identification code or information (for example, an ID number) 18 assigned to. The objective mirror 11a and the mirror 4b as the condensing optical system 11 are provided with holes for installing the X-ray capillary 12a as the X-ray optical element 12.

  An X-ray detector 9 for acquiring an X-ray diffraction pattern includes an X-ray detection device (X-ray scintillation counter) 9a having a detectable region having a diameter of about 20 mm to about 80 mm for X-ray diffraction detection from the test sample. The X-ray detection device 9a is irradiated with only a specific diffraction line and a slit 9b installed around the position on the extended line of the X-ray beam that irradiates the sample on the sample side of the X-ray detection device. And a linear movement type position adjusting mechanism 21 for transmitting the light.

  The test sample mounting plate 16 on which a large number of test samples 17 are installed is moved by the moving device 14 via the holding mechanism 13 on the basis of a command from the overall control unit 15, and each test sample is moved to the beam axis. It is positioned so that it may be located in. As a result, the overall control unit 15 obtains the position coordinates of the test sample on the test sample mounting plate continuously or discretely from the moving device 14, and stores the position coordinates of the test sample in the storage device 15c. Alternatively, it is registered as position information. At the same time, the X-ray is emitted from the X-ray generator 1 by the power supplied from the X-ray generator power supply 8. In response to a command from the overall control unit 15, the X-ray blocking device 6 is opened, and the X-ray beam is focused to a diameter of about 0.5 mm or less by the X-ray capillary 12 a as the X-ray optical element 12 and irradiated to the test sample. The The X-ray irradiated to the test sample 17 does not travel straight due to diffraction by the crystal of the test sample, but passes through the slit and is detected by the X-ray detector 9. That is, the specific cone-shaped X-ray diffraction pattern 20 from the test sample 17 is detected by the X-ray detection device 9a through the gap (annular region) between the slit 9b and the ring shutter 10. Thus, the data of the specific X-ray diffraction pattern is acquired by adjusting the linear movement type position adjusting mechanism 21 in the X-ray beam axis direction. In addition, a two-dimensional position sensitive X-ray detector is used as the X-ray detector 9, and the sample to be detected is one of the values detected from the two-dimensional position sensitive X-ray detector in the data processing unit 15a, for example. X-ray diffraction pattern data can also be obtained by obtaining a numerical value integrated for each annular region (circumferential region) centered on the position on the extended line of the X-ray beam that irradiates.

  A visible light source 2 and / or a Raman (infrared / ultraviolet) light source 22 is turned on (the shutter is turned on) on the same test sample 17 that has been X-ray diffracted simultaneously or continuously based on a command from the overall control unit 15. It may be opened and closed.) And irradiated with visible light and / or Raman light. That is, the visible light generated by the visible light source 2 is reflected by the half mirror 4a installed in the mount 4, and irradiates the test sample 17 through the total reflection mirror 4b and the objective mirror 11a. Reflected light from the test sample 17 by visible light irradiation is collected by the objective mirror 11a, totally reflected by the total reflection mirror 4b, passed through the half mirror 4a, reflected by the half mirror 4c, and crystallized by the sample observation camera 3. Data of the reflected optical image of the test sample indicating the form is acquired simultaneously or successively, and is input to the data processing unit 15a of the overall control unit 15 and stored as image data that can be displayed.

  Furthermore, the laser beam generated by the Raman excitation laser light source 22 is guided to the mount 4 through the optical fiber 23, passes through the half mirrors 4c and 4a, and is X-ray diffracted through the total reflection mirror 4b and the objective mirror 11a. The sample 17 is irradiated. The Raman scattered light generated in the test sample by laser light irradiation is collected by the objective mirror 11a, reflected by the total reflection mirror 4b, transmitted through the half mirrors 4a and 4c, and then received by Raman (infrared / ultraviolet) light. Introduced into the apparatus 5 and then introduced into the Raman (infrared / ultraviolet) light spectroscopic apparatus 7, Raman scattering (infrared / ultraviolet) spectrum data indicating binding analysis (basic structure analysis of the size of a functional group) is simultaneously or It is continuously acquired, input to the data processing unit 15a of the overall control unit 15, and stored as spectrum data that can be displayed.

  Next, a method for identifying a substance by X-ray will be specifically described. The X-rays generated by the X-ray generation source 1 are shaped into a narrow bundle through the X-ray capillary 12a and irradiate the test sample 17. When the test sample is a crystal, X-rays are diffracted only when the following equation (1) known as Bragg's law holds.

2dsin θ = λ (1)
Here, λ is the wavelength of the X-ray generated by the X-ray generation source 1, d is the spacing between the lattice planes of the crystal of the test sample, θ is the X-ray incident on the test sample and the lattice plane involved in diffraction It is an angle to be formed. θ is generally referred to as an incident angle. Since the direction of the diffraction line is reflected by the grating surface, it goes out in the direction of the incident angle 2θ that is twice that of the incident X-ray. In a test sample in which fine crystals are oriented in a random direction, diffracted X-rays are obtained in a conical shape with an angle 2θ with respect to the traveling direction of incident X-rays.

  Since the lattice plane differs depending on the atomic arrangement of the crystal of the test sample, generally, a diffraction pattern peculiar to the substance of the test sample can be obtained by measuring the intensity pattern of 2θ and diffraction X-rays. In addition, it is possible to identify the substance of the test sample by collating with the diffraction pattern of the known substance, and this is the X-ray diffraction technique used here.

  In order to efficiently measure this X-ray diffraction pattern, the present invention is configured as shown in FIG. In FIG. 6, X-rays that have passed through the X-ray capillary 12 a irradiate the test sample 17. A slit 52 (9b) provided with a circular X-ray passage 51 having a radius D is provided at a distance L from the test sample. The slit 52 uses a heavy metal such as tungsten (W) or tantalum (Ta), and the portion other than the X-ray passing portion 51 has a role of shielding X-rays. Thereby, the relationship between L, D, and diffraction angle θ is expressed by the following equation (2).

tan 2θ = D / L (2)
Here, an X-ray detector 53 such as a scintillation counter is installed behind the slit 52. By recording the relationship with the output of the X-ray detector 53 in the data processing unit 15a while changing L, the X-ray diffraction pattern of the crystal of the test sample can be measured.

  In FIG. 6, the X-ray beam is drawn horizontally, but in this embodiment, the X-ray beam is set vertical because of the necessity of placing the test sample 17 horizontally.

  The X-ray detector can be a two-dimensional pixel detector such as a CCD, and the slit 52 can be omitted. In the two-dimensional pixel detector, a large number of fine detection elements are two-dimensionally arranged, so that X-rays can be detected for each minute portion. For this reason, the X-ray diffraction pattern is concentric with the position on the two-dimensional pixel detector in the extending direction of the incident X-ray as the center C as shown in FIG.

  When a two-dimensional pixel detector is used, the X-ray diffraction intensity I (2θ) is obtained by the sum of the detection intensities of the respective pixels in the range represented by the following equation (3).

I (2θ) = ΣI (x, y): D−Δ <SQRT (x ² + y ² ) <D + Δ (3)
Here, D is the radius of a concentric circle centered on C (0,0), and I (x, y) is a detected X-ray of the pixel at coordinates (x, y) when C (0,0) is the origin. The intensity, Δ, corresponds to the detector window width, and 2Δ corresponds to the width of the diffracted X-ray.

  In an actual measurement system, a beam stopper made of heavy metal is installed at the position C so that high-intensity X-rays transmitted through the crystal of the sample 17 to be tested do not enter the detector. The X-ray diffraction pattern is measured by scanning the interval L between the slit + scintillation X-ray detector and the test sample in FIG. 6, whereas the latter is a single measurement on the two-dimensional detector. There is a great merit that a diffraction pattern can be measured. On the other hand, since a CCD two-dimensional X-ray pixel detector having a large size is very expensive, it is difficult to ensure the angular resolution of the X-ray diffraction pattern. When it is necessary to ensure the angular resolution of the X-ray diffraction pattern from the properties of the test sample, it is desirable to employ the former method of scanning the former interval L.

  The X-ray measurement method employed here captures all of the conical X-ray diffraction shown in the above formula (1), and has a much higher sensitivity than a commonly used X-ray diffraction apparatus. A general X-ray diffractometer is designed so that the angle resolution can be measured particularly high, and the diffracted X-ray to be captured is about 1% at most. Therefore, this method can measure the sensitivity sufficiently even if the amount of the test sample is small.

  Next, substance identification by Raman spectroscopy will be specifically described. The Raman scattered light spectrum is obtained by measuring light having a wavelength different from that of incident light generated when the test sample 17 is irradiated with monochromatic light by a laser or the like. This Raman scattered light spectrum varies depending on the basic structure in which atoms are bonded to surrounding atoms. Using the Raman spectrum of a known substance as in the case of the X-ray diffraction pattern, the substance of the test sample can be identified. is there.

  There are distinctive features in the identification of substances by X-ray diffraction and the identification of substances by Raman spectra. Since X-ray diffraction utilizes diffraction by crystals, a structure in which atoms are regularly arranged is distinguished over the entire crystal of the test sample. Therefore, in X-ray diffraction, even if the basic structure is the same, it can be distinguished if the arrangement is slightly different.

  On the other hand, the Raman spectrum can be captured if there is a structure about the size of a functional group from the principle. However, in the case of the Raman spectrum, when the basic structure is the same, unlike X-ray diffraction, it cannot be distinguished even if there is a slight difference in arrangement.

  Therefore, by using the two methods simultaneously as in the present invention, it is possible to identify and analyze the basic structure from the Raman spectrum even if the diffraction from the crystal cannot be measured by the X-ray diffraction measurement. In addition, crystals with the same basic structure in the Raman spectrum, such as polymorphs with different arrangements, can be distinguished by X-ray diffraction measurement, and the capability of identification and analysis as an instrument can be expanded. is there.

  Actually, when a crystal having a target structure is prepared from a certain raw material, it is necessary to confirm under various manufacturing conditions. However, if this apparatus is used, (1) the conditions for forming a basic structure without crystallization, ( 2) The quality is inferior but the conditions for crystallization can be clearly grasped, and (3) the conditions for forming the target crystal structure can be clearly understood.

  As described above, the data processing unit 15a of the overall control unit 15 includes the integrated nondestructive inspection 31 based on the X-ray diffraction pattern data acquired by the X-ray detector 9 simultaneously or continuously from the same test sample. It is possible to perform polymorphic analysis, and the inner crystal form of the integrated nondestructive inspection 31 based on the data of the reflected optical image by the visible light acquired by the sample observation camera (light receiving device) 3 simultaneously or successively from the same test sample Integrated nondestructive inspection 31 based on Raman scattering (reflected infrared / reflected ultraviolet) spectrum data acquired by the Raman (infrared / ultraviolet) optical spectroscopic device 7 simultaneously or successively from the same test sample. It is possible to perform an inner connection analysis. That is, the data processing unit 15a of the overall control unit 15 can obtain the nondestructive inspection result 31 integrated simultaneously from each test sample (for example, each recrystallized sample), thereby shortening the inspection path. Is possible.

  Then, the data processing unit 15a of the overall control unit 15 reads the individual identification code or information (for example, ID number) given to the test sample mounting plate 16 read by the reading device 19, and the individual identification code or information. Polymorphic analysis based on X-ray diffraction pattern data acquired by the X-ray detector 9 simultaneously or successively from the same test sample determined by position coordinates or position information determined corresponding to The crystal form based on the data of the reflected optical image by visible light acquired by the (light receiving device) 3 and the result of the binding analysis based on the data of the Raman scattering spectrum acquired by the Raman light spectroscopic device 7 are displayed on the display device 15b. And can be stored in the storage device 15c. That is, the data processing unit 15 a of the overall control unit 15 includes the individual identification code or information 18 given to the test sample mounting plate 16 read by the reading device 19 and the test sample mounting obtained from the moving device 14. The position coordinates or position information of each test sample on the plate is stored in the storage device 15c as a data set corresponding to data such as an X-ray diffraction pattern, a reflection optical image, and a Raman scattering spectrum acquired from each test sample. By memorizing, it becomes possible to manage the formation conditions (for example, medicinal components and recrystallization conditions) of the test sample. That is, among the many test samples placed as cells or wells on the test sample mounting plate 16, individual information given to the test sample mounting plate 16 is used as identification information of each test sample 17. It consists of an identification code or information 18 and position coordinates or position information of each test sample on the test sample mounting plate 16.

  Furthermore, the molecular structure composite identification apparatus 30 includes a storage sample holder (not shown) for storing a plurality of test sample mounting plates, and a test between the storage sample holder and the sample holding mechanism 13. A handling device (not shown) for automatically exchanging the sample mounting plate 16 is provided, and each time measurement for one test sample mounting plate is completed based on a command from the overall control unit 15. The test sample mounting plate in the storage sample holder is replaced with the sample holding mechanism 13 sequentially or in a designated order using the handling device, and the data set is stored in the storage device 15c. Thus, the formation conditions of the test sample and the X-ray diffraction pattern, Raman scattering spectrum, reflected infrared spectrum, reflected ultraviolet spectrum, and reflected optical image of the test sample formed under the formation conditions are Data will be stored in the storage unit 15c.

  As described above, according to the first embodiment, the number of data per test sample mounting plate 16 stored in the storage device 15c is significantly reduced from the number of test samples. It is possible to reduce the time of the nondestructive inspection 31 by executing the nondestructive inspection 31 simultaneously or successively on two test samples. Further, by using the test sample mounting plate 16 ′ shown in FIG. 8, the destructive test 2 (dissolution characteristic measurement) shown in FIG. 2 can be continuously performed.

  Thereafter, as shown in FIG. 2, the test sample 17 is subjected to a destructive test 1 (thermophysical property measurement) and a destructive test 3 (others). As a result, it is possible to shorten the inspection / test path by simultaneous nondestructive inspection.

  In addition, although the case where the Raman scattered light emitted from the test sample is received by the Raman light receiving device 5 and the Raman scattered spectrum is measured by the Raman light spectroscopic device 7 has been described, the reflected infrared spectrum or the reflected ultraviolet spectrum is measured. In this case, the Raman light measuring unit composed of the Raman light receiving device 5 and the Raman light spectroscopic device 7 is used as the reflected infrared light measuring unit or the reflected ultraviolet light receiving device composed of the reflected infrared light receiving device and the reflected infrared light spectroscopic device. In addition, a specific or a plurality of spectra can be acquired by exchanging with a reflected ultraviolet light measuring unit comprising a reflected ultraviolet light spectrometer. Moreover, it is necessary to exchange the illumination light source 22 of the sample so that infrared light or ultraviolet light is emitted. In any case, the reflected infrared spectrum or reflected ultraviolet spectrum can be measured by exchanging the measurement unit including the illumination light source of the sample.

[Second Embodiment]
Next, a second embodiment of the molecular structure composite identification apparatus according to the present invention will be described with reference to FIG. The second embodiment is different from the first embodiment in that the surface state of the X-ray optical element 12 is adjusted (controlled) so that the X-ray irradiated surface can almost totally reflect X-rays. In other words, the X-ray reflecting mirror 12b having a surface shape so that almost totally reflected X-rays converge to a diameter of about 0.5 mm or less. Therefore, the X-ray generation part (X-ray tube) 1 is slightly inclined. Thus, even if the X-ray optical element 12 is constituted by the X-ray reflecting mirror 12b, the X-ray beam is narrowed to a diameter of about 0.5 mm or less by the X-ray reflecting mirror 12b, and the objective mirror (Cassegrain reflection optical system) It is possible to irradiate the test sample 17 through a hole formed in the X-ray beam axis of 11a.

[Third Embodiment]
Next, a third embodiment of the molecular structure composite identification apparatus according to the present invention will be described with reference to FIG. The third embodiment is different from the first embodiment in that the condensing optical element 11 includes a perforated objective lens 11b into which an X-ray capillary 12a can be inserted. As described above, even if the condensing optical element 11 is constituted by the perforated objective lens 11b, visible light and Raman light can be condensed and irradiated on the test sample 17, and scattered light from the test sample 17 can be irradiated. In addition, it is possible to collect the reflected light and acquire an optical image of visible light with the sample observation camera 3, and to receive the Raman light with the Raman light receiving device 5. The perforated objective lens 11b has an advantage that it is easier to manufacture than the objective mirror.

[Fourth Embodiment]
Next, a fourth embodiment of the molecular structure composite identification apparatus according to the present invention will be described with reference to FIG. The fourth embodiment is different from the first embodiment in that the X-ray optical element 12 is composed of an X-ray reflecting mirror 12b. Therefore, the X-ray generation part (X-ray tube) 1 is slightly inclined. In the fourth embodiment, the point different from the second embodiment is that the condensing optical element 11 is constituted by a perforated objective lens 11b through which an X-ray beam passes. Thus, even if the X-ray optical element 12 is constituted by the X-ray reflecting mirror 12b, the X-ray beam is narrowed to a diameter of about 0.5 mm or less by the X-ray reflecting mirror 12b, and the X of the holed objective lens 11b is reduced. It is possible to irradiate the test sample 17 through a hole formed in the line beam axis. Further, even if the condensing optical element 11 is constituted by a perforated objective lens 11b, visible light and Raman light can be condensed and irradiated on the test sample 17, and scattered light and reflection from the test sample 17 can be irradiated. It is possible to collect the light and obtain an optical image of visible light with the sample observation camera 3, and it is possible to receive the Raman light with the Raman light receiving device 5. The perforated objective lens 11b has an advantage that it is easy to manufacture.

[Fifth Embodiment]
Next, a fifth embodiment of the molecular structure composite identification apparatus according to the present invention will be described with reference to FIG. The fifth embodiment is provided with means for measuring the solubility (melting point) of each test sample as the test sample mounting plate. FIG. 8 is a side cross-sectional view showing a case where the test sample mounting plate 16 ′ is composed of a glass (or plastic) substrate 161 and a functional bottom film 162b. In FIG. 8, the glass (or plastic) substrate 161 is separated from the functional bottom film 162b. As the functional bottom film 162b, on the surface side of a polyimide film (thickness of about 12.5 to 25 μm) 1621, a patterned individual resistance amorphous heating film (for example, non-heated) that can individually heat each test sample. A crystalline Cr—Si—O system) 1623 is formed, and glass (or plastic) is coated thereon, and the polyimide film 1621 has a patterned temperature for detecting the temperature of each test sample on the back side. An amorphous semiconductor film for detection (for example, an amorphous a-Si system) 1622 is formed, and glass (or plastic) is coated thereon. Thus, by comprising the bottom film with the functional bottom film 162b, the temperature of the individual heating amorphous resistance film 1623 is individually controlled to heat each test sample, so that the solubility of each test sample is increased. The (melting point) can be individually detected by the temperature detecting amorphous semiconductor film 1622. The individual temperature detecting amorphous semiconductor film 1622 and the individual heating amorphous resistance film 1623 are drawn out to the connector portion (not shown) at the end of the specimen mounting plate 16 by wiring, from the connector portion. It is connected to the overall control unit 15 and the data processing unit 15a. In this way, by configuring the test sample mounting plate 16 ′, the visible light optics showing the crystal form of each test sample 17 mounted as a cell or well on the test sample mounting plate 16 ′. After observing the image and obtaining an X-ray diffraction spectrum capable of polymorphic analysis and a Raman scattering spectrum capable of binding analysis, for example, each test sample 17 is heated to determine the solubility (melting point) of each test sample. It can be measured and input to the data processor 15a and stored in the storage device 15c.

  The time at which each test sample is melted can be detected, for example, by looking at the change in the spectrum of the Raman scattered light. Moreover, if the change of the measured temperature is observed, it is possible to detect the time when each test sample is melted. Therefore, the temperature (melting point) at the time when each test sample is melted can be measured by the individual semiconductor film 1622.

  If the solubility (melting point) of each test sample can be measured, an amorphous semiconductor film 1622 for individual temperature detection patterned on the front side of the polyimide film 1621 is formed and patterned on the back side of the polyimide film 1621. An individual heating amorphous resistance film 1623 may be formed. The reason why the semiconductor film 1622 and the resistance film 1623 are made amorphous is that an X-ray diffraction spectrum can be detected from each test sample 17.

[Example of test sample mounting plate]
Next, an embodiment of the test sample mounting plate 16 used in the molecular structure composite identification apparatus according to the present invention will be described with reference to FIG.

  FIG. 9A is a top view showing an embodiment of a 16 × 16 well array substrate. FIG. 9B is a perspective view showing a well array substrate equipped with an RFID (radiofrequency identification) 18a. As described above, the RFID 18a includes the individual identification code or information 18 given to the test sample mounting plate 16, the position coordinates or position information of each test sample on the test sample mounting plate, and each test sample. It is possible to record the formation conditions. As a result, by reading the information recorded on the RFID 18a, the overall control unit 15 can obtain the information without inputting it with the input means 15b.

  FIG. 9C is a side sectional view showing a case where the test sample mounting plate 16 is constituted by a glass (or plastic) substrate 161 and a bottom film 162a made of a polyimide film 1621. In FIG. 9C, the glass (or plastic) substrate 161 and the bottom film 162a are separated from each other.

  As described above, according to the embodiment of the molecular structure composite identification apparatus of the present invention, any one of X-ray diffraction and infrared light / visible light / ultraviolet light / Raman scattering is applied to a large number of test samples. Complex identification can be performed on molecular structures (crystal morphology, polymorphism analysis, binding analysis, etc.) accurately and efficiently in a short time without making errors by performing one or more simultaneously or sequentially. Further, as shown in the destructive test 2 in FIG. 2, it is possible to identify the solubility of each test sample.

  Further, according to the embodiment of the present invention, the Raman scattering spectrum, the reflected infrared spectrum, the reflected ultraviolet spectrum, and the X-ray diffraction pattern at the same site as the acquisition of the optical image of the test sample by visible light are simultaneously or spaced apart. It becomes possible to acquire without. For nondestructive measurement and identification of molecular structure in materials, bond analysis (the existence of functional groups and basic structures that are short-range ordered structures) is excellent in measurement analysis by Raman scattering, infrared and ultraviolet spectra, Measurement analysis by X-ray diffraction is excellent for polymorphic analysis (crystal structure and long-range ordered structure) of the specimen.

  Therefore, by using the complex molecular structure identification apparatus according to the present invention, it is possible to easily measure and analyze the molecular structure such as the crystal form of the test sample captured by an optical image and the presence or absence of a functional group, and identify the molecular structure. In addition, it is possible to quickly identify the optical image and molecular structure of the test sample with various preparation conditions, and the preparation conditions, measurement conditions, optical image, measurement spectrum and diffraction pattern of these test samples, Analysis / identification results can be automatically and sequentially stored in a computer recording device.

  The accumulated data is used to create the test sample and measure / analyze it. By organizing according to the identification results, it is possible to easily display the creation conditions of the molecular structure state of the target sample on the computer screen, making it possible to automate and shorten the creation condition search. Become. In addition, with regard to the preparation conditions and the handling of the test sample, a highly reliable system that minimizes human error is formed by reading the identification information attached to the sample mounting plate (test sample mounting plate). Yes. Therefore, these production conditions can be reproduced at any time, and a traceable material forming system can be configured.

It is a figure which shows 1st Embodiment of the molecular structure composite identification apparatus which concerns on this invention. It is a figure for demonstrating the content of the integrated nondestructive inspection about the recrystallized sample which concerns on this invention, and a subsequent destructive test. It is a figure which shows the principal part of 2nd Embodiment of the molecular structure composite identification apparatus which concerns on this invention. It is a figure which shows the principal part of 3rd Embodiment of the molecular structure composite identification apparatus which concerns on this invention. It is a figure which shows the principal part of 4th Embodiment of the molecular structure composite identification apparatus which concerns on this invention. FIG. 4 is a perspective view for explaining an example in which an X-ray diffraction pattern of a crystal of a test sample is measured using a scintillation counter or the like as an X-ray detector in the embodiment of the molecular structure composite identification apparatus according to the present invention. . In the embodiment of the molecular structure composite identification apparatus according to the present invention, an example in which an X-ray diffraction pattern of a crystal of a test sample is measured using a two-dimensional pixel detector such as a CCD as an X-ray detector will be described. FIG. It is side surface sectional drawing which shows the 5th Embodiment provided with the means to measure the solubility (melting | fusing point) of each test sample as a test sample mounting board which concerns on this invention. It is side surface sectional drawing which shows the Example of the test sample mounting plate used for the molecular structure composite identification apparatus which concerns on this invention.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 1 ... X-ray generation part (X-ray tube), 2 ... Sample illumination light source (visible light or Raman (infrared and ultraviolet) light illumination light source), 3 ... Sample observation camera (light receiving device), 4 ... Mount part, 4a ... All Reflection mirror, 4b ... half mirror, 4c ... half mirror, 5 ... Raman (infrared / ultraviolet) light receiving device, 6 ... X-ray blocking device (X-ray shutter device), 7 ... Raman (infrared / ultraviolet) light spectroscopic device, DESCRIPTION OF SYMBOLS 8 ... Power supply device for X-ray generation parts, 9, 53 ... X-ray detector (X-ray scintillation counter), 9b, 52 ... Slit, 10 ... Ring shutter, 11 ... Condensing optical element, 11a ... Objective mirror (Cassegrain reflection) Optical system), 11b ... objective lens, 12 ... X-ray optical element, 12a ... X-ray capillary, 12b ... X-ray reflector, 13 ... sample holding mechanism (sample mounting stage), 14 ... moving device (stage), 15 ... Overall control 15a ... data processing unit, 15b ... display device, 15c ... storage device, 16, 16 '... test sample mounting plate (test sample cell or sample plate with well), 17 ... test sample, 18 ... individual identification Reference code or information (for example, ID number), 18a ... RFID, 19 ... reading device, 20 ... X-ray diffraction, 21 ... linear movement type position adjustment mechanism, 22 ... Raman excitation laser light source (Raman illumination light source), 23 ... Optical fiber, 30 ... Molecular structure composite identification device, 31 ... Integrated nondestructive inspection, 51 ... X-ray passing part, 161 ... Glass (or plastic) substrate, 162a ... Bottom film, 162b ... Functional bottom film, 1621 ... Polyimide film , 1622... Amorphous semiconductor film for individual temperature detection, 1623... Amorphous resistor film for individual heating.

Claims (15)

A moving device that moves a sample holding mechanism for holding a test sample mounting plate to sequentially position each of a plurality of test samples mounted as cells or wells on the test sample mounting plate on a beam axis; ,
An X-ray generator for generating an X-ray beam;
A shutter device for controlling irradiation / non-irradiation of the X-ray beam generated from the X-ray generation unit;
An X-ray optical element that irradiates the test sample positioned on the beam axis by limiting the X-ray beam irradiated through the shutter device to a diameter of 0.5 mm or less;
An illumination light source that emits a wavelength beam of Raman light;
Condensing optics for condensing and irradiating the test sample located on the beam axis with the wavelength beam emitted from the illumination light source, and condensing the Raman scattered light emitted from the test sample The system,
An X-ray detector that is installed relative to the X-ray optical element across the test sample and detects an X-ray diffraction pattern from the test sample irradiated with the X-ray beam;
A detection optical system including a light receiving device that receives and detects Raman scattered light collected by the light collecting optical system;
In the condensing optical system , a hole for arranging the X-ray optical element or a hole for allowing the X-ray beam irradiated from the X-ray optical element to pass through is provided on the beam axis, whereby the position located on the beam axis is set. X-rays detected by the X-ray detector by performing X-ray beam irradiation by the X-ray optical element and wavelength beam condensing irradiation by the condensing optical system simultaneously or successively on the test sample A molecular structure composite identification apparatus characterized in that diffraction pattern data and Raman scattering spectrum data detected by the detection optical system are acquired simultaneously or successively from the test sample located on the beam axis. In the molecular structure composite identification apparatus according to claim 1,
Further, the test sample mounting plate includes a patterned individual heating amorphous resistance film formed on the surface side of the polyimide film and a patterned individual temperature detection formed on the back side of the polyimide film. A glass or plastic substrate is provided on a functional bottom film composed of an amorphous semiconductor film, and each test sample placed as a cell or well on the glass or plastic substrate is individually A means for individually measuring the solubility of each test sample by individually heating by the amorphous resistance film for heating and measuring the temperature of each test sample by the amorphous semiconductor film for individual temperature detection; A molecular structure composite identification apparatus characterized in that solubility data of each test sample is acquired by the means. In the molecular structure composite identification apparatus according to claim 1,
The moving device is configured such that the position coordinates of a test sample placed as a cell or well on the test sample mounting plate are controlled continuously or discretely with respect to the beam axis. Characteristic molecular structure composite identification device. In the molecular structure composite identification apparatus according to claim 1,
A molecular structure composite identification apparatus, wherein the X-ray optical element comprises a tubular reflective X-ray capillary having an inner diameter of 0.5 mm or less. In the molecular structure composite identification apparatus according to claim 1,
A molecular structure composite identification apparatus, wherein the X-ray optical element is composed of an X-ray reflecting mirror having a surface shape so that reflected X-rays converge on the test sample. In the molecular structure composite identification apparatus according to claim 1,
The molecular structure composite identification apparatus, wherein the condensing optical system is constituted by a reflecting mirror provided on the beam axis with a hole through which an X-ray beam irradiated from the X-ray optical element passes. In the molecular structure composite identification apparatus according to claim 1,
The molecular structure composite identification apparatus, wherein the condensing optical system is composed of an optical lens provided on the beam axis with a hole through which the X-ray beam irradiated from the X-ray optical element passes. In the molecular structure composite identification apparatus according to claim 1,
The X-ray detector is centered on an X-ray detection device having a detectable region with a diameter of 20 mm or more and 80 mm or less, and a position on the extended line of the X-ray beam that irradiates the sample to the sample side of the X-ray detection device. A molecular structure composite identification apparatus comprising: an installed circular slit; and a linear movement type position adjusting mechanism for transmitting only a specific diffraction line so as to irradiate the X-ray detection device. In the molecular structure composite identification apparatus according to claim 1,
A two-dimensional X-ray detector is used as the X-ray detector, and a numerical value integrated for each annular region centering on a position on an extended line of the X-ray beam irradiating the test sample is obtained. A molecular structure composite identification apparatus characterized by acquiring X-ray diffraction pattern data. In the molecular structure composite identification apparatus according to claim 1,
The test sample mounting plate is configured with at least an individual identification code or information,
A molecular structure composite identification apparatus comprising a reader for reading the assigned individual identification code or information by any one of mechanical, optical, electromagnetic, and magnetic methods or a plurality of methods. In the molecular structure composite identification apparatus according to claim 1,
Furthermore, the individual identification code or information given to the test sample mounting plate, and the position coordinates or position information of each test sample mounted as a cell or well on the test sample mounting plate A molecular structure composite identification apparatus comprising management means for managing data corresponding to data acquired from each test sample. In the molecular structure composite identification apparatus according to claim 1,
And a storage device for storing the identification information of each test sample placed as a cell or well on the test sample mounting plate in correspondence with the data acquired from each test sample. Molecular structure composite identification device characterized by In the molecular structure composite identification apparatus according to claim 1,
Further, the identification information of each test sample placed as a cell or well on the test sample mounting plate and the formation conditions of each test sample are made to correspond to the data acquired from each test sample. A molecular structure composite identification device comprising a storage device for storing information. In the molecular structure composite identification apparatus according to claim 1,
A storage sample holder for storing a plurality of test sample mounting plates; and an exchange device for automatically replacing the test sample mounting plate between the storage sample holder and the sample holding mechanism. Each time the measurement on a single test sample mounting plate is completed, the test sample mounting plate in the storage sample holder is replaced with the sample holding mechanism sequentially or in a designated order by the replacement device. Molecular structure composite identification apparatus characterized by the above. In the molecular structure composite identification apparatus according to claim 14,
Further, the identification information of each test sample placed as a cell or well on the test sample mounting plate and the formation conditions of each test sample are made to correspond to the data acquired from each test sample. A molecular structure composite identification device comprising a storage device for storing information.

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