Single crystal x-ray structure analysis device and single crystal x-ray structure analysis method

Abstract

Provided are a user-friendly single-crystal X-ray structure analysis device and method whereby single-crystal X-ray structure analysis based on a fine-pore complex crystal (crystal sponge) can be quickly performed and management of related information is facilitated. A single crystal X-ray structure analyzer is provided with: a sample holder containing a porous complex crystal capable of occluding a sample in a plurality of micropores formed therein; the goniometer is used for installing and rotating the sample holder; an X-ray irradiation unit that irradiates X-rays from the X-ray source to a sample held in a sample holder attached to a goniometer; an X-ray detection and measurement unit that detects and measures X-rays diffracted or scattered by the sample; and a structure analysis unit that performs structure analysis of the sample on the basis of the diffracted or scattered X-rays measured by the X-ray detection and measurement unit, the structure analysis unit performing structure analysis of the sample on the basis of the occlusion results in the step of occluding the sample with the porous complex crystal.

Description

[0001] This application is a divisional application of a patent application (application date November 21, 2019, international application number PCT / JP2019 / 045691, entered the Chinese national stage on July 12, 2021, Chinese national stage application number 201980088745.9, invention name is "Single crystal X-ray structure analysis device and method for the same"). Technical Field

[0002] The present invention relates to a next-generation single crystal X-ray structure analysis device capable of analyzing the structure of a material through its microscopic collective structure such as the arrangement of atoms and molecules, and in particular to a single crystal X-ray structure analysis device and a method therefor that has good yield, high efficiency, excellent versatility, and can be operated in a user-friendly manner. Background Art

[0003] In the research and development of new devices and materials, material synthesis, material evaluation, and the decision of the next research direction based on this are carried out on a daily basis. In the structural analysis of materials using X-ray diffraction for short-term material development, in order to efficiently explore the material structure that realizes the function / physical properties of the target material, a material structure exploration method centered on the structural analysis of materials that can effectively perform structural analysis and X-ray structural analysis used therein are required.

[0004] However, to perform structural analysis based on the results obtained using this method, an expert in X-rays is required. Therefore, an X-ray structural analysis system that can perform structural analysis even if one is not an expert in X-rays is required. Among them, single crystal X-ray structural analysis has attracted attention as a method that can obtain the three-dimensional structure of a molecule accurately and with high precision, as is also known in the following patent document 1.

[0005] On the other hand, in the single crystal X-ray structure analysis, there is a great restriction that the sample must be crystallized to prepare a single crystal. However, as also known in the following non-patent documents 1 and 2 and patent document 2, through the development of a material called "crystal sponge" (for example, a porous complex crystal with numerous pores of 0.5nm to 1nm in diameter), single crystal X-ray structure analysis can be widely applied to liquid compounds that are not crystallized and samples that cannot be ensured in an amount sufficient for crystallization.

[0006] Prior Art Literature

[0007] Patent Literature

[0008] Patent Document 1: Japanese Patent Application Publication No. 2007-3394

[0009] Patent Document 2: Japanese Patent Re-publication No. WO2016 / 017770

[0010] Non-patent literature

[0011] Non-patent literature 1: Makoto Fujita; X-ray analysis on the nanogram to microgram scale using porous complexes; Nature 495, 461-466; 28 March 2013

[0012] Non-patent literature 2: Hoshino et al. (2016), The updated crystalline sponge method IUCrJ, 3, 139-151 Summary of the invention

[0013] Problems to be solved by the invention

[0014] However, in the single crystal X-ray structure analysis which is the prior art using the above-mentioned crystal sponge, the following steps need to be performed quickly and accurately: the step of absorbing a very small amount of sample of about several ng to several μg separated by various devices in the skeleton of the extremely small and fragile crystal sponge of about 100 μm in size; and the step of taking out the extremely small crystal sponge absorbing the sample, installing it in an instrument, and carrying it at the X-ray irradiation position in the single crystal X-ray structure analysis device, which is accompanied by fine and meticulous operations. In addition, these fine and meticulous operations performed in a short time have a great influence on the measurement results of the sample absorbed in the crystal sponge, and become very important operations. Furthermore, in addition to this, the management of information related to the crystal sponge and the sample also becomes important in the preparation of the sample, its management, measurement and analysis, subsequent verification, storage, etc.

[0015] Therefore, the present invention has been completed in view of the problems in the above-mentioned prior art, and its purpose is to provide a single crystal X-ray structure analysis device and method, especially even without professional knowledge of X-ray structure analysis, and without the previous fine and meticulous operations that require speed, it is possible to quickly, reliably and easily perform single crystal X-ray structure analysis based on extremely small and fragile crystal sponge. In other words, the yield is good and efficient, and the versatility is excellent. In addition, in the preparation, management, measurement, subsequent storage, verification, etc. of the sample, it is easier to manage information related to the sample including the crystal sponge. In other words, it is user-friendly, and a sample holder (which may also include an applicator) is provided as an instrument therefor.

[0016] Means for solving problems

[0017] (1) To achieve the above-mentioned object, the single crystal X-ray structure analysis device of the present invention is a single crystal X-ray structure analysis device for performing structural analysis of a substance, characterized in that it comprises: an X-ray source for generating X-rays; a sample holder including a porous complex crystal capable of absorbing a sample in a plurality of micropores formed therein; a goniometer for mounting and rotating the sample holder; an X-ray irradiation unit for irradiating the sample held in the sample holder mounted on the goniometer with X-rays from the X-ray source; an X-ray detection and measurement unit for detecting and measuring X-rays diffracted or scattered by the sample; a structure analysis unit for performing structural analysis of the sample based on the diffracted or scattered X-rays measured by the X-ray detection and measurement unit; an information acquisition unit for acquiring invariant information related to the porous complex crystal or variable information after absorption of the sample; and an information storage unit for storing the invariant information or the variable information acquired by the information acquisition unit.

[0018] (2) In the single crystal X-ray structure analysis apparatus of the present invention, the variable information includes at least one of a condition in preparation of the sample, an absorption condition, an absorption result, a measurement condition, and a measurement result.

[0019] (3) In the single crystal X-ray structure analysis apparatus of the present invention, the invariant information includes at least one of the type, manufacturer, manufacturing location, manufacturing date and time, lot number, and supporting information of the porous complex crystal.

[0020] (4) In the single crystal X-ray structure analysis apparatus of the present invention, the detection and measurement of X-rays of the sample or the structural analysis of the sample is performed based on the invariant information or the variable information stored in the information storage unit.

[0021] (5) In addition, in the single crystal X-ray structure analysis device of the present invention, the invariant information or the variable information acquired by the information acquisition unit is information held in an information holding unit mounted on the sample holder or in an applicator that accommodates the sample holder.

[0022] (6) In the single crystal X-ray structure analysis apparatus of the present invention, the information storage unit is a bar code displayed on the sample holder or the applicator, and the constant information or the variable information is included in the bar code.

[0023] (7) In the single crystal X-ray structure analysis apparatus of the present invention, the information holding unit is a semiconductor storage device attached to the sample holder or the applicator, and the invariant information or the variable information is stored in the semiconductor storage device.

[0024] (8) In addition, the single crystal X-ray structure analysis device of the present invention is characterized in that:

[0025] The constant information or the variable information acquired by the information acquisition unit is information stored outside the sample holder and the applicator and is acquired based on unique information held or displayed by the sample holder or the applicator storing the sample holder therein.

[0026] (9) In addition, the single crystal X-ray structure analysis method of the present invention is a single crystal X-ray structure analysis method for performing structural analysis of a substance using a sample holder, and is characterized in that it includes: an absorption step, introducing a sample to be analyzed into the porous complex crystal held by the sample holder to absorb the sample; an installation step, installing the sample holder after the sample is absorbed on a goniometer of the single crystal X-ray structure analysis device; an information acquisition step, acquiring invariant information related to the porous complex crystal or variable information after the sample absorption step; an information storage step, storing the acquired invariant information or variable information; an X-ray detection and measurement step, irradiating the sample with X-rays from an X-ray source of the single crystal X-ray structure analysis device, detecting and measuring X-rays diffracted or scattered by the sample; and a structure analysis step, performing structure analysis of the sample based on the diffracted or scattered X-rays detected and measured by the X-ray detection and measurement step.

[0027] (10) In the single crystal X-ray structure analysis method of the present invention, the variable information includes at least one of conditions in preparation of the sample, absorption conditions, absorption results, measurement conditions, and measurement results.

[0028] (11) In addition, in the single crystal X-ray structure analysis method of the present invention, the invariant information includes at least one of the type, manufacturer, manufacturing location, manufacturing date and time, lot number, and supporting information of the porous complex crystal.

[0029] (12) In the single crystal X-ray structure analysis method of the present invention, the X-ray detection and measurement step or the structure analysis step is performed based on the invariant information or the variable information stored in the information storage step.

[0030] Effects of the Invention

[0031] According to the present invention described above, a single crystal X-ray structure analysis device is provided. By having a sample holder (which may also include an applicator) newly proposed by the present invention, a unit for obtaining relevant information, and further having a unit for storing the information, a series of operations including the absorption of the sample into an extremely small and fragile crystal sponge and the subsequent loading into the device can be performed quickly, reliably, and easily without the previous meticulous and fine operations that also require rapidity. In other words, the yield is good and efficient, and the versatility is excellent. In addition, the management of information related to the sample including the extremely small crystal sponge, including input operations and subsequent retrieval operations, can be made easier, that is, user-friendly. Furthermore, a method thereof and a sample holder (which may also include an applicator) as an instrument therefor are provided. Therefore, single crystal X-ray structure analysis based on the extremely small crystal sponge described above can be easily utilized and can be widely popularized. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is a diagram showing the overall configuration of a single crystal X-ray structure analysis apparatus including a single crystal X-ray diffraction apparatus according to one embodiment of the present invention.

[0033] Figure 2 It is a diagram showing the structure of the above-mentioned single crystal X-ray diffraction apparatus.

[0034] Figure 3 This is a block diagram showing the internal electrical structure of the above-mentioned single crystal X-ray structure analysis device.

[0035] Figure 4 The figures include photographs showing XRDS patterns or images obtained by the above-mentioned single crystal X-ray structure analysis device.

[0036] Figure 5 The figure includes a photograph showing an example of a screen in which the X-ray diffraction data measurement / processing software is executed in the above-mentioned single crystal X-ray structure analysis apparatus.

[0037] Figure 6 The figure includes a screen showing a molecular model created using a structure analysis program of the above-mentioned single crystal X-ray structure analysis apparatus.

[0038] Figure 7 The figure includes a photograph showing an example of a structure centered on a goniometer of the single crystal X-ray diffraction apparatus.

[0039] Figure 8 It is a perspective view showing the overall structure of a sample holder including a barcode attached to the goniometer.

[0040] Fig. 9 is a cross-sectional view of the sample holder.

[0041] Fig.10 This is a diagram showing an example of a mode in which the above-mentioned sample holders are provided as a batch.

[0042] Fig.11 This is a flowchart showing an example of a single crystal X-ray structure analysis method using the above-mentioned sample holder.

[0043] Fig.12 This is a diagram showing an example of a pre-processing device used in the above-mentioned single crystal X-ray structure analysis method.

[0044] Fig.13 This is a diagram showing a state where specific information is read by a barcode reader from the sample holder after the sample is absorbed into the crystal sponge.

[0045] Fig.14 This is a diagram showing an example of the structure of a single crystal X-ray structure analysis apparatus including a unit for capturing the above-mentioned specific information and a sample management information database for managing the specific information and its data structure. DETAILED DESCRIPTION

[0046] Hereinafter, a single crystal X-ray structure analysis device using a crystal sponge according to an embodiment of the present invention will be described in detail with reference to the accompanying drawings. In addition, in the present application, the expression "A or B" means "at least one of A and B", and includes "A and B" as long as there is no special situation in which A and B cannot appear.

[0047] In the attached Figure 1 The figure shows the overall appearance structure of a single crystal X-ray structure analysis device including a single crystal X-ray diffraction device according to an embodiment of the present invention. As can be seen from the figure, the single crystal X-ray structure analysis device 1 has a base 4 for storing a cooling device and an X-ray generating power supply unit, and an X-ray shield 6 mounted on the base 4.

[0048] The X-ray shield 6 includes a housing 7 surrounding the single crystal X-ray diffraction device 9 and a door 8 provided on the front surface of the housing 7. The door 8 provided on the front surface of the housing 7 can be opened, and various operations can be performed on the single crystal X-ray diffraction device 9 inside in the opened state. In addition, the present embodiment shown in the figure is a single crystal X-ray structure analysis device 1 including a single crystal X-ray diffraction device 9 for performing structural analysis of a substance using a crystal sponge described later.

[0049] like Figure 2 As shown in FIG. 1 , the single crystal X-ray diffraction device 9 includes an X-ray tube 11 and a goniometer 12. Although not shown in the figure, the X-ray tube 11 includes a filament, a target (also called a "counter cathode") arranged opposite to the filament, and a housing for storing them in an airtight manner. Figure 1 The X-ray generating power supply unit of the base 4 is energized to generate heat, thereby emitting thermal electrons. In addition, a high voltage is applied between the filament and the target by the X-ray generating power supply unit, and the thermal electrons emitted from the filament are accelerated by the high voltage and collide with the target. The collision area forms an X-ray focus, and X-rays are generated and diverged from the X-ray focus. In more detail, although not shown here, the X-ray tube 11 is configured to include optical elements such as a micro-focusing tube and a multi-layer film focusing reflector, and can irradiate a light beam with a higher brightness. In addition, it can be selected from a ray source such as Cu, Mo, Ag, etc. As exemplified above, the filament, the target arranged opposite to the filament, and the housing that hermetically stores them function as an X-ray source, and the structure for X-ray irradiation including optical elements such as a micro-focusing tube and a multi-layer film focusing reflector functions as an X-ray irradiation unit.

[0050] In addition, the goniometer 12 includes: a θ rotating table 16 that supports the sample S to be analyzed and can rotate around the sample axis ω passing through the X-ray incident point of the sample S; and a 2θ rotating table 17 that is arranged around the θ rotating table 16 and can rotate around the sample axis ω. In addition, in the case of the present embodiment, the sample S is absorbed in the inside of a crystal sponge that is pre-installed in a part of a sample holder 250 described in detail later. Inside the base 18 of the goniometer 12, a driving device (not shown) for driving the above-mentioned θ rotating table 16 and 2θ rotating table 17 is stored. By driving these driving devices, the θ rotating table 16 is intermittently or continuously rotated at a predetermined angular velocity, so-called θ rotation. In addition, by driving these driving devices, the 2θ rotating table 17 is intermittently or continuously rotated, so-called 2θ rotation. The above-mentioned driving device can be composed of any structure, for example, it can be composed of a power transmission structure composed of a worm and a worm wheel.

[0051] An X-ray detector 22 is mounted on a part of the outer periphery of the goniometer 12. The X-ray detector 22 is composed of, for example, a CCD type, a CMOS type two-dimensional pixel detector, a hybrid pixel detector, etc. The X-ray detection and measurement unit refers to a structure that detects X-rays diffracted or scattered by a sample for measurement, and includes the X-ray detector 22 and a control unit that controls the X-ray detector 22.

[0052] The single crystal X-ray diffraction device 9 is configured as described above, so that the sample S is θ-rotated about the sample axis ω by the θ rotation of the θ rotation table 16 of the goniometer 12. During the θ rotation of the sample S, the X-rays generated from the X-ray focus in the X-ray tube 11 and directed toward the sample S are incident on the sample S at a predetermined angle and are diffracted and diverged. That is, the incident angle of the X-rays incident on the sample S changes according to the θ rotation of the sample S.

[0053] If the Bragg diffraction condition is satisfied between the incident angle of the X-ray incident on the sample S and the lattice plane, diffracted X-rays are generated from the sample S. The diffracted X-rays are received by the X-ray detector 22 and the X-ray intensity is measured. By the above, the intensity of the diffracted X-rays corresponding to the angle of the X-ray detector 22 relative to the incident X-rays, that is, the diffraction angle, is measured, and the crystal structure related to the sample S is analyzed based on the measurement results.

[0054] then, Figure 3 (A) shows a detailed example of the electrical internal structure of the control unit 110 in the above-mentioned single crystal X-ray structure analysis apparatus. It is needless to say that the present invention is not limited to the embodiments described below.

[0055] The single crystal X-ray structure analysis device 1 includes the above-mentioned internal structure, and further has: a measuring device 102 for measuring a suitable substance as a sample; an input device 103 composed of a keyboard, a mouse, etc.; an image display device 104 as a display unit; a printer 106 as a unit for printing and outputting analysis results; a CPU (Central Processing Unit) 107; a RAM (Random Access Memory) 108; a ROM (Read Only Memory) 109; a hard disk 111 as an external storage medium, etc. These elements are electrically connected to each other via a bus 112.

[0056] The image display device 104 is composed of an image display device such as a CRT display and a liquid crystal display, and displays an image on a screen according to an image signal generated by an image control circuit 113. The image control circuit 113 generates an image signal based on the image data input thereto. The image data input to the image control circuit 113 is formed by the action of various computing units implemented by a computer including a CPU 107, a RAM 108, a ROM 109, and a hard disk 111. The printer 106 can use an ink plotter, a dot printer, an inkjet printer, an electrostatic transfer printer, or other printing devices of any structure. In addition, the hard disk 111 can also be composed of a magneto-optical disk, a semiconductor memory, or other storage media of any structure.

[0057] The hard disk 111 stores analysis application software 116 for controlling the overall operation of the single crystal X-ray structure analysis apparatus 1, measurement application software 117 for controlling the operation of measurement processing using the measurement device 102, and display application software 118 for controlling the operation of display processing using the image display device 104. These application software are read from the hard disk 111 and transferred to the RAM 108 as needed to realize predetermined functions.

[0058] The single crystal X-ray structure analysis device 1 also includes a database placed in a cloud region, for example, for storing various measurement results including the measurement data obtained by the above-mentioned measurement device 102. In the example of the figure, which will also be described later, there is shown an XRDS information database 120 storing XRDS image data obtained by the above-mentioned measurement device 102, a microscope image database 130 storing measured images obtained by a microscope, and other analysis databases 140 storing measurement results and physical property information obtained by analysis other than X-rays such as XRF and Raman rays. In addition, these databases do not necessarily need to be installed inside the single crystal X-ray structure analysis device 1, and for example, they can also be set outside and connected to each other via a network 150 or the like so that they can communicate with each other.

[0059] As a file management method for storing a plurality of measurement data in a data file, a method of storing each measurement data in a single file is also conceivable, but in this embodiment, Figure 3 As shown in (B), multiple measurement data are continuously stored in one data file. Figure 3 The storage area described as "condition" in (B) is an area for storing various information including device information and measurement conditions when obtaining measurement data.

[0060] As such measurement conditions, the following conditions can be considered: (1) the name of the substance to be measured, (2) the type of measurement device, (3) the measurement temperature range, (4) the measurement start time, (5) the measurement end time, (6) the measurement angle range, (7) the movement speed of the scanning movement system, (8) the scanning conditions, (9) the type of X-ray incident on the sample, (10) whether to use a sample high temperature device and other accessories, and various other conditions. In addition, the file management method of the measurement data is described in detail below.

[0061] XRDS (X-ray Diffraction and Scattering) pattern or image (refer to Figure 4 ) is obtained by receiving and accumulating X-rays received in a two-dimensional space, i.e., a plane, of the X-ray detector 22 constituting the above-mentioned measuring device 102, at each pixel arranged in a plane constituting the detector, and measuring the intensity thereof. For example, by detecting the intensity of the received X-rays by integration at each pixel of the X-ray detector 22, a pattern or image in a two-dimensional space of r and θ can be obtained.

[0062] <Measurement application software>

[0063] The XRDS pattern or image in the observation space obtained by diffraction and scattering of the X-rays of the object material irradiated with X-rays reflects the information of the electron density distribution in the actual space of the object material. However, the XRDS pattern is a two-dimensional space of r and θ, and does not directly express the symmetry of the object material in the actual space as a three-dimensional space. Therefore, in general, it is difficult to determine the (spatial) arrangement of atoms and molecules constituting the material using only the existing XRDS image, and professional knowledge of X-ray structure analysis is required. Therefore, in this embodiment, the above-mentioned measurement application software is used to achieve automation. In this way, the single crystal X-ray structure analysis device 1 controls the action of the measurement processing using the measurement device 102 through the X-ray detection measurement unit, and accepts and manages various measurement results including the measurement data obtained by detecting the X-rays diffracted or scattered by the sample. In addition, the structure analysis unit performs the structure analysis of the sample based on various measurement results including the measurement data obtained by detecting the X-rays diffracted or scattered by the sample.

[0064] As an example, Figure 5 As shown in (A) and (B) of FIG. 1 , the CrysAlis Pro " X-ray diffraction data measurement / processing software, performs preliminary measurement, measurement condition setting, actual measurement, data processing, etc. Furthermore, by installing an automatic structure analysis plug-in called "AutoChem", structural analysis and structural refinement are performed in parallel with X-ray diffraction data collection. Then, by Figure 6 The one shown is called "Olex 2 " structural analysis program, from space group determination to phase determination, molecular model construction and correction, structure refinement, final report, and CIF file preparation.

[0065] The overall structure and functions of the single crystal X-ray structure analysis device 1 are described above. Hereinafter, the crystal sponge and the devices and instruments related thereto according to the present invention will be described in detail with particular reference to the accompanying drawings.

[0066] <Crystal Sponge>

[0067] As described above, by developing a material called "crystal sponge" that is an extremely tiny and fragile porous complex crystal with a size of about 10 μm to 100 μm and countless pores with a diameter of 0.5 nm to 1 nm inside, single crystal X-ray structure analysis can be widely applied to uncrystallized liquid compounds or extremely small amounts of samples of several ng to several μg that cannot be ensured to be sufficient for crystallization.

[0068] However, in the current situation, in order to perform crystallization (post-crystallization) as a sample in the skeleton of the above-mentioned crystal sponge, it is necessary to absorb an extremely small amount of sample of about several ng to several μg separated by various pre-treatment (separation) devices into the skeleton of an extremely small and fragile crystal sponge of about 100 μm in outer diameter provided by immersing in a storage solvent (carrier) such as cyclohexane in a container as described above. Furthermore, it is necessary to take out the extremely small and fragile crystal sponge that is difficult to handle and absorb the sample from the container quickly (in a short time so that the crystal sponge is not destroyed by drying) and accurately place it at the X-ray irradiation position in the single crystal X-ray diffraction device, more specifically, at the tip of the sample shaft (so-called goniometer head pin) of the goniometer 12 while centering it. These processes are very delicate and quick operations that require operators to be extremely precise regardless of whether they have professional knowledge of X-ray structure analysis, and they have a great impact on the measurement results of the sample after being absorbed in the crystal sponge. In other words, these operations make the yield of single crystal X-ray structure analysis using extremely small crystal sponges poor, which has become a factor that hinders the widespread use of single crystal X-ray structure analysis using crystal sponges.

[0069] In addition, since the outer diameter of the crystal sponge is extremely small at about 100 μm, it is not only difficult to handle it, but also difficult to store, verify, and manage it after measurement.

[0070] The present invention is achieved based on the insights of the inventors as mentioned above, and realizes a single crystal X-ray structure analysis device. By using the crystal sponge sample holder (also simply referred to as the sample holder) described below and the applicator as its processing (operation) tool, it is possible to quickly, reliably and easily perform single crystal X-ray structure analysis based on extremely small and fragile crystal sponges, and can easily and reliably manage the information of samples including extremely small crystal sponges, including its input operation and further including the retrieval of the information such as verification, storage, and management after measurement. In other words, the yield is good and efficient, the versatility is excellent, and it is user-friendly. That is, in the next-generation single crystal X-ray structure analysis device involved in the present invention, there are major constraints as follows: it is necessary to prepare an extremely small and fragile crystal sponge that absorbs an extremely small amount of sample, and further take out the sample S (crystal sponge) from the absorption container and quickly, accurately and quickly install it at a specified position at the front end of the goniometer 12 in a short time to the extent that the crystal sponge will not be destroyed by drying; but in order to realize a user-friendly device with excellent versatility, it is necessary to be able to perform this operation quickly and easily without requiring high-level professional knowledge and meticulous work.

[0071] In order to solve this problem, the present invention provides a single crystal X-ray structure analysis device and method thereof, which can be used by anyone quickly, reliably, and easily with good yield, high efficiency, and is user-friendly, while using extremely small and fragile crystal sponges that are difficult to handle, and has excellent versatility. At the same time, including its input operation and subsequent retrieval operation, anyone can easily and reliably manage the related information of the sample including the crystal sponge (information required for preparation, processing, storage, management before measurement, verification, storage, etc. after measurement) and further provides a sample holder including an applicator as an instrument therefor, which is described in detail below.

[0072] Figure 7 (A) shows the front end of the goniometer 12 in an enlarged manner. In this figure, a so-called sample holder 250 is mounted (assembled) on the goniometer head 121 at the front end of the goniometer 12. The sample holder 250 is a device proposed by the present invention in which a crystal sponge 200 for absorbing a sample to be analyzed is pre-mounted at its front end. Figure 7 The sample holder 250 can be attached to and detached from the goniometer head 121 at the front end of the goniometer 12 by a mounting / positioning mechanism using magnetic force, etc., and can be easily and accurately mounted at a correct position by anyone.

[0073] <Specimen holder and applicator for crystal sponge>

[0074] Figure 8 The whole perspective view of the sample holder 250 is shown, and Fig. 9 The cross section thereof is shown in FIG. 2 . In the sample holder 250, the goniometer head 121 (see FIG. 2 ) mounted on the front end of the goniometer 12 is Figure 7 In the base part 251 of the disc-shaped or conical holder made of metal or the like of (A)), a pin (cylindrical)-shaped sample holding part (hereinafter, also referred to as a holding part) 252 (corresponding to the so-called goniometer pin) stands upright at the center of one surface (the lower surface in the figure), and the crystal sponge 200 for absorbing the sample to be analyzed is pre-installed and fixed integrally with the sample holder 250 at a predetermined position at the front end of the pin-shaped holding part 252. In addition, a positioning mechanism such as a magnet (not shown) is provided on the other surface (the upper surface in the figure) of the disc-shaped base part 251. By means of this positioning mechanism, the sample holder 250 is detachably mounted on the front end of the goniometer 12.

[0075] In addition, Figure 8 as well as Fig. 92 shows a so-called applicator 300 as a processing (handling) tool used together with the sample holder 250 and for absorbing the sample into the crystal sponge 200 pre-installed in the sample holder. The applicator 300 is formed of a transparent or opaque member such as glass, resin, metal, etc., and has a storage space 301 for storing the sample holder 250 formed therein, and an opening 302 for inserting and removing the sample holder 250 formed at the top thereof.

[0076] Furthermore, a sealing portion (indicated by a hatched portion in the figure) is provided at a part of the opening 302 of the applicator 300, for example, so that the sample holder 250 is stored in the storage space 301 inside the applicator 300 and the airtightness is maintained from the outside. On the other hand, a pair of through pores 253, 253 for introducing the sample to be analyzed into the crystal sponge 200 located inside the applicator 300 (storage space 301) is formed in the base portion 251 of the sample holder 250. The pores 253, 253 are a preferred example of a sample introduction structure, and other structures can also be adopted. In addition, although not shown in the figure, a sealing portion is also provided at these pores 253, 253, thereby, as shown in the figure, even in a state where the sample introduction tubes (hereinafter, also referred to as introduction tubes) 254, 254 for introducing the sample into the crystal sponge 200 are inserted into the pores 253, 253, the storage space 301 inside the applicator 300 is maintained in an airtight state.

[0077] According to the sample holder 250 of such a structure, or by further integrating (assembling) with the applicator 300 as its processing (operation) tool, the crystal sponge 200 attached to the front end of the pin-shaped holding portion 252 (corresponding to the goniometer head pin) constituting a part of the sample holder 250 can be handled safely and easily without damaging it or detaching from the sample holder 250. That is, the crystal sponge 200 that has absorbed a very small amount of the sample can be safely, simply, and easily prepared on the goniometer head 121 in a short time without being damaged by being taken out individually from the absorption container as in the past. In the present embodiment, the sample holder 250 that has finished absorbing the sample is removed from the applicator 300 and the goniometer head 121 (see FIG. 1 ) attached to the front end of the goniometer 12 is removed. Figure 7 (A)). Thus, the sample S absorbed in the crystal sponge 200 can be easily, accurately and quickly arranged at a predetermined position in the single crystal X-ray diffraction apparatus 9 without requiring high expertise or careful work.

[0078] In addition, in a part of the sample holder 250, for example, by pasting a sheet or embossing, information for identifying the crystal sponge 200 that is pre-attached to the front end of the pin-shaped holding portion 252 and is used to absorb the sample to be analyzed, that is, unique information 220 (see Figure 8 ). More specifically, in this example, the information is displayed as a barcode 220 on the outer peripheral surface of the base portion 251 which is a part of the sample holder 250. The barcode 220 as the inherent information can be installed in a place covered by the applicator 300 as shown in 220a in the figure when the applicator 300 is transparent, or can be installed on the outer peripheral surface of the applicator 300 when the applicator 300 is opaque (see Figure 8 That is, it is desirable that the barcode as the unique information is attached to a location where it can be visually recognized from the outside even when the sample holder 250 is accommodated inside the applicator 300.

[0079] In addition, the inherent information is preferably information related to the measurement, such as the inherent number and associated information related to the crystal sponge and the sample, and the inherent number and associated information related to the sample holder and the applicator, but is not limited to this, as long as the corresponding invariant information and variable information can be determined and obtained. Fig.10 The storage position of each applicator of the sample housing shown is used as inherent information. In addition, the sample holder 250 is integrated (moduleized) with the applicator 300 as its processing (operation) tool, and further, as shown in FIG. Fig.10 As shown, the quantity required for the analysis operation can be prepared and stored in a box-shaped casing to provide as a so-called batch.

[0080] <Single crystal X-ray structure analysis method using a crystal sponge sample holder>

[0081] Next, a single crystal X-ray structure analysis method performed by using a sample holder 250 pre-installed with the crystal sponge 200 and an applicator 300 as a processing tool thereof will be described below. In addition, as described above, the sample holder 250 and the applicator 300 may also be provided as a whole (assembly) or as a set.

[0082] Fig.11The present invention conceptually shows a single crystal X-ray structure analysis method using a sample holder 250 and an applicator 300 as one embodiment of the present invention. In this method, as described above, a very small amount of sample is introduced into the sample holder 250 provided as a whole (assembly) with the applicator 300, and necessary absorption is performed. At this time, in the above-mentioned example, in a state where the sample holder 250 is stored in the applicator 300, a pair of through holes 253, 253 (see FIG. 2 ) formed in the sample holder 250 are opened. Fig. 9 ) is inserted into a pair of sample introduction tubes 254, 254 from a pre-processing device described later, thereby enabling the sample to be absorbed in the crystal sponge 200 attached to the front end of the sample holder 250.

[0083] More specifically, if Fig.12 As shown, for example, a very small amount of sample S extracted by LC (liquid chromatograph) 401, GC (gas chromatograph) 402, SFC (supercritical fluid chromatograph) 403, CE (capillary electrophoresis) 404, etc. constituting a pretreatment device 400 is supplied together with the carrier (carrier) to a pair of sample introduction tubes 254, 254 inserted into the fine holes 253, 253 of the sample holder 250 through an absorption device (permeation device) 500 equipped with various switching valves and a pressure regulating device to supply a fluid under necessary conditions (flow rate, pressure) (see Fig. 9 ), the sample is selectively introduced into the storage space 301 inside the applicator 300. That is, the sample is transported from the supply side piping to the sample introduction tube 254 on the supply side, and is supplied from the front end portion of the sample introduction tube 254 on the supply side to the sample holder 250 inside the applicator 300. Only the sample, or a solution mixed with the sample and the storage solvent (carrier) flows and is supplied in the sample introduction tube 254 on the supply side. Thus, the introduced extremely small amount of sample S contacts the crystal sponge 200 at the front end of the pin-shaped holding portion 252 attached to the sample holder 250 in the storage space 301 of the applicator 300, and the sample is absorbed. In addition, the electrophoresis device here includes various electrophoresis devices such as capillary electrophoresis and isoelectric point electrophoresis. When the absorption device 500 is used, after a predetermined time has passed in the state where the sample is injected, the excess sample or the solution mixed with the sample and the storage solvent (carrier) is discharged from the sample introduction tube 254 on the discharge side. When the storage device 500 is not used, unnecessary storage solvent (carrier) or solution flows in the sample introduction tube 254 on the discharge side and is discharged. Therefore, there is a possibility that the sample does not flow in the sample introduction tube 254 on the discharge side. In addition, when a gas or a supercritical fluid is used as a carrier, the carrier including the sample is discharged.

[0084] After the absorption step is completed, the sample holder 250 is removed from the applicator 300 and accurately mounted at a predetermined position in the single crystal X-ray diffraction apparatus 9, that is, at the goniometer head 121 at the front end of the goniometer 12 (see FIG. Figure 7 (A)). Thus, the crystal sponge 200 attached to a portion (front end) of the pin-shaped holding portion 252 of the sample holder 250 is arranged at the front end of the goniometer 12, that is, the position where the X-ray beam from the X-ray tube 11 is focused and irradiated after the absorption of the sample is completed. In other words, the sample S absorbed in the crystal sponge 200 is accurately arranged at a predetermined position in the single crystal X-ray diffraction device 9, and then the intensity of the diffracted X-ray from the sample S is measured by the X-ray detector 22 to analyze the crystal structure, etc.

[0085] Thus, according to the sample holder 250 and the applicator 300 provided as the sample holder assembly of the present invention, anyone can easily and safely absorb a very small amount of sample in the very small size crystal sponge 200 pre-installed integrally in the sample holder 250, and then the sample S can be quickly and safely placed at a high-precision and accurate position in a short time on the goniometer 12 without the crystal sponge being damaged by drying. In addition, after that, while irradiating the sample S with X-rays of a required wavelength by the above-mentioned single crystal X-ray diffraction device 9, the diffraction and scattering of the X-rays by the target material are measured, and the structure analysis is performed using the measurement application software constituting the above-mentioned single crystal X-ray structure analysis device to perform the components of the molecular model, the preparation of the final report, etc., which is the same as the existing situation. That is, according to this embodiment, not only in drug development and life science, but also in the field of various material research, the molecular structure / collective structure (real space) of the new structure discovered or designed can be quickly, safely and simply confirmed.

[0086] <Management of samples using the crystal sponge sample holder>

[0087] Next, a method of managing the crystal sponge 200 preliminarily integrally mounted on the sample holder 250 (or the applicator 300 ) by utilizing unique information held as a part of the sample holder, more specifically unique information displayed by the barcode 220 as an example thereof, will be described below.

[0088] As described above, the sample holder 250, to which the crystal sponge 200 is pre-installed integrally, is removed from the applicator 300 after the sample has been absorbed, and is mounted on the goniometer head 121 at the front end of the goniometer 12. Fig.13As shown, for example, a barcode reader or the like, so-called imaging unit 600, reads the barcode 220 as information held by the sample holder (or the applicator 300), and then uses the information as specific information inherent to the sample in the structural analysis. Fig.14 As shown in (A), additional settings have been set in the above Figure 3 The components of the single crystal X-ray structure analysis device 1 are shown.

[0089] More specifically, the data of the barcode 220 obtained by the imaging unit 600 is stored in a so-called sample management information DB 1000 provided in addition to the existing components (see Fig.14 (A)), as sample-specific number / mark data, respectively. At this time, the sample-specific number / mark used to identify the crystal sponge 200 may include the manufacturer, manufacturing site, manufacturing date and time, batch number, etc. of the crystal sponge 200, and further, may include supporting information indicating the billing status of the crystal sponge. In addition, information indicating the type of crystal sponge 200 (for liquid, gas, etc.) may also be included. Moreover, as Fig.14 As shown in (B), this information is recorded as invariant information and is also used as search information for associating and identifying the measured samples in various automatic structural analysis processes based on the measurement application software. Invariant information refers to information determined in the process before absorption, and variable information refers to information obtained in the process after absorption.

[0090] In addition, in the above description, it is explained that the acquisition of the sample-specific number / mark data of the barcode 220 is performed when the sample holder 250 is installed on the goniometer head 121 at the front end of the goniometer 12. However, the present invention is not limited to this. For example, in the single crystal X-ray structure analysis device 1, it can be performed at the time when the X-rays from the X-ray tube 11 are irradiated toward the sample, or before that. This is obvious to those skilled in the art.

[0091] In addition, since the amount of data that can be displayed by the bar code 220 is limited, it is also possible to display only a portion of the above-mentioned unchanged information, and the necessary other information is pre-stored in other storage units (for example, sample management information DB1000, USB and other removable recording media, etc.) and provided, which can be retrieved through the display data of the bar code 220.

[0092] On the other hand, in addition to the above-mentioned invariant information, the processing performed by the structure analysis device before the measurement, such as the presence or absence of the use of the storage device (permeation device), the conditions and results of the parameters in the storage process (pressure, sample amount, solvent, etc.), and the measurement data such as the XRDS pattern or image actually measured after the measurement (see above Figure 3 (B)) etc. are stored as information recorded by actual measurement, i.e., so-called variable / recorded information. Such information is then used as sample data of actual measurement in various automatic structural analysis processes based on measurement application software.

[0093] For example, during measurement, the measurement range can be determined based on the type of solvent and sample as invariant information. In addition, the number of measurements, measurement time, etc. can be determined based on the absorption result (absorption amount) as variable information, and the conditions for repeated measurements and high-redundancy measurements can be determined. In addition, the center position of the crystal sponge to be measured can also be determined based on the "size information (invariant information) of the crystal sponge".

[0094] During analysis, information about the type of medium is used to identify weak signals from the solvent, making it possible to see through the target and the solvent. In addition, the amount of the target and the solvent can be known from the absorption rate (amount), making it easy to identify the electron density. For example, based on "information inherent to the crystal sponge such as the structure and composition of the crystal (invariant information)" and "information about the sample absorbed in the crystal sponge and the solvent used for absorption (variable information)", it is possible to determine the measurement conditions and analysis conditions.

[0095] In addition, the invariant information includes the type of crystal sponge, manufacturer, manufacturing location, manufacturing date and time, batch number, and supporting information. The variable information is the adsorption conditions, adsorption results, measurement conditions, measurement results, and information obtained in the process after adsorption, including the conditions in sample preparation, conditions in adsorption, conditions in measurement, and their results.

[0096] In this way, by recording and utilizing the unique information attached to the sample holder or the applicator in the sample management information DB 1000 as the sample management unit, the data obtained in various measurement processes to be performed later, including the measurement conditions, etc., can be processed in a mutually related manner. For example, by searching for the conditions for absorption provided via the cloud structure based on the above-mentioned unique information, the necessary absorption conditions can be easily obtained and automatically input / set. Therefore, the data obtained by the processing performed by the subsequent structure analysis program can be managed in a one-dimensional manner, and in addition, an operation environment can be constructed in which the appropriateness of the sample introduced into the sample holder, the setting of the measurement conditions, etc., including the input operation, can be easily and user-friendly. Furthermore, the storage, verification, and management of the sample after measurement / analysis can also be performed more easily. In addition, the sample management information DB 1000 can also be integrated with the XRDS information database 120 that stores the existing XRDS image data. In addition, in the above-mentioned example, the information is stored in the cloud, but it is not limited to this, and it can also be stored in the memory (HDD) of the single crystal X-ray structure analysis device 1. Furthermore, when the order of samples to be measured is determined in advance, the inherent information may not be acquired from the sample holder or applicator but may be stored in a memory in advance and read out sequentially to acquire the corresponding constant information and variable information.

[0097] In this way, by utilizing a sample holder 250 (and furthermore, an applicator serving as a processing tool thereof) which retains specific information inherent to the sample in a portion thereof, a single crystal X-ray structure analysis device is realized, wherein the processing of samples including crystal sponges including their storage, measurement, management and subsequent verification is made easier and more user-friendly via a sample management information DB1000 which one-dimensionally manages measurement information associated with the specific information.

[0098] In addition, in this example, the case where the inherent identification information is displayed as a bar code 220 installed on a part of the sample holder and / or the applicator is described, but the present invention is not limited to this, as long as the information used to identify the crystal sponge 200 is displayed. For example, a computing unit or a storage unit (for example, a memory, etc.) of a semiconductor chip can be used instead of the above-mentioned bar code. In addition, at this time, it is preferred that the unit can communicate its content with an external device in a non-contact manner. In addition, the content of the information is not limited to the inherent identification information corresponding to the measurement sample mentioned above, and in addition, it can also include conditions of measurement data, etc. In addition, in the above, an example of installing the bar code 220 on the outer peripheral surface of the sample holder and / or the applicator and displaying it is described, but the present invention is not limited to this, and it can also be displayed in other places. In this case, according to the unit that can communicate with an external device in a non-contact manner, the freedom of its installation place is further expanded, so it is particularly preferred.

[0099] In addition, as information indicating the type of crystal sponge 200, if the convenience of the user at the measurement site is taken into consideration, it is more effective to display it not only by the above-mentioned bar code, but also by changing the color of the appearance of the sample holder and / or the applicator (for example, red for liquid, yellow for gas, etc.). In this case, the information indicating the type of crystal sponge 200 can also be set as information obtained by encoding by pigment dots. Moreover, as the above-mentioned imaging unit 600, it is also possible to input the information indicating the type of crystal sponge 200 according to the color of the appearance of the sample holder and / or the applicator by using a camera that can read the pigment dots.

[0100] As described in detail above, according to the present invention, a so-called user-friendly single crystal X-ray structure analysis device is realized, and even without professional knowledge of X-ray structure analysis, single crystal X-ray structure analysis using extremely small and fragile crystal sponges can be performed quickly, reliably, and easily without the meticulous and fine work required in the past. In other words, single crystal X-ray structure analysis using crystal sponges can be performed with good yield and high efficiency, and it is excellent in versatility. At the same time, including its input operation and subsequent search operation, anyone can easily and reliably manage information related to samples containing extremely small crystal sponges (management of information required for operations such as preparation, processing, storage, management before measurement, and verification and storage after measurement), and further, a method and a sample holder (which may also include an applicator) therefor are provided. In other words, single crystal X-ray structure analysis based on the above-mentioned extremely small crystal sponges can be easily used and can be widely popularized.

[0101] In addition, various embodiments of the present invention are described above, but the present invention is not limited to the above embodiments, and includes various modified examples. For example, the above embodiments are examples in which the entire system is described in detail in order to easily understand the present invention, and are not limited to all the structures described. In addition, a part of the structure of a certain embodiment can be replaced with the structure of other embodiments, and the structure of other embodiments can be added to the structure of a certain embodiment. In addition, for a part of the structure of each embodiment, other structures can be added / deleted / replaced. Furthermore, the above-mentioned structures, functions, processing units, processing units, etc. can also be implemented by hardware by, for example, designing a part or all of them using an integrated circuit. In addition, the above-mentioned structures, functions, etc. can also be implemented by software by interpreting and executing programs that implement each function through a processor. Information such as programs, tables, files, etc. that implement each function can also be placed in a recording device such as a memory, a hard disk, an SSD (Solid State Drive), or a recording medium such as an IC card, an SD card, and a DVD.

[0102] The present invention can be widely used in methods for exploring material structures, X-ray structure analysis devices used therefor, and the like.

[0103] In addition, the present international application claims the priority based on Japanese Patent Application No. 2018-218733 filed on November 22, 2018, and all the contents of Japanese Patent Application No. 2018-218733 are hereby incorporated by reference into the present international application.

[0104] Description of Reference Numerals

[0105] 1…Single crystal X-ray structure analysis device (overall),

[0106] 9…Single crystal X-ray diffraction device,

[0107] 11…X-ray tube,

[0108] 12…Anglometer,

[0109] 22…X-ray detector,

[0110] 102 ... measuring device,

[0111] 103…input device,

[0112] 104 ... an image display device,

[0113] 107…CPU,

[0114] 108...RAM,

[0115] 109...ROM,

[0116] 111…hard disk,

[0117] 116…Analysis application software,

[0118] 117…Measurement application software,

[0119] 121…Angle measuring head,

[0120] 250...Specimen holder,

[0121] 200…Crystal sponge,

[0122] 251…Abutment,

[0123] 252 ... a pin-shaped retaining portion,

[0124] 253…pores,

[0125] 254…Sample introduction tube,

[0126] 300…Applicator,

[0127] 301…storage space,

[0128] 302… opening,

[0129] 220…Inherent information, barcode,

[0130] 600…Camera unit,

[0131] 1000…Sample management DB.

Claims

1. A single crystal X-ray structure analysis device for performing structural analysis of a substance, characterized in that: have: An X-ray source, generating X-rays; A sample holder including a porous complex crystal capable of absorbing a sample in a plurality of fine pores formed inside; a goniometer, which mounts and rotates the sample holder; An X-ray irradiation unit irradiates the sample held in the sample holder mounted on the goniometer with X-rays from the X-ray source; An X-ray detection and measurement unit detects and measures X-rays diffracted or scattered by the sample; as well as a structural analysis unit that performs structural analysis of the sample based on the diffracted or scattered X-rays measured by the X-ray detection and measurement unit, The structural analysis unit performs structural analysis of the sample based on the absorption result in the step of causing the porous complex crystal to absorb the sample.

2. The single crystal X-ray structure analysis device according to claim 1, wherein: The absorption result is the absorption amount of the sample.

3. The single crystal X-ray structure analysis device according to claim 1 or 2, wherein: The information acquisition unit acquires invariant information related to the porous complex crystal, The information storage unit stores the invariant information acquired by the information acquisition unit, The invariant information includes at least one of a manufacturer, a manufacturing location, a manufacturing date and time, a batch number, and supporting information.

4. The single crystal X-ray structure analysis device according to claim 1 or 2, wherein: The detection and measurement of X-rays of the sample or the structural analysis of the sample is performed based on the invariant information or the variable information stored in the information storage unit.

5. The single crystal X-ray structure analysis device according to claim 1 or 2, wherein: The invariable information or the variable information acquired by the information acquisition unit is information held in an information holding unit of an applicator mounted on the sample holder or accommodating the sample holder.

6. The single crystal X-ray structure analysis device according to claim 5, wherein: The information holding portion is a bar code displayed on the sample holder or the applicator, The constant information or the variable information is included in a barcode.

7. The single crystal X-ray structure analysis device according to claim 5, wherein: The information holding unit is a semiconductor storage device mounted on the sample holder or the applicator. The invariable information or the variable information is stored in a semiconductor memory device.

8. The single crystal X-ray structure analysis device according to claim 1 or 2, wherein: The constant information or the variable information acquired by the information acquisition unit is information stored outside the sample holder and the applicator and is acquired based on unique information held or displayed by the sample holder or the applicator storing the sample holder therein.

9. A single crystal X-ray structure analysis method, which is a single crystal X-ray structure analysis method for performing structural analysis of a substance using a sample holder, characterized in that: include: an absorbing step of introducing a sample to be analyzed into the porous complex crystal held by the sample holder to absorb the sample; An installation step of installing the sample holder after the sample is absorbed on a goniometer of a single crystal X-ray structure analysis device; An X-ray detection and measurement step of irradiating the sample with X-rays from an X-ray source of the single crystal X-ray structure analysis device and detecting and measuring the X-rays diffracted or scattered by the sample; as well as The structural analysis step performs structural analysis of the sample based on the absorption result in the absorption step of the sample.

10. The single crystal X-ray structure analysis method according to claim 9, wherein: In the information acquisition step, invariant information related to the porous complex crystal is acquired, In the information saving step, the obtained invariant information is saved. The invariant information includes at least one of a manufacturer, a manufacturing location, a manufacturing date and time, a batch number, and supporting information.

11. The single crystal X-ray structure analysis method according to claim 9, wherein: The X-ray detection and measurement step or the structure analysis step is performed based on the invariant information or the variable information stored in the information storage step.

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