Crystal of naphthalene derivative
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2025-11-26
- Publication Date
- 2026-03-16
AI Technical Summary
KUS121 crystals exhibit poor storage stability, leading to crystallinity decline and increased water content, necessitating stringent storage conditions and a stable manufacturing method for a single crystal form.
The development of a crystalline form of 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt dihydrate, characterized by specific X-ray powder diffraction patterns, and a production method involving controlled dissolution, cooling, and drying under defined conditions to stabilize the crystal.
The dihydrate form demonstrates excellent storage stability, enabling stable drug substance production with improved reproducibility and resistance to crystallinity collapse.
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Abstract
Description
[Technical Field]
[0001] The present invention relates to novel crystals of KUS121 that are useful as pharmaceuticals and a method for producing the same. [Background technology]
[0002] 4-Amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt (hereinafter sometimes referred to as "KUS121") is a compound with a naphthalene skeleton, and is currently being developed as a therapeutic agent for central retinal artery occlusion (Patent Document 1). KUS121 is dissolved and administered topically as an injection, but the manufactured drug substance before being formulated must be quality-assured and stored for a certain period of time. Therefore, the drug substance is stored and quality-controlled in a crystalline form, which is generally known to have excellent storage stability.
[0003] However, KUS121 crystals do not necessarily have high storage stability. For example, under standard accelerated testing conditions, crystallinity declines, the crystalline form collapses, and the water content tends to increase significantly. From the perspective of pharmaceutical quality control, it has been necessary to store the product under more stringent storage conditions than usual. Furthermore, multiple crystalline forms have been confirmed for the KUS121 drug substance, and from the perspective of quality control, it was ideal to produce a stable single crystal and establish a stable manufacturing method for it.
[0004] As described above, it has been desired to find a more stable crystal of the active pharmaceutical ingredient for KUS121 and to establish a manufacturing method that can stably obtain a single crystal with good reproducibility. [Prior art documents] [Patent documents]
[0005] [Patent Document 1] WO 2012 / 014994 Summary of the Invention [Problem to be solved by the invention]
[0006] The present invention aims to find a stable crystalline form of the active ingredient KUS121, which is useful as a pharmaceutical, and to establish a method for producing it. [Means for solving the problem]
[0007] In light of the above-mentioned problems, the inventors first began to investigate the crystalline forms of KUS121 and found that there were as many as 20 different crystalline polymorphs. Further analysis of these polymorphs revealed that they included several solvates containing the solvent used in the crystallization process, as well as several hydrates. Further investigation revealed that one crystalline form, the dihydrate, had particularly excellent storage stability. They then established a method for specifically preparing only this dihydrate from among the numerous crystalline polymorphs, thereby completing the present invention.
[0008] The aspects of the present invention are as follows.
[0009] [Section 1] A crystalline form of 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt dihydrate, characterized by an X-ray powder diffraction pattern having four or more diffraction angles (2θ±0.5) selected from the following: 6.9°, 13.3°, 14.2°, 15.0°, 17.1°, 18.5°, 19.6°, 21.1°, 22.9°, 23.7°, 26.7°, 27.4°, 29.5°, 34.1°, and 36.1°.
[0010] [Section 2] A crystalline form of 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt dihydrate, characterized by an X-ray powder diffraction pattern having four or more diffraction angles (2θ±0.2) selected from the following: 6.9°, 13.3°, 14.2°, 15.0°, 17.1°, 18.5°, 19.6°, 21.1°, 22.9°, 23.7°, 26.7°, 27.4°, 29.5°, 34.1°, and 36.1°.
[0011] [Section 3] The crystalline substance of item 1 or 2, in which five or more diffraction angles are selected.
[0012] [Section 4] The crystalline substance of item 1 or 2, wherein the number of selected diffraction angles is 10 or more.
[0013] [Section 5] The crystal of item 3, wherein the five or more selected diffraction angles are 6.9°, 13.3°, 14.2°, 15.0°, and 17.1°.
[0014] [Section 6] The crystal of item 4, in which the ten or more selected diffraction angles are 6.9°, 13.3°, 14.2°, 15.0°, 17.1°, 19.6°, 21.1°, 26.7°, 27.4°, and 29.5°.
[0015] [Section 7] A method for producing a crystalline form of 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt dihydrate, comprising: (i) KUS121 is dissolved in a water-containing solvent that is commonly used in the manufacture of pharmaceuticals, with appropriate heating, and the solution is stirred at 40 to 100°C. (ii) gradually cooling to precipitate crystals, and filtering to obtain crystals; (iii) A production method characterized by drying the obtained crystals at a temperature of 30 to 70°C under an atmosphere of 10 to 100% relative humidity to obtain a crystal of 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt dihydrate.
[0016] [Section 8] A method for producing a crystalline form of 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt dihydrate, comprising: (i) KUS121 is dissolved in an aqueous solvent commonly used in pharmaceutical manufacturing at a concentration of 1 to 20% (w / v) with appropriate heating, and the solution is stirred at 40 to 100°C for 5 minutes or more. (ii) cooling the mixture to -20°C to 30°C at a cooling rate of 0.01°C / min to 1°C / min to precipitate crystals, and filtering the mixture to obtain crystals; (iii) A production method characterized by drying the obtained crystals at a temperature of 30 to 70°C under an atmosphere of 10 to 100% relative humidity to obtain a crystal of 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt dihydrate.
[0017] [Section 9] Item 7 or 8, the production method, wherein the commonly used solvent includes an alcohol-based solvent.
[0018] [Section 10] Item 10. The production method of Item 9, wherein the alcohol solvent is methanol, ethanol, 1-propanol, and / or 2-propanol.
[0019] [Section 11] 11. The method according to any one of items 7 to 10, wherein the drying step (iii) is carried out under normal pressure for 10 hours or more.
[0020] [Section 12] 11. The method of any one of items 7 to 10, wherein the drying step (iii) is carried out by placing a tray filled with water in a drying chamber at 30 to 50°C and a pressure of 2 to 5 kPa for 10 hours or more.
[0021] [Section 13] 11. The manufacturing method of any one of items 7 to 10, wherein the drying step (iii) is carried out at 30 to 50°C and a pressure of 1 to 7 kPa for 5 hours or more while blowing nitrogen saturated with water vapor into a drying chamber. [Effects of the Invention]
[0022] The dihydrate crystalline form of KUS121 of the present invention has excellent storage stability among the many polymorphic forms of KUS121, and is useful as a stable drug substance for manufacturing. Furthermore, the method for manufacturing the dihydrate crystalline form of KUS121 established in the present invention enables stable production of the dihydrate crystalline form of KUS121. [Brief explanation of the drawings]
[0023] [Figure 1] 1 shows a powder X-ray diffraction chart of the dried dihydrate crystals of an example. [Figure 2] 1 shows the results of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of the dried dihydrate crystals of the example. [Figure 3] 1 shows a Raman scattering spectrum (FT-Raman) of the dihydrate crystals after drying in an example. [Figure 4] 1 shows a photomicrograph (PLM) of the dihydrate crystals after drying in the example. [Figure 5] 1 shows a powder X-ray diffraction chart of the anhydrous crystals of an example. [Figure 6] 1 shows a powder X-ray diffraction chart of the monohydrate crystal of an example. [Figure 7] 1 shows the results of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of the monohydrate crystal of an example. [Figure 8] 1 shows a powder X-ray diffraction chart of the tetrahydrate crystal of an example. [Figure 9]1 shows the results of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of the tetrahydrate crystals of the example. DETAILED DESCRIPTION OF THE INVENTION
[0024] The compound of the present invention, 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt (KUS121), has the following structure, and its production method and spectral data are disclosed in Patent Document 1. [ka]
[0025] In the present invention, the crystalline material can be analyzed using conventional techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Raman scattering spectroscopy (FT-Raman), and photomicrography (PLM).
[0026] The 2θ values in X-ray powder diffraction patterns may vary slightly from instrument to instrument or sample to sample, so the values reported herein are not absolute. Generally, the measurement error of the diffraction angle in an X-ray powder diffraction spectrum is, for example, approximately ±0.2° in 2θ, and this level of measurement error should be taken into account when examining X-ray powder diffraction data. Furthermore, in the present invention, the diffraction angle values of the KUS121 dihydrate crystals vary significantly between instruments, so the measurement error of the diffraction angle should be considered even larger, for example, approximately ±0.5° in 2θ. Furthermore, intensities may vary depending on experimental conditions and sample preparation (preferred orientation). In this application, values are shown as measured using copper radiation (Cu Kα, 45 kV / 20 mA, λ=1.5418 Å).
[0027] Preparation of KUS121 dihydrate crystals The method for producing crystalline 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt dihydrate is characterized by comprising the following steps: (i) dissolving KUS121 in a water-containing solvent commonly used in pharmaceutical manufacturing with appropriate heating, and then heating and stirring; (ii) cooling the heated KUS121 solution to precipitate crystals, and filtering the wet crystals; and (iii) drying the wet crystals. Preferably, in step (ii), seed crystals are added to improve the reliability of controlling the formation of KUS121 dihydrate crystals.
[0028] In step (i), the "solvent commonly used in the production of pharmaceuticals" is not particularly limited as long as it is a solvent commonly used in the production of pharmaceuticals, and examples thereof include alcoholic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methoxyethanol, 1-methoxy-2-propanol, 2-methyl-1-propanol, 3-methyl-1-butanol, and 1-pentanol; and other solvents commonly used in the production of pharmaceuticals, such as acetone, anisole, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, t-butyl methyl ether, dimethyl sulfoxide, diethyl ether, ethyl formate, heptane, methyl ethyl ketone, methyl isobutyl ketone, pentane, nitromethane, acetonitrile, acetone, 4-methoxy-2-pentanone, 1,2-dimethoxyethane, toluene, pyridine, tetrahydrofuran, cyclohexane, heptane, and bis(2-methoxyethyl) ether. Mixed solvents of these or mixed solvents of these solvents with other solvents may also be used. Methanol, ethanol, or 2-propanol is preferred, and ethanol is more preferred. The water content of "aqueous solvents commonly used in the production of pharmaceuticals" varies depending on the type of solvent used, but is usually 5% to 90%, preferably 10% to 50% for methanol, 10% to 90% (more preferably 10% to 60%) for ethanol, and approximately 30% for 2-propanol.
[0029] The concentration of KUS121 dissolved in the aqueous solvent in step (i) may be 1 to 20% (w / v), and preferably 2 to 10% (w / v).
[0030] The heating temperature in step (i) may be 40 to 100°C, preferably 50 to 80°C, and more preferably 60 to 80°C, although it depends on the type of solvent used. The stirring time in step (i) is not particularly limited as long as the KUS121 is sufficiently dissolved, but is usually 5 minutes or more, and preferably 10 minutes or more.
[0031] The cooling rate in (ii) is usually 0.01 to 1° C. / min, preferably 0.05 to 0.5° C. / min. Cooling is usually carried out to −20 to 30° C., preferably 0 to 30° C. After reaching these temperatures, stirring is usually continued until the crystals have ripened, or stirring is stopped and the mixture is left standing.
[0032] The drying conditions of (iii) are generally in an atmosphere with a relative humidity of 10 to 100% RH and a temperature of 30 to 70° C., preferably in an atmosphere with a relative humidity of 30 to 95% RH and a temperature of 30 to 60° C., and more preferably in an atmosphere with a relative humidity of 40 to 70% RH and a temperature of 40 to 60° C. The drying time is generally 3 hours or longer, and preferably 10 hours or longer. In addition, air is blown as needed to dry the material.
[0033] The drying step is carried out under reduced pressure as appropriate. The pressure under reduced pressure is usually 0.05 to 20 kPa, preferably 1 to 20 kPa. The temperature under reduced pressure is usually 30 to 60°C, preferably 30 to 50°C, and the humidity is adjusted by placing a tray filled with water in the drying chamber or by blowing in nitrogen gas containing water vapor. In a preferred embodiment under reduced pressure, drying is carried out for 5 hours or more at a pressure of 1 to 7 kPa while blowing nitrogen saturated with water vapor into the drying chamber at 30 to 50° C. Another preferred embodiment under reduced pressure is to place a tray filled with water in the drying chamber and dry for 10 hours or more at 30 to 50° C. and a pressure of 2 to 5 kPa. [Example]
[0034] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.
[0035] (1)Analysis method Each of the prepared crystals was analyzed using the following analytical methods under the conditions described below.
[0036] X-ray powder diffraction (XRPD) (Measurement condition 1) Powder X-ray diffraction data were acquired using a PhotonMax high-flux 9kW rotating anode X-ray generator (SmartLab 9kW, Rigaku). All diffractograms were acquired using copper radiation (CuKα, 45kV / 200mA, λ = 1.5418Å) with a Kβ filter to reduce unwanted radiation. The specimen was gently ground in an agate mortar and placed on the measurement stage. Scanning conditions were a 3-40° scan range, a scan speed of 20° / min, and a 0.02° step size in 2θ.
[0037] (Measurement condition 2) Powder X-ray diffraction data were acquired on Si zero-background wafers using a diffractometer (X'PertPro, PANalytical). All diffractograms were acquired using copper radiation (CuKα, 45 kV / 40 mA, λ = 1.5418 Å) and an X'celerator™ RTMS (Real Time Multi-Strip) detector, with a nickel filter used to reduce unwanted radiation. Scans were performed over a 2θ range of 2–40° with a step size of 0.02°. The incident beam configuration was a fixed divergence slit (1 / 4°), a 0.04 radian Soller slit, an anti-scatter slit (1 / 4°), and a 10 mm beam mask. The diffracted beam configuration was a fixed divergence slit (1 / 4°) and a 0.04 radian Soller slit.
[0038] (Measurement condition 3) Powder X-ray diffraction data were obtained using a diffractometer (MiniFlex600, Rigaku). All diffractograms were obtained using copper radiation (CuKα, 40 kV / 15 mA, λ = 1.5418 Å) with a Kβ filter to reduce unwanted radiation. Scanning was performed over a 5-50° scan range, a scan speed of 5° / min, and a 0.02° 2θ step size.
[0039] Differential scanning calorimetry (DSC) Differential scanning calorimetry was performed using a differential scanning calorimeter (TA Instruments Q100 or Q2000, manufactured by TA Instruments) equipped with an autosampler and a refrigerated cooling system. DSC thermograms were acquired by placing approximately 1–10 mg of solid sample in a crimped aluminum pan and heating at 10 or 15 °C / min under a 40 mL / min N2 purge.
[0040] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed using a thermogravimetric analyzer (TA Instruments Q50 or Q500, manufactured by TA Instruments). TGA thermograms were obtained by heating approximately 1–10 mg of solid sample in an aluminum pan at 10 or 15 °C / min under a 40 mL / min N2 purge.
[0041] Raman scattering spectrum (FT-Raman) Raman spectra were obtained using a Raman instrument (Nicolet NXR9650 or NXR960 spectrometer, Thermo Electron) equipped with a 1064 nm Nd:YVO4 excitation laser, InGaAs and liquid nitrogen-cooled Ge detectors, and a MicroStage. All spectra were acquired at 4 cm-1 resolution with 64–1024 scans using the Happ-Genzel apodization function and two levels of zero-filling. A neutral density filter (1.0 optical density) was used when detector saturation was observed.
[0042] Photomicrograph (PLM) Micrographs were taken using a BX60 polarizing microscope (Olympus) equipped with an Olympus DP70 camera.
[0043] Moisture measurement The water content of each crystal was measured using one of the following three methods. (Water content measurement of KUS121 anhydrous crystals) The moisture value was measured using a coulometric moisture meter (CA-100, manufactured by Nitto Seiko Analytech) using approximately 0.5 g of solid sample, Aquamicron GEX as the solvent, and 3 mg of Aquamicron SS as the titrant.
[0044] (Water content measurement of KUS121 dihydrate crystals) The moisture content was measured using a Karl Fischer moisture meter (AQUACOUNTER AQV-2100, manufactured by Hiranuma Sangyo) equipped with an iodine generating electrolytic bath stirrer and a constant current potentiometer, using approximately 0.2 g of solid sample, Aquamicron GEX as the solvent, and 3 mg of Aquamicron SS-Z as the titrant.
[0045] (Water content measurement of KUS121 monohydrate and tetrahydrate crystals) The moisture content was calculated from DSC thermograms measured using differential scanning calorimetry (TA Instruments Q100 or Q2000 differential scanning calorimeter, manufactured by TA Instruments) and TGA thermograms measured using thermogravimetric analysis (TA Instruments Q50 or Q500 thermogravimetric analyzer, manufactured by TA Instruments). The measurements were carried out by placing approximately 1 to 10 mg of solid sample in an aluminum pan and heating at 10 or 15 °C / min under a 40 mL / min N2 purge.
[0046] (2) Crystal production Dihydrate, anhydrous, monohydrate, and tetrahydrate crystals of KUS121 were prepared using the following procedure. The dihydrate crystals were dried under atmospheric pressure and under reduced pressure.
[0047] Dihydrate crystal production (crystallization) KUS121 (5.00 g) was added to 90% aqueous ethanol (120 mL) and dissolved by stirring at 67°C or higher. This solution was filtered while hot, and the container and filter were rinsed with 90% aqueous ethanol (5 mL). The filtrate was heated to 67°C or higher and stirred for 30 minutes, then cooled to 60°C at a rate of 0.1°C / min. Stirring was continued at 60°C for 1 hour to mature the crystals, and the mixture was then cooled to 22°C at a rate of 0.05-0.5°C / min. The precipitated crystals were collected by filtration and washed with 90% aqueous ethanol (5 mL) to obtain wet crystals of KUS121 dihydrate (net yield 97.3%). Moisture content: 13.0%
[0048] Dihydrate crystal production (atmospheric drying) The wet crystals of KUS121 dihydrate obtained by the above procedure (24.0 g, net 17.4 g) were dried with air at 50°C to obtain dry crystals of KUS121 dihydrate (yield 91.7%). Moisture content: 7.4%
[0049] Production of dihydrate crystals (vacuum drying) The wet crystals (2.32 kg) of KUS121 dihydrate obtained by the above procedure were spread across two trays and placed on shelves in a vacuum dryer along with a beaker containing distilled water (4.56 g). The external temperature of the dryer was controlled at 35°C and the vacuum level was set to 2.86-2.96 kPa. The dryer was then dried under reduced pressure for approximately 16 hours, yielding 1.92 kg of dried KUS121 dihydrate crystals. Moisture content: 7.7%
[0050] Analysis results of dihydrate crystals after drying Powder X-ray diffraction (measurement condition 1, see Figure 1) (2θ): 6.9°, 13.3°, 14.2°, 15.0°, 17.1°, 18.5°, 19.6°, 21.1°, 22.9°, 23.7°, 26.7°, 27.4°, 29.5°, 34.1°, 36.1° Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA): see Figure 2 Raman scattering spectrum (FT-Raman): See Figure 3 Photomicrograph (PLM): see Figure 4
[0051] Production of anhydrous crystals KUS121 (71.8 g) and ethanol (5840 g) were placed in a Kolben and dissolved by stirring at 76-77°C (reflux) for 30 minutes. The mixture was cooled to 65-70°C while stirring, and hot filtered to remove insoluble matter. This procedure was repeated three times, and the filtrates were combined to form one batch. The mixture was cooled to 27°C in a water bath while stirring, and then further cooled to 4°C in an ice bath. The precipitated solid was aged at 3-4°C for 1 hour while stirring, after which the crystals were collected by filtration and washed three times with 292 g of ethanol. The crystals were dried under reduced pressure at 30-80°C for 61 hours to obtain anhydrous KUS121 crystals (yield: 54.8%). Moisture content: 2.3%. Powder X-ray diffraction (measurement condition 3, see Figure 5) (2θ): 7.2°, 13.2°, 15.4°, 16.2°, 17.5°, 20.0°, 22.6°, 25.9°, 27.3°
[0052] Preparation of monohydrate crystals The KUS121 dihydrate crystals (67 mg) obtained by the above procedure were dried under reduced pressure (17 inHg, 40°C) while flowing dry nitrogen to obtain KUS121 monohydrate crystals (yield 100%). Moisture content: 3.4% Powder X-ray diffraction (measurement condition 2, see Figure 6) (2θ): 10.1°, 10.9°, 13.2°, 15.2°, 20.4°, 23.1°, 23.8°, 26.4°, 29.6°, 30.6° Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA): see Figure 7
[0053] Preparation of tetrahydrate crystals KUS121 (250 mg) was dissolved in 40% ethanol (2.5 mL) at 67°C. The solution was cooled to 60°C at a rate of 0.1°C / min and stirred for 1 hour. The solution was further cooled to 55°C at a rate of 0.1°C / min and stirred for 1 hour to precipitate crystals. The suspension was cooled to 22°C at a rate of 0.1°C / min and stirred overnight. The precipitated crystals were filtered under reduced pressure and dried with a blower for 1 hour to obtain KUS121 tetrahydrate crystals (yield 74%). Moisture content: 13.9% Powder X-ray diffraction (measurement condition 2, see Figure 8) (2θ): 6.9°, 12.5°, 13.0°, 14.4°, 16.3°, 18.8°, 21.5°, 23.5°, 24.3°, 25.1° Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA): see Figure 9
[0054] (3) Stability testing The dihydrate crystals of KUS121 were subjected to standard storage stability testing (25°C / 60% RH, 18 months) and accelerated storage stability testing (40°C / 75% RH, 6 months). For comparison, the anhydrate crystals of KUS121 were subjected to accelerated storage stability testing (40°C / 75% RH, 6 months) and stability observations under room temperature conditions (30 months). The results are shown in the table below. The stability of the monohydrate and tetrahydrate crystals of KUS121 was also observed, and the results are shown in the table below. TIFF2026032131000002.tif50155 TIFF2026032131000003.tif55155 TIFF2026032131000004.tif39155
[0055] As described above, the dihydrate crystals have superior storage stability to other hydrate crystals, and are extremely stable even under accelerated testing conditions.
Claims
1. A crystalline form of 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonate sodium salt dihydrate, characterized by a powder X-ray diffraction pattern having four or more diffraction angles (2θ±0.2) selected from 6.9°, 13.3°, 14.2°, 15.0°, 17.1°, 18.5°, 19.6°, 21.1°, 22.9°, 23.7°, 26.7°, 27.4°, 29.5°, 34.1°, and 36.1° in X-ray powder diffraction.
2. The crystal according to claim 1, wherein there are five or more selectable diffraction angles.
3. The crystal according to claim 1, wherein there are 10 or more selectable diffraction angles.
4. The crystal according to claim 2, wherein the five or more selected diffraction angles are 6.9°, 13.3°, 14.2°, 15.0°, and 17.1°.
5. The crystal according to claim 3, wherein the ten or more selected diffraction angles are 6.9°, 13.3°, 14.2°, 15.0°, 17.1°, 19.6°, 21.1°, 26.7°, 27.4°, and 29.5°.