WO2021254445A1 - Crystal form of gaba inhibitor and preparation method therefor - Google Patents

Crystal form of gaba inhibitor and preparation method therefor Download PDF

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Publication number
WO2021254445A1
WO2021254445A1 PCT/CN2021/100649 CN2021100649W WO2021254445A1 WO 2021254445 A1 WO2021254445 A1 WO 2021254445A1 CN 2021100649 W CN2021100649 W CN 2021100649W WO 2021254445 A1 WO2021254445 A1 WO 2021254445A1
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crystal form
aforana
ray powder
present
powder diffraction
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PCT/CN2021/100649
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French (fr)
Chinese (zh)
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徐巾超
黄河
张�杰
叶辉青
李东明
陈勇
黄芳芳
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东莞市东阳光仿制药研发有限公司
广东东阳光药业有限公司
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Priority to CN202180040410.7A priority Critical patent/CN115768753B/en
Publication of WO2021254445A1 publication Critical patent/WO2021254445A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

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  • the invention belongs to the technical field of medicine and chemical engineering, and specifically relates to a new crystal form of a GABA inhibitor and a preparation method thereof.
  • Aforana is a GABA ( ⁇ -aminobutyric acid) inhibitor that inhibits the GABA chloride ion channel and makes arthropod nerves highly excited and leads to death. It is a powerful insecticide.
  • NexGard a new generation of oral in vitro anthelmintic for dogs (NexGard, common name: Aphrana Chewable Tablets), is the first domestic oral anthelmintic for dogs that kills both tick and flea parasites.
  • Aforana is 4-(5-(3-chloro-5-(trifluoromethyl)-phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-iso Oxazolyl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl-1-naphthylcarboxamide, the structural formula is as follows:
  • Patent CN102947278B discloses multiple crystal forms of Aforana: crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H and toluene solvate , Most of the crystal forms are solvates, such as crystal form C is ethyl acetate solvate, crystal form D is dioxane cyclohexane solvate, crystal form F is n-propanol solvate, crystal Form G is acetonitrile solvate, crystal form H is isopropanol solvate, while crystal form A, crystal form B, and crystal form E have poor crystallinity, high amorphous content, and easy to crystallize, so this patent is developed The new crystal form of Aforana and the preparation method thereof have greatly improved the stability and purity of the crystal form, and the operation is simple, the yield is high, and the industrial production is easy.
  • the present invention provides multiple crystal forms of Aforana.
  • the Aforana crystal form XXI and the crystal form XXII provided by the present invention have the advantages of good product stability and high crystallinity.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXI contains diffraction peaks with 2 ⁇ angles of 15.8, 18.0, 18.4, 19.6 and 21.8 degrees.
  • the aforana crystal form XXI has better stability under high temperature conditions, which is beneficial to the preparation of pharmaceutical preparations.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXII contains diffraction peaks with 2 ⁇ angles of 4.4, 10.7, 13.2, 17.5, 19.3 and 25.2 degrees.
  • the first aspect of the present invention provides a crystal form of Aforana.
  • the crystal forms of Aforana are named as the crystal form XXI and the crystal form XXII, and the crystal form I, the crystal form II, the crystal form III, the crystal form IV, the crystal form V, and the crystal form respectively.
  • VI Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, Form XIX and Crystal Form XX.
  • the Aforana crystal form XXI and the crystal form XXII provided by the present invention have the advantages of good product stability and high crystallinity.
  • the X-ray powder diffraction pattern of Aforana Form I of the present invention contains 2 ⁇ angles of 3.9, 7.7, 9.8, 11.5, 13.0, 15.4, 16.6, 19.3, 20.2, 23.2, 24.0, 26.3, 27.1, 27.8, 31.7, 35.1, 35.7 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form I is substantially as shown in FIG. 1.
  • the differential scanning calorimetry curve of Aforana crystal form I of the present invention has an endothermic peak at 105°C.
  • the X-ray powder diffraction pattern of Aforana Form II of the present invention contains 2 ⁇ angles of 11.1, 11.8, 13.5, 15.8, 16.8, 17.6, 18.0, 19.1, 19.6, 20.5, 21.8, 22.6, 23.5, 24.4, 27.2, 27.7 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form II is substantially as shown in FIG. 2.
  • the differential scanning calorimetry curve of the crystal form II of Aforana of the present invention has an endothermic peak at 73°C.
  • the X-ray powder diffraction pattern of Aforana Form III of the present invention contains 2 ⁇ angles of 3.8, 11.5, 12.9, 13.5, 15.0, 16.1, 16.4, 17.4, 18.9, 19.7, 19.9, 20.6, 21.2, 21.7, 22.0, 22.3, 22.8, 23.6, 24.7, 25.4, 26.0, 26.4, 27.1, 29.6, 30.3, 30.8, 31.1, 34.8, 36.2, 37.6 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form III is substantially as shown in FIG. 3.
  • the differential scanning calorimetry curve of Aforana Form III of the present invention has an endothermic peak at 135°C.
  • the X-ray powder diffraction pattern of Aforana Form IV of the present invention contains 2 ⁇ angles of 3.9, 11.2, 12.4, 13.5, 15.6, 16.6, 17.0, 17.4, 19.3, 19.9, 20.3, 20.8, 21.0, 21.7, 21.9, 22.3, 22.6, 23.0, 23.3, 24.0, 25.0, 26.2, 26.8, 27.2, 27.6, 29.4, 29.7, 30.0, 31.1, 31.8, 33.2, 34.5, 37.4 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form IV is substantially as shown in FIG. 4.
  • the differential scanning calorimetry curve of the crystal form IV of Aforana of the present invention has an endothermic peak at 112°C.
  • the X-ray powder diffraction pattern of Aforana Form V of the present invention contains 2 ⁇ angles of 11.4, 12.0, 12.6, 15.4, 17.7, 18.5, 19.2, 19.9, 20.5, 20.7, 21.4, 21.9, 22.5, 23.3, 24.2, 25.4, 25.8, 27.5, 29.8, 34.1 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form V is substantially as shown in FIG. 5.
  • the differential scanning calorimetry curve of the Aforana crystal form V of the present invention has an endothermic peak at 105°C.
  • the X-ray powder diffraction pattern of Aforana Form VI of the present invention contains 2 ⁇ angles of 3.9, 11.5, 12.6, 13.2, 14.8, 15.8, 16.5, 17.5, 18.1, 19.1, 19.4, 20.2, 21.3, 22.0, 22.3, 22.5, 22.8, 23.4, 23.9, 25.4, 25.7, 26.3, 26.9, 27.4, 29.2, 29.9, 30.3 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form VI is substantially as shown in FIG. 6.
  • the differential scanning calorimetry curve of Aforana Form VI of the present invention has an endothermic peak at 96°C.
  • the differential scanning calorimetry curve of Aforana Form VI of the present invention has an endothermic peak at 113°C.
  • the Aforana crystal form VIII of the present invention contains a diffraction peak with a 2 ⁇ angle of 18.0 degrees in the X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern of the Aforana Form VIII is substantially as shown in FIG. 7.
  • the differential scanning calorimetry curve of the Aforana crystal form VIII of the present invention has no obvious endothermic peak.
  • the X-ray powder diffraction pattern of Aforana Form IX of the present invention contains 2 ⁇ angles of 4.0, 9.8, 11.3, 11.8, 12.4, 13.6, 15.2, 16.7, 17.0, 17.7, 19.4, 19.6, 20.2, 20.5, 21.4, 21.6, 22.4, 22.7, 23.3, 23.7, 24.4, 24.9, 25.6, 26.5, 27.8, 29.9, 31.2 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form IX is substantially as shown in FIG. 8.
  • the differential scanning calorimetry curve of Aforana Form IX of the present invention has an endothermic peak at 106°C.
  • the differential scanning calorimetry curve of Aforana Form IX of the present invention has an endothermic peak at 138°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form X of the present invention contains 2 ⁇ angles of 11.2, 15.1, 15.6, 16.3, 16.6, 18.1, 19.1, 19.5, 20.0, 20.2, 20.4, 20.9, 22.3, 22.8, 24.2, 24.9, 26.1, 26.8, 27.5 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form X is substantially as shown in FIG. 9.
  • the X-ray powder diffraction pattern of the Aforana crystal form XI of the present invention contains 2 ⁇ angles of 11.2, 12.4, 12.9, 14.6, 15.5, 15.9, 16.5, 17.3, 19.0, 19.2, 20.1, 20.8, 21.6, 22.2, 22.5, 23.1, 23.4, 23.8, 24.1, 24.9, 25.5, 25.9, 26.8, 27.3, 28.3, 29.1, 29.5, 29.7, 34.1, 34.8, 39.6 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form XI is substantially as shown in FIG. 10.
  • the differential scanning calorimetry curve of the Aforana crystal form XI of the present invention has an endothermic peak at 77°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XII of the present invention contains 2 ⁇ angles of 3.8, 11.4, 12.7, 13.2, 14.7, 15.8, 16.4, 17.4, 18.8, 19.4, 19.9, 20.5, 21.2, 21.3, 22.0, 22.6, 22.7, 23.2, 23.6, 24.1, 24.5, 25.1, 25.4, 26.1, 26.6, 26.9, 27.3, 27.8, 28.5, 28.9, 29.6, 29.8, 30.3, 31.9, 34.2, 36.2, 37.4 degree diffraction peak.
  • the X-ray powder diffraction pattern of the Aforana Form XII is substantially as shown in FIG. 11.
  • the differential scanning calorimetry curve of the Aforana crystal form XII of the present invention has an endothermic peak at 101°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIII of the present invention contains 2 ⁇ angles of 11.3, 11.8, 12.5, 13.5, 15.3, 16.5, 17.0, 18.8, 19.5, 20.3, 21.2, 21.7, 22.0, 22.3, 22.7, 23.1, 24.0, 24.4, 25.2, 25.5, 27.2, 28.5, 29.4, 31.0, 36.3 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form XIII is substantially as shown in FIG. 12.
  • the differential scanning calorimetry curve of the Aforana crystal form XIII of the present invention has an endothermic peak at 83°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIV of the present invention contains 2 ⁇ angles of 3.9, 9.6, 11.5, 12.1, 12.9, 16.4, 17.7, 18.9, 19.3, 20.2, 22.5, 23.1, 23.9, 24.3, 25.1, 27.1, 27.6, 29.5, 37.4 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIV is substantially as shown in FIG. 13.
  • the differential scanning calorimetry curve of the Aforana crystal form XIV of the present invention has endothermic peaks at 77°C and 134°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XV of the present invention contains 2 ⁇ angles of 4.0, 7.8, 9.8, 11.8, 12.5, 13.2, 15.7, 16.8, 17.4, 18.0, 18.3, 18.8, 19.6, 20.5, 21.4, 21.8, 23.0, 23.6, 23.9, 24.4, 24.8, 25.2, 25.5, 25.9, 27.6, 28.2, 29.5, 29.8, 30.2, 32.3, 36.9 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XV is substantially as shown in FIG. 14.
  • the differential scanning calorimetry curve of the Aforana crystal form XV of the present invention has an endothermic peak at 104°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XVI of the present invention contains 2 ⁇ angles of 11.0, 12.1, 12.7, 14.7, 16.4, 18.8, 19.2, 20.5, 22.1, 24.4, 25.4, 26.9, 35.9 degrees.
  • the X-ray powder diffraction pattern of the Aforana crystal form XVI is basically as shown in FIG. 15.
  • the differential scanning calorimetry curve of the Aforana crystal form XVI of the present invention has an endothermic peak at 73°C.
  • the X-ray powder diffraction pattern of Aforana Form XVII of the present invention contains 2 ⁇ angles of 3.9, 7.8, 9.9, 11.2, 12.3, 12.9, 15.5, 16.7, 17.0, 17.2, 17.6, 19.4, 20.0, 20.4, 20.8, 21.9, 22.1, 22.5, 22.9, 23.1, 23.4, 24.2, 24.8, 25.9, 27.4, 27.8, 29.6, 31.4, 33.1, 37.0, 37.6 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana Form XVII is substantially as shown in FIG. 16.
  • the differential scanning calorimetry curve of the Aforana crystal form XVII of the present invention has an endothermic peak at 96°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XVIII of the present invention contains 2 ⁇ angles of 3.9, 7.3, 9.9, 11.4, 12.3, 12.9, 15.6, 16.9, 18.1, 19.2, 20.1, 20.9, 21.2, 21.6, 22.0, 22.6, 24.3, 25.0, 26.5, 27.2, 29.4, 31.7, 33.4, 35.0 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XVIII is substantially as shown in FIG. 17.
  • the differential scanning calorimetry curve of the Aforana crystal form XVIII of the present invention has an endothermic peak at 89°C.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIX of the present invention contains 2 ⁇ angles of 4.0, 9.9, 11.1, 11.8, 12.1, 12.7, 13.2, 15.2, 16.9, 17.5, 18.1, 19.1, 19.8, 20.6, 21.2, 21.7, 21.9, 22.6, 23.4, 23.6, 24.1, 24.4, 24.7, 26.1, 26.9, 27.1, 28.3, 29.1, 29.6, 30.7, 31.5, 32.9, 34.1, 34.6, 35.6 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XIX is basically as shown in FIG. 18.
  • the differential scanning calorimetry curve of the Aforana crystal form XIX of the present invention has an endothermic peak at 140°C.
  • the X-ray powder diffraction pattern of Aforana Form XX of the present invention contains 2 ⁇ angles of 4.4, 7.6, 8.7, 10.8, 12.6, 13.2, 14.3, 19.3, 20.0, 23.2, 25.2, 27.2 degree diffraction peak.
  • the X-ray powder diffraction pattern of the Aforana crystal form XX is substantially as shown in FIG. 19.
  • the differential scanning calorimetry curve of the Aforana crystal form XX of the present invention has an endothermic peak at 106°C.
  • the Aforana crystal form XXI of the present invention has an X-ray powder diffraction pattern containing diffraction peaks with 2 ⁇ angles of 15.8, 18.0, 18.4, 19.6 and 21.8 degrees.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXI includes diffraction peaks with 2 ⁇ angles of 4.7, 15.8, 16.8, 18.0, 18.4, 19.3, 19.6 and 21.8 degrees.
  • the Aforana crystal form XXI has an X-ray powder diffraction pattern including 2 ⁇ angles of 4.7, 9.3, 11.2, 15.8, 16.8, 18.0, 18.4, 19.3, 19.6, 19.9, 20.8 , 21.2, 21.4, 21.8, 23.0, 23.6, 24.0, 26.4, 28.0 and 29.7 degree diffraction peaks.
  • the Aforana crystal form XXI has an X-ray powder diffraction pattern including 2 ⁇ angles of 4.7, 5.7, 9.3, 10.8, 11.2, 12.1, 12.8, 13.8, 14.0, 15.1, 15.8 , 16.8, 18.0, 18.4, 19.3, 19.6, 19.9, 20.8, 21.2, 21.4, 21.8, 23.0, 23.6, 24.0, 24.5, 25.3, 26.0, 26.4, 27.2, 28.0, 29.7 and 31.4 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXI is substantially as shown in FIG. 20.
  • the differential scanning calorimetry curve of the Aforana crystal form XXI of the present invention has an endothermic peak at 116°C-126°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXI has an endothermic peak at 118°C-123°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXI has an endothermic peak at 121°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXI is substantially as shown in FIG. 21.
  • thermogravimetric analysis curve shows that the crystalline form XXI loses 0.7% in the temperature range of 30°C to 150°C.
  • the crystalline form XXI contains water.
  • the crystalline form XXI contains water, and the molar ratio of Aforana to water is about 4:1.
  • the thermogravimetric analysis curve of the crystalline form XXI is substantially as shown in FIG. 22.
  • the Aforana crystal form XXII of the present invention contains diffraction peaks with 2 ⁇ angles of 10.7, 13.2, 17.5, 19.3 and 25.2 degrees in the X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern of the Aforana Form XXII includes diffraction peaks with 2 ⁇ angles of 4.4, 10.7, 13.2, 17.5, 19.3 and 25.2 degrees.
  • the Aforana crystal form XXII has an X-ray powder diffraction pattern including 2 ⁇ angles of 4.4, 10.7, 12.6, 13.2, 15.7, 17.5, 19.3, 19.9, 23.2, 25.2, and 26.5. Degree of diffraction peaks.
  • the Aforana crystal form XXII has an X-ray powder diffraction pattern including 2 ⁇ angles of 4.4, 6.6, 7.6, 8.7, 10.7, 12.6, 13.2, 14.2, 15.7, 16.7, 17.5 , 18.1, 19.3, 19.9, 21.4, 23.2, 25.2, 26.5 and 27.4 degree diffraction peaks.
  • the X-ray powder diffraction pattern of the Aforana crystal form XXII is substantially as shown in FIG. 23.
  • the differential scanning calorimetry curve of the Aforana crystal form XXII of the present invention has an endothermic peak at 108°C-118°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXII has an endothermic peak at 110°C-116°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXII has an endothermic peak at 113°C. In some embodiments, the differential scanning calorimetry curve of the crystal form XXII is substantially as shown in FIG. 24.
  • thermogravimetric analysis curve shows that the crystal form XXII loses 0.1% in the temperature range of 30°C to 150°C.
  • thermogravimetric analysis curve of the Aforana crystal form XXII is substantially as shown in FIG. 25.
  • the amorphous form of Aforana of the present invention has an X-ray powder diffraction pattern, as shown in FIG. 26.
  • the second aspect of the present invention provides a method for preparing the new crystal form of Aforana.
  • the preparation method of the new crystal form is simple, has good repeatability, and is suitable for industrial production.
  • the present invention provides a method for preparing the crystal form I of Aforana.
  • the preparation method of the crystal form I of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form I of aforana comprises: dissolving solid aforana in methyl ethyl ketone, cooling to precipitate crystals, filtering and drying to obtain crystal form I product.
  • the Aforana solid is dissolved in methyl ethyl ketone, and after the solution is clear, an anti-solvent is added dropwise to precipitate crystals, filtered and dried to obtain the crystal form I product.
  • the anti-solvent is one or more of n-heptane, n-hexane, cyclohexane, and isopropyl ether; in some specific embodiments, the anti-solvent is dripped It is a positive drop; in some embodiments, the anti-solvent is added in a reverse drop.
  • Aphrana is dissolved in methyl ethyl ketone and volatilized to obtain the crystal form I product.
  • the present invention provides a method for preparing the crystal form II of Aforana.
  • the preparation method of the crystal form II of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrialized production.
  • a method for preparing crystal form II of aforana includes: dissolving aforana in a good solvent, slowly adding purified water to precipitate crystals after dissolving, filtering and drying to obtain crystal form II product.
  • the good solvent is one or more of acetone, isopropanol, and acetonitrile.
  • the present invention provides a preparation method of the Aforana crystal form III.
  • the preparation method of the crystal form III of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form III of aforana comprising: dissolving aforana in dichloromethane, dissolving and adding an anti-solvent to precipitate crystals, filtering and drying to obtain crystal form III; according to the present invention
  • the anti-solvent is dimethyl carbonate.
  • Aforana is dissolved in a mixed solvent, and after dissolving, the temperature is lowered to crystallize, filtered, and dried to obtain the crystal form III product; according to the embodiment of the present invention, the mixed solvent is dichloromethane Mixed solvent with dimethyl carbonate.
  • Aforana is dissolved in a mixed solvent to prepare a crystal form III product.
  • the organic solvent is one or more of dimethyl carbonate, methyl ethyl ketone, and isopropyl acetate.
  • the mixed solvent is a mixed solvent of dimethyl carbonate, methyl ethyl ketone, and isopropyl acetate; in some specific embodiments, the preparation method is suspension; in some specific embodiments, In an embodiment, the preparation method is volatilization.
  • the present invention provides a method for preparing the aforana crystal form IV.
  • the preparation method of the crystal form IV of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form IV of aforana includes: dissolving aforana in n-butanol and volatilizing to obtain crystal form IV product.
  • Aforana is dissolved in n-butanol, and after the solution is clear, an anti-solvent is added dropwise to precipitate crystals, filtered, and dried to obtain a crystal form IV product.
  • the anti-solvent is one or more of n-heptane, n-hexane, cyclohexane, and isopropyl ether; in some specific embodiments, the dropping method is normal drop ; In some specific embodiments, the dripping method is reverse dripping.
  • Aforana is dissolved in an organic solvent, the crystals are precipitated by cooling, filtered, and dried to obtain the crystal form IV product.
  • the organic solvent is one or more of n-butanol, ethylene glycol monomethyl ether, and isopropyl ether.
  • the present invention provides a preparation method of the Aforana crystal form V.
  • the preparation method of the crystal form V of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form V of Aforana includes: dissolving Aforana in 1,4-dioxane, back-dripping water to precipitate solids, filtering and drying to obtain crystal form V products.
  • the present invention provides a preparation method of the Aforana crystal form VI.
  • the preparation method of the crystal form VI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form VI of aforana includes: dissolving aforana in butyl formate and volatilizing to obtain crystal form VI product.
  • aforana is dissolved in butyl formate, after dissolving, n-heptane or isopropyl ether is added to precipitate crystals, filtered and dried to obtain the crystal form VI product.
  • the addition method is positive drop; in some embodiments, the addition method is reverse drop.
  • the present invention provides a method for preparing the aforana crystal form VIII.
  • the preparation method of the crystal form VIII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form VIII of Aforana includes: dissolving Aforana in an organic solvent and volatilizing to obtain crystal form VIII product.
  • the organic solvent is one or more of acetonitrile, methyl tert-butyl ether, methanol, and isopropyl ether.
  • the organic solvent is a mixed solvent of methanol and isopropyl ether.
  • the present invention provides a preparation method of the Aforana crystal form IX.
  • the preparation method of the crystal form IX of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form IX of Aforana includes: suspending Aforana in water and an organic solvent, filtering and drying to obtain crystal form IX product.
  • the organic solvent is one or more of isopropanol, N-methylpyrrolidone, and sec-butanol.
  • Aforana is dissolved in an organic solvent such as isopropanol and cooled to precipitate a solid, filtered, and dried to obtain the crystal form IX product.
  • the present invention provides a method for preparing the Aforana crystal form X.
  • the preparation method of the crystal form X of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form X of aforana comprising: suspending aforana in a mixed solvent of water and ethylene glycol dimethyl ether for 2h-20h at room temperature, filtering and drying to obtain crystal form X product.
  • the present invention provides a method for preparing the crystal form XI of Aforana.
  • the preparation method of the crystal form XI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form IX of Aforana includes: dissolving Aforana in an organic solvent, cooling to precipitate a solid, filtering and drying to obtain crystal form XI product.
  • the organic solvent is one or more of isopropyl acetate and n-heptane.
  • the organic solvent is a mixed solvent of isopropyl acetate and n-heptane.
  • Aforana is dissolved in isopropyl acetate, the solution is slowly added dropwise to n-heptane until crystals are precipitated, filtered and dried to obtain the crystalline form XI product.
  • the present invention provides a method for preparing the Aforana crystal form XII.
  • the preparation method of the crystal form XII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing the crystal form XII of aforana includes: dissolving the aforana in ethyl acetate, slowly dripping the clear solution into toluene until the crystals are precipitated, filtering and drying to obtain the crystal form XII product.
  • the present invention provides a preparation method of the Aforana crystal form XIII.
  • the preparation method of the crystal form XIII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing Aforana crystal form XIII including: dissolving Aforana in ethylene glycol dimethyl ether, slowly adding the dissolved clear liquid to purified water until crystals are precipitated, filtering and drying to obtain crystals Type XIII products.
  • aforana is suspended in a binary solvent of ethylene glycol dimethyl ether and purified water for 2-24 hours at room temperature, filtered and dried to obtain the crystal form XIII product.
  • the present invention provides a method for preparing the Aforana crystal form XIV.
  • the preparation method of the crystal form XIV of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form XIV of aforana includes: dissolving aforana in toluene, cooling to precipitate a solid, and filtering to obtain crystal form XIV product.
  • the ratio of the aforana to the volume of toluene used is 10 mg/mL to 200 mg/mL; according to the embodiment of the present invention, the dissolution temperature is 40° C. to 80° C.; according to the present invention
  • the cooling temperature is -20°C to 10°C.
  • the present invention provides a method for preparing the Aforana crystal form XV.
  • the preparation method of the crystal form XV of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing the crystal form XV of Aforana includes: dissolving Aforana in a methanol organic solvent to precipitate a solid, filtering and drying to obtain the crystal form XV product.
  • the organic solvent is one or more of methanol and 1,4-dioxane.
  • the organic solvent is a mixed solvent of 1,4-dioxane and water; in some specific embodiments, the solid precipitation operation step is volatilization; in some specific embodiments, the The operation step for the precipitation of solids is cooling.
  • Aforana is dissolved in 1,4-dioxane, and purified water is slowly added dropwise to precipitate a solid after the solution is cleared, filtered and dried to obtain the crystalline form XV product.
  • the present invention provides a preparation method of the Aforana crystal form XVI.
  • the preparation method of the crystal form XVI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrialized production.
  • a method for preparing crystal form XVI of Aforana includes: dissolving Aforana in 1-hexanol, cooling to precipitate a solid, filtering and drying to obtain crystal form XVI product.
  • the present invention provides a method for preparing the Aforana crystal form XVII.
  • the preparation method of the crystal form XVII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form XVII of Aforana includes: dissolving Aforana in an organic solvent, cooling to precipitate a solid, filtering and drying to obtain crystal form XVII product.
  • the organic solvent is one or more of n-propanol, trifluoroethanol, and ethanol; according to the embodiment of the present invention, the organic solvent is n-propanol, trifluoroethanol , A mixed solvent of ethanol and water.
  • Aforana is dissolved in trifluoroethanol, and purified water is slowly added dropwise until the solid precipitates out, filtered and dried to obtain the crystal form XVII product.
  • the dripping method may also be reverse dripping.
  • the present invention provides a preparation method of the Aforana crystal form XVIII.
  • the preparation method of the crystal form XVIII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form XVIII of aforana comprises: dissolving aforana in a mixed solvent of acetone and water, cooling to precipitate a solid, filtering, and drying to obtain a product of crystal form XVIII.
  • the present invention provides a method for preparing the Aforana crystal form XIX.
  • the preparation method of the crystal form XIX of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing the crystal form XIX of aforana includes: dissolving aforana in methanol, cooling to precipitate a solid, filtering, and drying to obtain the crystal form XIX product.
  • Aforana is dissolved in N-methylpyrrolidone, the solution is slowly added dropwise to purified water until a solid precipitates, filtered, and dried to obtain the crystal form XIX product.
  • the present invention provides a preparation method of the Aforana crystal form XX.
  • the preparation method of the crystal form XX of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrialized production.
  • a method for preparing Aforana crystal form XX includes: vacuum drying Aforana crystal form XIV product at 50° C. for 20 hours to obtain crystal form XX product.
  • the present invention provides a preparation method of the Aforana crystal form XXI.
  • the preparation method of the crystal form XXI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing Aforana crystal form XXI includes: dissolving Aforana in an organic alcohol solvent under certain temperature conditions, then mixing with water, stirring to precipitate solids, filtering, and heating at 55°C-65°C. Vacuum drying at °C to obtain crystal form XXI.
  • a method for preparing Aforana Form XXI includes: dissolving Aforana in an organic alcohol solvent at a certain temperature, adding water, stirring to precipitate solids, filtering, and heating at 60°C. Under vacuum drying conditions, the crystal form XXI was obtained.
  • the water includes purified water. In some embodiments, the water is purified water.
  • the organic alcohol solvent includes methanol or ethanol.
  • the organic alcohol solvent includes methanol; in some embodiments, the organic alcohol solvent includes ethanol. In some embodiments, the organic alcohol solvent is ethanol and/or methanol.
  • the amount of water is 1-10 times that of the alcohol solvent.
  • the amount of water used is 2-10 times that of alcoholic solvents; in some embodiments, the amount of water used is 3-10 times that of alcoholic solvents; in some embodiments, the amount of water used is alcoholic solvents.
  • the amount of water is 5-10 times that of alcohol solvents; in some embodiments, the amount of water is 6-10 times that of alcohol solvents; in some embodiments , The amount of water is 7-10 times that of alcohol solvents; in some embodiments, the amount of water is 8-10 times that of alcohol solvents; in some embodiments, the amount of water is 9-10 times that of alcohol solvents Times; In some embodiments, the amount of water is 1 times that of alcohol solvents; in some embodiments, the amount of water is twice that of alcohol solvents; in some embodiments, the amount of water is that of alcohol solvents 3 times; in some embodiments, the amount of water used is 4 times that of alcohol solvents; in some embodiments, the amount of water used is 5 times that of alcohol solvents; in some embodiments, the amount of water used is alcohol solvents In some embodiments, the amount of water is 7 times that of alcohol solvents; in some embodiments, the amount of water is 8 times that of alcohol solvents; in some embodiments, the amount of water is alcohol solvents In some embodiments, the amount of
  • the stirring time is 4h-24h.
  • the stirring time is 4h-20h; in some embodiments, the stirring time is 4h-16h; in some embodiments, the stirring time is 4h-12h; in some embodiments ,
  • the stirring time is 4h-8h; in some embodiments, the stirring time is 4h; in some embodiments, the stirring time is 8h; in some embodiments, the stirring time is 12h; In some embodiments, the stirring time is 16h; in some embodiments, the stirring time is 24h.
  • the vacuum drying time is 16h-40h.
  • the vacuum drying time is 16h-36h; in some embodiments, the vacuum drying time is 16h-30h; in some embodiments, the vacuum drying time is 16h-24h; in some embodiments, the vacuum drying time is 16h-24h; In an embodiment, the vacuum drying time is 16h; in some embodiments, the vacuum drying time is 24h; in some embodiments, the vacuum drying time is 30h; in some embodiments, the vacuum drying The time is 36h; in some embodiments, the vacuum drying time is 40h.
  • the temperature is room temperature to 80°C. In some embodiments, the temperature is between room temperature and 80°C. In some embodiments, the temperature is 20°C-80°C. In some embodiments, the temperature is from room temperature to 70°C; in some embodiments, the temperature is from room temperature to 60°C; in some embodiments, the temperature is from room temperature to 50°C; in some embodiments , The temperature is room temperature-40°C; in some embodiments, the temperature is 80°C; in some embodiments, the temperature is 75°C; in some embodiments, the temperature is 70°C; In some embodiments, the temperature is 65°C; in some embodiments, the temperature is 60°C; in some embodiments, the temperature is 55°C; in some embodiments, the temperature is 50°C In some embodiments, the temperature is 45°C; in some embodiments, the temperature is 40°C; in some embodiments, the temperature is room temperature.
  • a method for preparing the crystal form XXI of aforana includes: dissolving aforana in ethanol at 60° C., adding purified water, and stirring to obtain the crystal form XXI.
  • a method for preparing the crystal form XXI of Aforana includes: dissolving Aforana in methanol at room temperature, adding purified water, and stirring to obtain the crystal form XXI.
  • the present invention provides a preparation method of the Aforana crystal form XXII.
  • the preparation method of the crystal form XXII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing crystal form XXII of Aforana includes: drying crystal form VI of Aforana in vacuum at 50°C-70°C for 16h-48h to obtain crystal form XXII.
  • a method for preparing the crystal form of Aforana XXII includes: drying the crystal form of Aforana VI under vacuum at 60° C. for 24 hours to obtain the crystal form XXII.
  • the invention provides a preparation method of the amorphous Aforana.
  • the amorphous preparation method of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
  • a method for preparing amorphous afrana comprising: dissolving afrana in a good solvent, adding purified water dropwise after dissolving, separating solids, filtering and drying to obtain an amorphous product; according to the present invention
  • the good solvent is one or more of methanol, ethanol, dimethylformamide, and dimethyl sulfoxide.
  • the dripping method is forward dripping; in some specific embodiments, the dripping method is reverse dripping.
  • Aforana is dissolved in dichloromethane, the temperature is lowered, and an amorphous form is precipitated.
  • Aforana is dissolved in an organic solvent and evaporated to dryness to obtain an amorphous product.
  • the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, acetone, butanone, ethyl acetate, butyl formate, One or more of ethyl formate, isopropyl acetate, tetrahydrofuran, acetonitrile, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, dichloromethane, methyl isobutyl ketone cyclohexane, and toluene.
  • the volatilization process is rotary evaporation; in some specific embodiments, the volatilization process is volatilization.
  • Crystal form or amorphous form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) ), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • dissolution calorimetry scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • X-ray powder diffraction can detect the change of crystal form, crystallinity, crystal structure state and other information, and it is a common method to identify crystal form.
  • the peak position of the XRPD spectrum mainly depends on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the drawings of the present invention.
  • the 2 ⁇ measurement of the XRPD pattern may have experimental errors.
  • the 2 ⁇ measurement of the XRPD pattern may be slightly different between different instruments and different samples, so the 2 ⁇ value cannot be regarded as absolute. According to the condition of the instrument used in this experiment, the diffraction peak has an error tolerance of ⁇ 0.2°.
  • Differential scanning calorimetry is a technique that measures the energy difference between a sample and an inert reference material (commonly used ⁇ -Al 2 O 3) with temperature changes under program control through continuous heating or cooling.
  • the melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, and the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline form of the present invention is characterized by a DSC chart with characteristic peak positions, which is substantially as shown in the DSC chart provided in the accompanying drawings of the present invention.
  • the DSC spectrum may have experimental errors.
  • the peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute. According to the condition of the instrument used in this experiment, the melting peak has an error tolerance of ⁇ 3°C.
  • Thermogravimetric analysis is a technique for measuring the quality of a substance with temperature changes under program control. It is suitable for checking the loss of solvent in the crystal or the process of sample sublimation and decomposition. It can be inferred that the crystal contains crystal water or crystal solvent. Case.
  • the quality change displayed by the TGA curve depends on many factors such as sample preparation and instrument; the quality change of TGA detection varies slightly between different instruments and different samples. According to the condition of the instrument used in this experiment, there is an error tolerance of ⁇ 0.1% for the mass change.
  • substantially as shown in the figure refers to a certain "crystal form” that is substantially pure and has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least in the X-ray powder diffraction pattern. 90%, or at least 95%, or at least 99% of the peaks appear in the X-ray powder diffraction pattern given.
  • the content of a certain crystal form in the sample gradually decreases, some diffraction peaks attributable to the crystal form in the X-ray powder diffraction pattern may be reduced due to the detection sensitivity of the instrument.
  • the diffraction angle 2 ⁇ also called 2theta or diffraction peak
  • the diffraction angle 2 ⁇ also called 2theta or diffraction peak
  • the term "diffraction peak" refers to a feature that is not attributed to background noise by those skilled in the art.
  • room temperature refers to a temperature of about 20°C to 35°C or about 23°C to 28°C or about 25°C.
  • mg/mL means milligram/ml
  • h means hour
  • g means gram
  • ml means milliliter
  • °C means degrees Celsius
  • mL/min means milliliters/minute.
  • Figure 1 shows the XRPD spectrum of Form I.
  • Figure 2 shows the XRPD spectrum of Form II.
  • Figure 3 shows the XRPD spectrum of Form III.
  • Figure 4 shows the XRPD spectrum of Form IV.
  • Figure 5 shows the XRPD spectrum of Form V.
  • Figure 6 shows the XRPD spectrum of Form VI.
  • Figure 7 shows the XRPD spectrum of Form VIII.
  • Figure 8 shows the XRPD spectrum of Form IX.
  • Figure 9 shows the XRPD spectrum of Form X.
  • Figure 10 shows the XRPD spectrum of Form XI.
  • Figure 11 shows the XRPD spectrum of Form XII.
  • Figure 12 shows the XRPD spectrum of Form XIII.
  • Figure 13 shows the XRPD spectrum of Form XIV.
  • Figure 14 shows the XRPD spectrum of Form XV.
  • Figure 15 shows the XRPD spectrum of Form XVI.
  • Figure 16 shows the XRPD spectrum of Form XVII.
  • Figure 17 shows the XRPD spectrum of Form XVIII.
  • Figure 18 shows the XRPD spectrum of Form XIX.
  • Figure 19 shows the XRPD spectrum of Form XX.
  • Figure 20 shows the XRD spectrum of the crystalline form XXI.
  • Figure 21 shows the DSC spectrum of the crystalline form XXI.
  • Figure 22 shows the TGA spectrum of Form XXI.
  • Figure 23 shows the XRD spectrum of Form XXII.
  • Figure 24 shows the DSC spectrum of Form XXII.
  • Figure 25 shows the TGA spectrum of Form XXII.
  • Figure 26 shows the XRPD spectrum of the amorphous form.
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • crystal forms IX, XIX, XXI and XXII were investigated, including high temperature test, high humidity test and strong light irradiation test, to investigate the stability of the crystal form.
  • High temperature test Take appropriate amounts of the above crystal samples, lay them flat in a weighing bottle, and place them in a constant temperature and humidity box at 60°C ⁇ 5°C, RH 75 ⁇ 5%, and then take the samples in 0, 5, and 15 days. About 100 mg, the crystal form was tested by powder X-ray powder diffraction (XRPD), and the results are shown in Table 1.
  • High humidity test Take appropriate amounts of the above-mentioned crystal samples, and place them in a weighing bottle, place them in a constant temperature and humidity box at 25°C, RH 92.5 ⁇ 5%, and then take about 100mg of the above samples on 0, 5, and 15 days. , Using powder X-ray powder diffraction (XRPD) to test its crystal form, the results are shown in Table 1.
  • XRPD powder X-ray powder diffraction
  • Illumination test Take appropriate amounts of the above crystal samples and spread them in a weighing bottle. Place them in a constant temperature and humidity box (25°C, RH 60) with visible light 4500Lux ⁇ 500Lux(VIS) and ultraviolet light % ⁇ 5%), and then about 100 mg of the above sample was taken at 0, 5, and 15 days, and the crystal form was tested by powder X-ray powder diffraction (XRPD). The results are shown in Table 1.
  • Table 1 Stability test results of crystal forms IX, XIX, XXI and XXII
  • the crystal form XXI, the crystal form XXII and the crystal form A and the crystal form B disclosed in CN102947278B were mixed and stirred in water at room temperature, 37°C and 60°C for 24 hours, respectively.
  • the crystal form of the obtained solid was filtered, dried and tested, and the results are shown in Table 2 below.
  • crystal form B transforms into crystal form XXI with high crystallinity, indicating that the crystal
  • the stability of Form XXI is higher than that of Form A and Form B, that is, the order of stability is: Form XXI>Form B>Form XXII>Form A.
  • Table 3 Bulk density, tap density and Carr index of crystal form B and crystal form XXI and XXII samples
  • the DSC method parameters are as follows:
  • the TGA method parameters are as follows:

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Abstract

The present invention relates to the technical field of pharmaceutical and chemical industry, and specifically, to a crystal form of a GABA inhibitor and a preparation method therefor. The GABA crystal form has the advantages of good product stability, high crystallinity, etc. In addition, the preparation method for the crystal form is simple, good in repeatability, and suitable for industrial production.

Description

一种GABA抑制剂的晶型及其制备方法A kind of crystal form of GABA inhibitor and preparation method thereof 技术领域Technical field
本发明属于医药化工技术领域，具体涉及一种GABA抑制剂的新晶型及其制备方法。The invention belongs to the technical field of medicine and chemical engineering, and specifically relates to a new crystal form of a GABA inhibitor and a preparation method thereof.
背景技术Background technique
阿福拉纳是一种GABA(γ-氨基丁酸)抑制剂，其通过抑制GABA氯离子通道，使节肢动物神经高度兴奋导致死亡，是一种强效杀虫剂。新一代犬用口服体外驱虫药尼可信(NexGard，通用名：阿福拉纳咀嚼片)，是国内首个兼杀蜱虫和跳蚤两种寄生虫的犬用口服驱虫药。Aforana is a GABA (γ-aminobutyric acid) inhibitor that inhibits the GABA chloride ion channel and makes arthropod nerves highly excited and leads to death. It is a powerful insecticide. NexGard, a new generation of oral in vitro anthelmintic for dogs (NexGard, common name: Aphrana Chewable Tablets), is the first domestic oral anthelmintic for dogs that kills both tick and flea parasites.
阿福拉纳的化学名为4-(5-(3-氯-5-(三氟甲基)-苯基)-4,5-二氢-5-(三氟甲基)-3-异恶唑基)-N-(2-氧代-2-((2,2,2-三氟乙基)氨基)乙基-1-萘甲酰胺，结构式如下：The chemical name of Aforana is 4-(5-(3-chloro-5-(trifluoromethyl)-phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-iso Oxazolyl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl-1-naphthylcarboxamide, the structural formula is as follows:
Figure PCTCN2021100649-appb-000001
Figure PCTCN2021100649-appb-000001
专利CN102947278B公开了阿福拉纳的多种晶型：晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H以及甲苯溶剂合物，其中大多数晶型是溶剂合物，如晶型C为乙酸乙酯溶剂合物、晶型D为二氧六环环己烷溶剂合物、晶型F为正丙醇溶剂合物、晶型G为乙腈溶剂合物、晶型H为异丙醇溶剂合物，而晶型A、晶型B、晶型E的结晶度较差，无定型含量高，易转晶，故本专利开发了阿福拉纳的新晶型及其制备方法，大大提高了稳定性和晶型纯度，且操作简单，收率高、易于工业化生产。Patent CN102947278B discloses multiple crystal forms of Aforana: crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H and toluene solvate , Most of the crystal forms are solvates, such as crystal form C is ethyl acetate solvate, crystal form D is dioxane cyclohexane solvate, crystal form F is n-propanol solvate, crystal Form G is acetonitrile solvate, crystal form H is isopropanol solvate, while crystal form A, crystal form B, and crystal form E have poor crystallinity, high amorphous content, and easy to crystallize, so this patent is developed The new crystal form of Aforana and the preparation method thereof have greatly improved the stability and purity of the crystal form, and the operation is simple, the yield is high, and the industrial production is easy.
发明概述Summary of the invention
本发明提供了阿福拉纳的多种晶型。The present invention provides multiple crystal forms of Aforana.
本发明提供的阿福拉纳晶型XXI和晶型XXII相对于现有技术中的阿福拉纳晶型具有产品稳定性好、结晶度高等优点。Compared with the Aforana crystal form in the prior art, the Aforana crystal form XXI and the crystal form XXII provided by the present invention have the advantages of good product stability and high crystallinity.
所述阿福拉纳晶型XXI，其X-射线粉末衍射图中包含2θ角为15.8，18.0，18.4，19.6和21.8度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XXI contains diffraction peaks with 2θ angles of 15.8, 18.0, 18.4, 19.6 and 21.8 degrees.
所述阿福拉纳晶型XXI在高温条件下，具有较好的稳定性，有利于药物制剂的制备。The aforana crystal form XXI has better stability under high temperature conditions, which is beneficial to the preparation of pharmaceutical preparations.
所述阿福拉纳晶型XXII，其X-射线粉末衍射图中包含2θ角为4.4，10.7，13.2，17.5，19.3和25.2度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XXII contains diffraction peaks with 2θ angles of 4.4, 10.7, 13.2, 17.5, 19.3 and 25.2 degrees.
发明详述Detailed description of the invention
本发明第一方面提供了阿福拉纳的晶型。The first aspect of the present invention provides a crystal form of Aforana.
根据本发明所述实施例，所述阿福拉纳晶型分别命名为晶型XXI和晶型XXII，及晶型I、晶型II、晶 型III、晶型IV、晶型V、晶型VI、晶型VIII、晶型IX、晶型X、晶型XI、晶型XII、晶型XIII、晶型XIV、晶型XV、晶型XVI、晶型XVII、晶型XVIII、晶型XIX和晶型XX。According to the embodiment of the present invention, the crystal forms of Aforana are named as the crystal form XXI and the crystal form XXII, and the crystal form I, the crystal form II, the crystal form III, the crystal form IV, the crystal form V, and the crystal form respectively. VI, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, Form XIX and Crystal Form XX.
本发明提供的阿福拉纳晶型XXI和晶型XXII相对于现有技术中的阿福拉纳晶型具有产品稳定性好、结晶度高等优点。Compared with the Aforana crystal form in the prior art, the Aforana crystal form XXI and the crystal form XXII provided by the present invention have the advantages of good product stability and high crystallinity.
本发明所述的阿福拉纳晶型I的X-射线粉末衍射图中包含2θ角为3.9，7.7，9.8，11.5，13.0，15.4，16.6，19.3，20.2，23.2，24.0，26.3，27.1，27.8，31.7，35.1，35.7度的衍射峰。The X-ray powder diffraction pattern of Aforana Form I of the present invention contains 2θ angles of 3.9, 7.7, 9.8, 11.5, 13.0, 15.4, 16.6, 19.3, 20.2, 23.2, 24.0, 26.3, 27.1, 27.8, 31.7, 35.1, 35.7 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型I，其X-射线粉末衍射图基本上如图1所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form I is substantially as shown in FIG. 1.
本发明所述的阿福拉纳晶型I的差示扫描量热曲线在105℃处具有吸热峰。The differential scanning calorimetry curve of Aforana crystal form I of the present invention has an endothermic peak at 105°C.
本发明所述的阿福拉纳晶型II的X-射线粉末衍射图谱中包含2θ角为11.1，11.8，13.5，15.8，16.8，17.6，18.0，19.1，19.6，20.5，21.8，22.6，23.5，24.4，27.2，27.7度的衍射峰。The X-ray powder diffraction pattern of Aforana Form II of the present invention contains 2θ angles of 11.1, 11.8, 13.5, 15.8, 16.8, 17.6, 18.0, 19.1, 19.6, 20.5, 21.8, 22.6, 23.5, 24.4, 27.2, 27.7 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型II，其X-射线粉末衍射图基本上如图2所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form II is substantially as shown in FIG. 2.
本发明所述的阿福拉纳晶型II的差示扫描量热曲线在73℃处具有吸热峰。The differential scanning calorimetry curve of the crystal form II of Aforana of the present invention has an endothermic peak at 73°C.
本发明所述的阿福拉纳晶型III的X-射线粉末衍射图谱中包含2θ角为3.8，11.5，12.9，13.5，15.0，16.1，16.4，17.4，18.9，19.7，19.9，20.6，21.2，21.7，22.0，22.3，22.8，23.6，24.7，25.4，26.0，26.4，27.1，29.6，30.3，30.8，31.1，34.8，36.2，37.6度的衍射峰。The X-ray powder diffraction pattern of Aforana Form III of the present invention contains 2θ angles of 3.8, 11.5, 12.9, 13.5, 15.0, 16.1, 16.4, 17.4, 18.9, 19.7, 19.9, 20.6, 21.2, 21.7, 22.0, 22.3, 22.8, 23.6, 24.7, 25.4, 26.0, 26.4, 27.1, 29.6, 30.3, 30.8, 31.1, 34.8, 36.2, 37.6 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型III，其X-射线粉末衍射图基本上如图3所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form III is substantially as shown in FIG. 3.
本发明所述的阿福拉纳晶型III的差示扫描量热曲线在135℃处具有吸热峰。The differential scanning calorimetry curve of Aforana Form III of the present invention has an endothermic peak at 135°C.
本发明所述的阿福拉纳晶型IV的X-射线粉末衍射图谱中包含2θ角为3.9，11.2，12.4，13.5，15.6，16.6，17.0，17.4，19.3，19.9，20.3，20.8，21.0，21.7，21.9，22.3，22.6，23.0，23.3，24.0，25.0，26.2，26.8，27.2，27.6，29.4，29.7，30.0，31.1，31.8，33.2，34.5，37.4度的衍射峰。The X-ray powder diffraction pattern of Aforana Form IV of the present invention contains 2θ angles of 3.9, 11.2, 12.4, 13.5, 15.6, 16.6, 17.0, 17.4, 19.3, 19.9, 20.3, 20.8, 21.0, 21.7, 21.9, 22.3, 22.6, 23.0, 23.3, 24.0, 25.0, 26.2, 26.8, 27.2, 27.6, 29.4, 29.7, 30.0, 31.1, 31.8, 33.2, 34.5, 37.4 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型IV，其X-射线粉末衍射图基本上如图4所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form IV is substantially as shown in FIG. 4.
本发明所述的阿福拉纳晶型IV的差示扫描量热曲线在112℃处具有吸热峰。The differential scanning calorimetry curve of the crystal form IV of Aforana of the present invention has an endothermic peak at 112°C.
本发明所述的阿福拉纳晶型V的X-射线粉末衍射图谱中包含2θ角为11.4，12.0，12.6，15.4，17.7，18.5，19.2，19.9，20.5，20.7，21.4，21.9，22.5，23.3，24.2，25.4，25.8，27.5，29.8，34.1度的衍射峰。The X-ray powder diffraction pattern of Aforana Form V of the present invention contains 2θ angles of 11.4, 12.0, 12.6, 15.4, 17.7, 18.5, 19.2, 19.9, 20.5, 20.7, 21.4, 21.9, 22.5, 23.3, 24.2, 25.4, 25.8, 27.5, 29.8, 34.1 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型V，其X-射线粉末衍射图基本上如图5所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form V is substantially as shown in FIG. 5.
本发明所述的阿福拉纳晶型V的差示扫描量热曲线在105℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form V of the present invention has an endothermic peak at 105°C.
本发明所述的阿福拉纳晶型VI的X-射线粉末衍射图谱中包含2θ角为3.9，11.5，12.6，13.2，14.8，15.8，16.5，17.5，18.1，19.1，19.4，20.2，21.3，22.0，22.3，22.5，22.8，23.4，23.9，25.4，25.7，26.3，26.9，27.4，29.2，29.9，30.3度的衍射峰。The X-ray powder diffraction pattern of Aforana Form VI of the present invention contains 2θ angles of 3.9, 11.5, 12.6, 13.2, 14.8, 15.8, 16.5, 17.5, 18.1, 19.1, 19.4, 20.2, 21.3, 22.0, 22.3, 22.5, 22.8, 23.4, 23.9, 25.4, 25.7, 26.3, 26.9, 27.4, 29.2, 29.9, 30.3 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型VI，其X-射线粉末衍射图基本上如图6所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form VI is substantially as shown in FIG. 6.
在一些实施方式中，本发明所述的阿福拉纳晶型VI的差示扫描量热曲线在96℃处具有吸热峰。In some embodiments, the differential scanning calorimetry curve of Aforana Form VI of the present invention has an endothermic peak at 96°C.
在一些实施方式中，本发明所述的阿福拉纳晶型VI的差示扫描量热曲线在113℃处具有吸热峰。In some embodiments, the differential scanning calorimetry curve of Aforana Form VI of the present invention has an endothermic peak at 113°C.
本发明所述的阿福拉纳晶型VIII在X-射线粉末衍射图谱中包含2θ角为18.0度的衍射峰。The Aforana crystal form VIII of the present invention contains a diffraction peak with a 2θ angle of 18.0 degrees in the X-ray powder diffraction pattern.
在一些实施方式中，所述的阿福拉纳晶型VIII，其X-射线粉末衍射图基本上如图7所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form VIII is substantially as shown in FIG. 7.
本发明所述的阿福拉纳晶型VIII的差示扫描量热曲线没有明显吸热峰。The differential scanning calorimetry curve of the Aforana crystal form VIII of the present invention has no obvious endothermic peak.
本发明所述的阿福拉纳晶型IX的X-射线粉末衍射图谱中包含2θ角为4.0，9.8，11.3，11.8，12.4，13.6，15.2，16.7，17.0，17.7，19.4，19.6，20.2，20.5，21.4，21.6，22.4，22.7，23.3，23.7，24.4，24.9，25.6，26.5，27.8，29.9，31.2度的衍射峰。The X-ray powder diffraction pattern of Aforana Form IX of the present invention contains 2θ angles of 4.0, 9.8, 11.3, 11.8, 12.4, 13.6, 15.2, 16.7, 17.0, 17.7, 19.4, 19.6, 20.2, 20.5, 21.4, 21.6, 22.4, 22.7, 23.3, 23.7, 24.4, 24.9, 25.6, 26.5, 27.8, 29.9, 31.2 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型IX，其X-射线粉末衍射图基本上如图8所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form IX is substantially as shown in FIG. 8.
在一些实施方式中，本发明所述的阿福拉纳晶型IX的差示扫描量热曲线在106℃处具有吸热峰。In some embodiments, the differential scanning calorimetry curve of Aforana Form IX of the present invention has an endothermic peak at 106°C.
在一些实施方式中，本发明所述的阿福拉纳晶型IX的差示扫描量热曲线在138℃处具有吸热峰。In some embodiments, the differential scanning calorimetry curve of Aforana Form IX of the present invention has an endothermic peak at 138°C.
本发明所述的阿福拉纳晶型X的X-射线粉末衍射图谱中包含2θ角为11.2，15.1，15.6，16.3，16.6，18.1，19.1，19.5，20.0，20.2，20.4，20.9，22.3，22.8，24.2，24.9，26.1，26.8，27.5度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form X of the present invention contains 2θ angles of 11.2, 15.1, 15.6, 16.3, 16.6, 18.1, 19.1, 19.5, 20.0, 20.2, 20.4, 20.9, 22.3, 22.8, 24.2, 24.9, 26.1, 26.8, 27.5 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型X，其X-射线粉末衍射图基本上如图9所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form X is substantially as shown in FIG. 9.
本发明所述的阿福拉纳晶型XI的X-射线粉末衍射图谱中包含2θ角为11.2，12.4，12.9，14.6，15.5，15.9，16.5，17.3，19.0，19.2，20.1，20.8，21.6，22.2，22.5，23.1，23.4，23.8，24.1，24.9，25.5，25.9，26.8，27.3，28.3，29.1，29.5，29.7，34.1，34.8，39.6度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XI of the present invention contains 2θ angles of 11.2, 12.4, 12.9, 14.6, 15.5, 15.9, 16.5, 17.3, 19.0, 19.2, 20.1, 20.8, 21.6, 22.2, 22.5, 23.1, 23.4, 23.8, 24.1, 24.9, 25.5, 25.9, 26.8, 27.3, 28.3, 29.1, 29.5, 29.7, 34.1, 34.8, 39.6 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XI，其X-射线粉末衍射图基本上如图10所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form XI is substantially as shown in FIG. 10.
本发明所述的阿福拉纳晶型XI的差示扫描量热曲线在77℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XI of the present invention has an endothermic peak at 77°C.
本发明所述的阿福拉纳晶型XII的X-射线粉末衍射图谱中包含2θ角为3.8，11.4，12.7，13.2，14.7，15.8，16.4，17.4，18.8，19.4，19.9，20.5，21.2，21.3，22.0，22.6，22.7，23.2，23.6，24.1，24.5，25.1，25.4，26.1，26.6，26.9，27.3，27.8，28.5，28.9，29.6，29.8，30.3，31.9，34.2，36.2，37.4度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XII of the present invention contains 2θ angles of 3.8, 11.4, 12.7, 13.2, 14.7, 15.8, 16.4, 17.4, 18.8, 19.4, 19.9, 20.5, 21.2, 21.3, 22.0, 22.6, 22.7, 23.2, 23.6, 24.1, 24.5, 25.1, 25.4, 26.1, 26.6, 26.9, 27.3, 27.8, 28.5, 28.9, 29.6, 29.8, 30.3, 31.9, 34.2, 36.2, 37.4 degree diffraction peak.
在一些实施方式中，所述的阿福拉纳晶型XII，其X-射线粉末衍射图基本上如图11所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form XII is substantially as shown in FIG. 11.
本发明所述的阿福拉纳晶型XII的差示扫描量热曲线在101℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XII of the present invention has an endothermic peak at 101°C.
本发明所述的阿福拉纳晶型XIII的X-射线粉末衍射图谱中包含2θ角为11.3，11.8，12.5，13.5，15.3，16.5，17.0，18.8，19.5，20.3，21.2，21.7，22.0，22.3，22.7，23.1，24.0，24.4，25.2，25.5，27.2，28.5，29.4，31.0，36.3度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XIII of the present invention contains 2θ angles of 11.3, 11.8, 12.5, 13.5, 15.3, 16.5, 17.0, 18.8, 19.5, 20.3, 21.2, 21.7, 22.0, 22.3, 22.7, 23.1, 24.0, 24.4, 25.2, 25.5, 27.2, 28.5, 29.4, 31.0, 36.3 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XIII，其X-射线粉末衍射图基本上如图12所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form XIII is substantially as shown in FIG. 12.
本发明所述的阿福拉纳晶型XIII的差示扫描量热曲线在83℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XIII of the present invention has an endothermic peak at 83°C.
本发明所述的阿福拉纳晶型XIV的X-射线粉末衍射图谱中包含2θ角为3.9，9.6，11.5，12.1，12.9，16.4，17.7，18.9，19.3，20.2，22.5，23.1，23.9，24.3，25.1，27.1，27.6，29.5，37.4度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XIV of the present invention contains 2θ angles of 3.9, 9.6, 11.5, 12.1, 12.9, 16.4, 17.7, 18.9, 19.3, 20.2, 22.5, 23.1, 23.9, 24.3, 25.1, 27.1, 27.6, 29.5, 37.4 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XIV，其X-射线粉末衍射图基本上如图13所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form XIV is substantially as shown in FIG. 13.
本发明所述的阿福拉纳晶型XIV的差示扫描量热曲线在77℃、134℃两处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XIV of the present invention has endothermic peaks at 77°C and 134°C.
本发明所述的阿福拉纳晶型XV的X-射线粉末衍射图谱中包含2θ角为4.0，7.8，9.8，11.8，12.5，13.2，15.7，16.8，17.4，18.0，18.3，18.8，19.6，20.5，21.4，21.8，23.0，23.6，23.9，24.4，24.8，25.2，25.5，25.9，27.6，28.2，29.5，29.8，30.2，32.3，36.9度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XV of the present invention contains 2θ angles of 4.0, 7.8, 9.8, 11.8, 12.5, 13.2, 15.7, 16.8, 17.4, 18.0, 18.3, 18.8, 19.6, 20.5, 21.4, 21.8, 23.0, 23.6, 23.9, 24.4, 24.8, 25.2, 25.5, 25.9, 27.6, 28.2, 29.5, 29.8, 30.2, 32.3, 36.9 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XV，其X-射线粉末衍射图基本上如图14所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form XV is substantially as shown in FIG. 14.
本发明所述的阿福拉纳晶型XV的差示扫描量热曲线在104℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XV of the present invention has an endothermic peak at 104°C.
本发明所述的阿福拉纳晶型XVI的X-射线粉末衍射图谱中包含2θ角为11.0，12.1，12.7，14.7，16.4，18.8，19.2，20.5，22.1，24.4，25.4，26.9，35.9度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XVI of the present invention contains 2θ angles of 11.0, 12.1, 12.7, 14.7, 16.4, 18.8, 19.2, 20.5, 22.1, 24.4, 25.4, 26.9, 35.9 degrees. The diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XVI，其X-射线粉末衍射图基本上如图15所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form XVI is basically as shown in FIG. 15.
本发明所述的阿福拉纳晶型XVI的差示扫描量热曲线在73℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XVI of the present invention has an endothermic peak at 73°C.
本发明所述的阿福拉纳晶型XVII的X-射线粉末衍射图谱中包含2θ角为3.9，7.8，9.9，11.2，12.3，12.9，15.5，16.7，17.0，17.2，17.6，19.4，20.0，20.4，20.8，21.9，22.1，22.5，22.9，23.1，23.4，24.2，24.8，25.9，27.4，27.8，29.6，31.4，33.1，37.0，37.6度的衍射峰。The X-ray powder diffraction pattern of Aforana Form XVII of the present invention contains 2θ angles of 3.9, 7.8, 9.9, 11.2, 12.3, 12.9, 15.5, 16.7, 17.0, 17.2, 17.6, 19.4, 20.0, 20.4, 20.8, 21.9, 22.1, 22.5, 22.9, 23.1, 23.4, 24.2, 24.8, 25.9, 27.4, 27.8, 29.6, 31.4, 33.1, 37.0, 37.6 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XVII，其X-射线粉末衍射图基本上如图16所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form XVII is substantially as shown in FIG. 16.
本发明所述的阿福拉纳晶型XVII的差示扫描量热曲线在96℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XVII of the present invention has an endothermic peak at 96°C.
本发明所述的阿福拉纳晶型XVIII的X-射线粉末衍射图谱中包含2θ角为3.9，7.3，9.9，11.4，12.3，12.9，15.6，16.9，18.1，19.2，20.1，20.9，21.2，21.6，22.0，22.6，24.3，25.0，26.5，27.2，29.4，31.7，33.4，35.0度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XVIII of the present invention contains 2θ angles of 3.9, 7.3, 9.9, 11.4, 12.3, 12.9, 15.6, 16.9, 18.1, 19.2, 20.1, 20.9, 21.2, 21.6, 22.0, 22.6, 24.3, 25.0, 26.5, 27.2, 29.4, 31.7, 33.4, 35.0 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XVIII，其X-射线粉末衍射图基本上如图17所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form XVIII is substantially as shown in FIG. 17.
本发明所述的阿福拉纳晶型XVIII的差示扫描量热曲线在89℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XVIII of the present invention has an endothermic peak at 89°C.
本发明所述的阿福拉纳晶型XIX的X-射线粉末衍射图谱中包含2θ角为4.0，9.9，11.1，11.8，12.1，12.7，13.2，15.2，16.9，17.5，18.1，19.1，19.8，20.6，21.2，21.7，21.9，22.6，23.4，23.6，24.1，24.4，24.7，26.1，26.9，27.1，28.3，29.1，29.6，30.7，31.5，32.9，34.1，34.6，35.6度的衍射峰。The X-ray powder diffraction pattern of the Aforana crystal form XIX of the present invention contains 2θ angles of 4.0, 9.9, 11.1, 11.8, 12.1, 12.7, 13.2, 15.2, 16.9, 17.5, 18.1, 19.1, 19.8, 20.6, 21.2, 21.7, 21.9, 22.6, 23.4, 23.6, 24.1, 24.4, 24.7, 26.1, 26.9, 27.1, 28.3, 29.1, 29.6, 30.7, 31.5, 32.9, 34.1, 34.6, 35.6 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XIX，其X-射线粉末衍射图基本上如图18所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form XIX is basically as shown in FIG. 18.
本发明所述的阿福拉纳晶型XIX的差示扫描量热曲线在140℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XIX of the present invention has an endothermic peak at 140°C.
在一些实施方式中，本发明所述的阿福拉纳晶型XX的X-射线粉末衍射图谱中包含2θ角为4.4，7.6，8.7，10.8，12.6，13.2，14.3，19.3，20.0，23.2，25.2，27.2度的衍射峰。In some embodiments, the X-ray powder diffraction pattern of Aforana Form XX of the present invention contains 2θ angles of 4.4, 7.6, 8.7, 10.8, 12.6, 13.2, 14.3, 19.3, 20.0, 23.2, 25.2, 27.2 degree diffraction peak.
在一些实施方式中，所述的阿福拉纳晶型XX，其X-射线粉末衍射图基本上如图19所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form XX is substantially as shown in FIG. 19.
本发明所述的阿福拉纳晶型XX的差示扫描量热曲线在106℃处具有吸热峰。The differential scanning calorimetry curve of the Aforana crystal form XX of the present invention has an endothermic peak at 106°C.
本发明所述的阿福拉纳晶型XXI，其X-射线粉末衍射图中包含2θ角为15.8，18.0，18.4，19.6和21.8度的衍射峰。The Aforana crystal form XXI of the present invention has an X-ray powder diffraction pattern containing diffraction peaks with 2θ angles of 15.8, 18.0, 18.4, 19.6 and 21.8 degrees.
在一些实施方式中，所述的阿福拉纳晶型XXI，其X-射线粉末衍射图中包含2θ角为4.7，15.8，16.8，18.0，18.4，19.3，19.6和21.8度的衍射峰。在一些实施方式中，所述的阿福拉纳晶型XXI，其X-射线粉末衍射图中包含2θ角为4.7，9.3，11.2，15.8，16.8，18.0，18.4，19.3，19.6，19.9，20.8，21.2，21.4，21.8，23.0，23.6，24.0，26.4，28.0和29.7度的衍射峰。在一些实施方式中，所述的阿福拉纳晶型XXI，其X-射线粉末衍射图中包含2θ角为4.7，5.7，9.3，10.8，11.2，12.1，12.8，13.8，14.0，15.1，15.8，16.8，18.0，18.4，19.3，19.6，19.9，20.8，21.2，21.4，21.8，23.0，23.6，24.0，24.5，25.3，26.0，26.4，27.2，28.0，29.7和31.4度的衍射峰。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form XXI includes diffraction peaks with 2θ angles of 4.7, 15.8, 16.8, 18.0, 18.4, 19.3, 19.6 and 21.8 degrees. In some embodiments, the Aforana crystal form XXI has an X-ray powder diffraction pattern including 2θ angles of 4.7, 9.3, 11.2, 15.8, 16.8, 18.0, 18.4, 19.3, 19.6, 19.9, 20.8 , 21.2, 21.4, 21.8, 23.0, 23.6, 24.0, 26.4, 28.0 and 29.7 degree diffraction peaks. In some embodiments, the Aforana crystal form XXI has an X-ray powder diffraction pattern including 2θ angles of 4.7, 5.7, 9.3, 10.8, 11.2, 12.1, 12.8, 13.8, 14.0, 15.1, 15.8 , 16.8, 18.0, 18.4, 19.3, 19.6, 19.9, 20.8, 21.2, 21.4, 21.8, 23.0, 23.6, 24.0, 24.5, 25.3, 26.0, 26.4, 27.2, 28.0, 29.7 and 31.4 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XXI，其X-射线粉末衍射图基本上如图20所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form XXI is substantially as shown in FIG. 20.
在一些实施方式中，本发明所述的阿福拉纳晶型XXI的差示扫描量热曲线在116℃-126℃处具有吸热峰。在一些实施例中，所述晶型XXI的差示扫描量热曲线在118℃-123℃处具有吸热峰。在一些实施例中，所述晶型XXI的差示扫描量热曲线在121℃处具有吸热峰。在一些实施例中，所述晶型XXI的差示扫描量热曲线基本上如图21所示。In some embodiments, the differential scanning calorimetry curve of the Aforana crystal form XXI of the present invention has an endothermic peak at 116°C-126°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXI has an endothermic peak at 118°C-123°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXI has an endothermic peak at 121°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXI is substantially as shown in FIG. 21.
在一些实施方式中，热重分析曲线显示晶型XXI在30℃-150℃的温度范围内失重0.7％。在一些实施方式中，所述晶型XXI含水。在一些实施方式中，所述晶型XXI含水，阿福拉纳与水的摩尔比约为4:1。在一些实施例中，所述晶型XXI的热重分析曲线基本上如图22所示。In some embodiments, the thermogravimetric analysis curve shows that the crystalline form XXI loses 0.7% in the temperature range of 30°C to 150°C. In some embodiments, the crystalline form XXI contains water. In some embodiments, the crystalline form XXI contains water, and the molar ratio of Aforana to water is about 4:1. In some embodiments, the thermogravimetric analysis curve of the crystalline form XXI is substantially as shown in FIG. 22.
本发明所述的阿福拉纳晶型XXII，其X-射线粉末衍射图中包含2θ角为10.7，13.2，17.5，19.3和25.2度的衍射峰。The Aforana crystal form XXII of the present invention contains diffraction peaks with 2θ angles of 10.7, 13.2, 17.5, 19.3 and 25.2 degrees in the X-ray powder diffraction pattern.
在一些实施方式中，所述的阿福拉纳晶型XXII，其X-射线粉末衍射图中包含2θ角为4.4，10.7，13.2，17.5，19.3和25.2度的衍射峰。在一些实施方式中，所述的阿福拉纳晶型XXII，其X-射线粉末衍射图中包含2θ角为4.4，10.7，12.6，13.2，15.7，17.5，19.3，19.9，23.2，25.2和26.5度的衍射峰。在一些实施方式中，所述的阿福拉纳晶型XXII，其X-射线粉末衍射图中包含2θ角为4.4，6.6，7.6，8.7，10.7，12.6，13.2，14.2，15.7，16.7，17.5，18.1，19.3，19.9，21.4，23.2，25.2，26.5和27.4度的衍射峰。In some embodiments, the X-ray powder diffraction pattern of the Aforana Form XXII includes diffraction peaks with 2θ angles of 4.4, 10.7, 13.2, 17.5, 19.3 and 25.2 degrees. In some embodiments, the Aforana crystal form XXII has an X-ray powder diffraction pattern including 2θ angles of 4.4, 10.7, 12.6, 13.2, 15.7, 17.5, 19.3, 19.9, 23.2, 25.2, and 26.5. Degree of diffraction peaks. In some embodiments, the Aforana crystal form XXII has an X-ray powder diffraction pattern including 2θ angles of 4.4, 6.6, 7.6, 8.7, 10.7, 12.6, 13.2, 14.2, 15.7, 16.7, 17.5 , 18.1, 19.3, 19.9, 21.4, 23.2, 25.2, 26.5 and 27.4 degree diffraction peaks.
在一些实施方式中，所述的阿福拉纳晶型XXII，其X-射线粉末衍射图基本上如图23所示。In some embodiments, the X-ray powder diffraction pattern of the Aforana crystal form XXII is substantially as shown in FIG. 23.
在一些实施方式中，本发明阿福拉纳晶型XXII的差示扫描量热曲线在108℃-118℃处具有吸热峰。在一些实施例中，所述晶型XXII的差示扫描量热曲线在110℃-116℃处具有吸热峰。在一些实施例中，所述晶型XXII的差示扫描量热曲线在113℃处具有吸热峰。在一些实施例中，所述晶型XXII的差示扫描量热曲线基本上如图24所示。In some embodiments, the differential scanning calorimetry curve of the Aforana crystal form XXII of the present invention has an endothermic peak at 108°C-118°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXII has an endothermic peak at 110°C-116°C. In some embodiments, the differential scanning calorimetry curve of the crystalline form XXII has an endothermic peak at 113°C. In some embodiments, the differential scanning calorimetry curve of the crystal form XXII is substantially as shown in FIG. 24.
在一些实施方式中，热重分析曲线显示晶型XXII在30℃-150℃的温度范围内失重0.1％。在一些实施例中，所述阿福拉纳晶型XXII，其热重分析曲线基本上如图25所示。In some embodiments, the thermogravimetric analysis curve shows that the crystal form XXII loses 0.1% in the temperature range of 30°C to 150°C. In some embodiments, the thermogravimetric analysis curve of the Aforana crystal form XXII is substantially as shown in FIG. 25.
在一些实施方式中，本发明所述的阿福拉纳无定型在X-射线粉末衍射图谱，如图26所示。In some embodiments, the amorphous form of Aforana of the present invention has an X-ray powder diffraction pattern, as shown in FIG. 26.
本发明第二方面，提供了阿福拉纳新晶型的制备方法。该新晶型的制备方法简单，重复性好，适合工业化生产。The second aspect of the present invention provides a method for preparing the new crystal form of Aforana. The preparation method of the new crystal form is simple, has good repeatability, and is suitable for industrial production.
本发明提供了所述阿福拉纳晶型I的制备方法。The present invention provides a method for preparing the crystal form I of Aforana.
本发明所述晶型I的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form I of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型I的方法，包括：将阿福拉纳固体溶于丁酮中，降温析出晶体，过滤、干燥，得到晶型I产品。A method for preparing crystal form I of aforana comprises: dissolving solid aforana in methyl ethyl ketone, cooling to precipitate crystals, filtering and drying to obtain crystal form I product.
在一些实施方式中，将阿福拉纳固体溶于丁酮中，溶清后滴加反溶剂至析出晶体，过滤、干燥，得到晶型I产品。根据本发明所述实施例，所述反溶剂为正庚烷、正己烷、环己烷、异丙醚中是一种或多种；在一些具体实施方式中，所述反溶剂的滴加方式为正滴；在一些具体实施方式中，所述反溶剂的滴加方式为反滴。In some embodiments, the Aforana solid is dissolved in methyl ethyl ketone, and after the solution is clear, an anti-solvent is added dropwise to precipitate crystals, filtered and dried to obtain the crystal form I product. According to the embodiment of the present invention, the anti-solvent is one or more of n-heptane, n-hexane, cyclohexane, and isopropyl ether; in some specific embodiments, the anti-solvent is dripped It is a positive drop; in some embodiments, the anti-solvent is added in a reverse drop.
在一些实施方式中，将阿福拉纳溶于丁酮中，挥发，得到晶型I产品。In some embodiments, Aphrana is dissolved in methyl ethyl ketone and volatilized to obtain the crystal form I product.
本发明提供了所述阿福拉纳晶型II的制备方法。The present invention provides a method for preparing the crystal form II of Aforana.
本发明所述晶型II的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form II of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrialized production.
一种制备阿福拉纳晶型II的方法，包括：将阿福拉纳溶于良溶剂中，溶清后缓慢滴加纯化水至析出晶体，过滤、干燥，得到晶型II产品。根据本发明所述实施例，所述良溶剂为丙酮、异丙醇、乙腈中的一种或多种。A method for preparing crystal form II of aforana includes: dissolving aforana in a good solvent, slowly adding purified water to precipitate crystals after dissolving, filtering and drying to obtain crystal form II product. According to the embodiment of the present invention, the good solvent is one or more of acetone, isopropanol, and acetonitrile.
本发明提供了所述阿福拉纳晶型III的制备方法。The present invention provides a preparation method of the Aforana crystal form III.
本发明所述晶型III的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form III of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型III的方法，包括：将阿福拉纳溶于二氯甲烷中，溶清后滴加反溶剂至析出晶体，过滤、干燥得到晶型III产品；根据本发明所述实施例，所述反溶剂为碳酸二甲酯。A method for preparing crystal form III of aforana, comprising: dissolving aforana in dichloromethane, dissolving and adding an anti-solvent to precipitate crystals, filtering and drying to obtain crystal form III; according to the present invention In the embodiment, the anti-solvent is dimethyl carbonate.
在一些实施方式中，将阿福拉纳溶于混合溶剂中，溶清后降温析晶，过滤、干燥，得到晶型III产品；根据本发明所述实施例，所述混合溶剂为二氯甲烷和碳酸二甲酯的混合溶剂。In some embodiments, Aforana is dissolved in a mixed solvent, and after dissolving, the temperature is lowered to crystallize, filtered, and dried to obtain the crystal form III product; according to the embodiment of the present invention, the mixed solvent is dichloromethane Mixed solvent with dimethyl carbonate.
在一些实施方式中，将阿福拉纳溶于混合溶剂中，制备得到晶型III产品。根据本发明所述实施例，所述有机溶剂为碳酸二甲酯、丁酮、乙酸异丙酯中的一种或多种。在一些具体实施方式中，所述混合溶剂为碳酸二甲酯和丁酮、乙酸异丙酯中的一种的混合溶剂；在一些具体实施方式中，所述制备方式为混悬；在一些具体实施方式中，所述制备方式为挥发。In some embodiments, Aforana is dissolved in a mixed solvent to prepare a crystal form III product. According to the embodiment of the present invention, the organic solvent is one or more of dimethyl carbonate, methyl ethyl ketone, and isopropyl acetate. In some specific embodiments, the mixed solvent is a mixed solvent of dimethyl carbonate, methyl ethyl ketone, and isopropyl acetate; in some specific embodiments, the preparation method is suspension; in some specific embodiments, In an embodiment, the preparation method is volatilization.
本发明提供了所述阿福拉纳晶型IV的制备方法。The present invention provides a method for preparing the aforana crystal form IV.
本发明所述晶型IV的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form IV of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型IV的方法，包括：将阿福拉纳溶于正丁醇中，挥发，得到晶型IV产品。A method for preparing crystal form IV of aforana includes: dissolving aforana in n-butanol and volatilizing to obtain crystal form IV product.
在一些实施方式中，将阿福拉纳溶于正丁醇中，溶清后滴加反溶剂至析出晶体，过滤、干燥，得到晶型IV产品。根据本发明所述实施例，所述反溶剂为正庚烷、正己烷、环己烷、异丙醚中的一种或多种；在一些具体实施方式中，所述滴加方式为正滴；在一些具体实施方式中，所述滴加方式为反滴。In some embodiments, Aforana is dissolved in n-butanol, and after the solution is clear, an anti-solvent is added dropwise to precipitate crystals, filtered, and dried to obtain a crystal form IV product. According to the embodiment of the present invention, the anti-solvent is one or more of n-heptane, n-hexane, cyclohexane, and isopropyl ether; in some specific embodiments, the dropping method is normal drop ; In some specific embodiments, the dripping method is reverse dripping.
在一些实施方式中，将阿福拉纳溶于有机溶剂中，降温析出晶体，过滤、干燥，得到晶型IV产品。根据本发明所述实施例，所述有机溶剂为正丁醇、乙二醇单甲醚，异丙醚中的一种或多种。In some embodiments, Aforana is dissolved in an organic solvent, the crystals are precipitated by cooling, filtered, and dried to obtain the crystal form IV product. According to the embodiment of the present invention, the organic solvent is one or more of n-butanol, ethylene glycol monomethyl ether, and isopropyl ether.
本发明提供了所述阿福拉纳晶型V的制备方法。The present invention provides a preparation method of the Aforana crystal form V.
本发明所述晶型V的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form V of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型V的方法，包括：将阿福拉纳溶于1,4-二氧六环中，反滴水析出固体，过滤、干燥，得到晶型V产品。A method for preparing crystal form V of Aforana includes: dissolving Aforana in 1,4-dioxane, back-dripping water to precipitate solids, filtering and drying to obtain crystal form V products.
本发明提供了所述阿福拉纳晶型VI的制备方法。The present invention provides a preparation method of the Aforana crystal form VI.
本发明所述晶型VI的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form VI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型VI的方法，包括：将阿福拉纳溶于甲酸丁酯中，挥发，得到晶型VI产品。A method for preparing crystal form VI of aforana includes: dissolving aforana in butyl formate and volatilizing to obtain crystal form VI product.
在一些实施方式中，将阿福拉纳溶于甲酸丁酯中，溶清后加入正庚烷或异丙醚至析出晶体，过滤、干燥，得到晶型VI产品。在一些实施方式中，加入方式为正滴；在一些实施方式中，加入方式为反滴。In some embodiments, aforana is dissolved in butyl formate, after dissolving, n-heptane or isopropyl ether is added to precipitate crystals, filtered and dried to obtain the crystal form VI product. In some embodiments, the addition method is positive drop; in some embodiments, the addition method is reverse drop.
本发明提供了所述阿福拉纳晶型VIII的制备方法。The present invention provides a method for preparing the aforana crystal form VIII.
本发明所述晶型VIII的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form VIII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型VIII的方法，包括：将阿福拉纳溶于有机溶剂中挥发得到晶型VIII产品。根据本发明所述实施例，所述有机溶剂为乙腈、甲基叔丁基醚、甲醇、异丙醚中的一种或多种。在一些具体实施方式中，所述有机溶剂为甲醇和异丙醚的混合溶剂。A method for preparing crystal form VIII of Aforana includes: dissolving Aforana in an organic solvent and volatilizing to obtain crystal form VIII product. According to the embodiment of the present invention, the organic solvent is one or more of acetonitrile, methyl tert-butyl ether, methanol, and isopropyl ether. In some specific embodiments, the organic solvent is a mixed solvent of methanol and isopropyl ether.
本发明提供了所述阿福拉纳晶型IX的制备方法。The present invention provides a preparation method of the Aforana crystal form IX.
本发明所述晶型IX的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form IX of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型IX的方法，包括：，将阿福拉纳置于水和有机溶剂中混悬，过滤干燥得到晶型IX产品。根据本发明所述实施例，所述有机溶剂为异丙醇、N-甲基吡咯烷酮、仲丁醇中的一种或多种。A method for preparing crystal form IX of Aforana includes: suspending Aforana in water and an organic solvent, filtering and drying to obtain crystal form IX product. According to the embodiment of the present invention, the organic solvent is one or more of isopropanol, N-methylpyrrolidone, and sec-butanol.
在一些实施方式中，将阿福拉纳溶于异丙醇等有机溶剂中冷却，析出固体，过滤、干燥，得到晶型IX产品。In some embodiments, Aforana is dissolved in an organic solvent such as isopropanol and cooled to precipitate a solid, filtered, and dried to obtain the crystal form IX product.
本发明提供了所述阿福拉纳晶型X的制备方法。The present invention provides a method for preparing the Aforana crystal form X.
本发明所述晶型X的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form X of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型X的方法，包括：，将阿福拉纳置于水和乙二醇二甲醚混合溶剂中室温下混悬2h-20h，过滤、干燥，得到晶型X产品。A method for preparing crystal form X of aforana, comprising: suspending aforana in a mixed solvent of water and ethylene glycol dimethyl ether for 2h-20h at room temperature, filtering and drying to obtain crystal form X product.
本发明提供了所述阿福拉纳晶型XI的制备方法。The present invention provides a method for preparing the crystal form XI of Aforana.
本发明所述晶型XI的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型IX的方法，包括：，将阿福拉纳溶于有机溶剂中，降温析出固体，过滤、干燥，得到晶型XI产品。根据本发明所述实施例，所述有机溶剂为乙酸异丙酯、正庚烷中的一种或多种。在一些具体实施方式中，所述有机溶剂为乙酸异丙酯、正庚烷的混合溶剂。A method for preparing crystal form IX of Aforana includes: dissolving Aforana in an organic solvent, cooling to precipitate a solid, filtering and drying to obtain crystal form XI product. According to the embodiment of the present invention, the organic solvent is one or more of isopropyl acetate and n-heptane. In some specific embodiments, the organic solvent is a mixed solvent of isopropyl acetate and n-heptane.
在一些实施方式中，将阿福拉纳溶于乙酸异丙酯中，将溶清液向正庚烷中缓慢滴加至析出晶体，过滤、干燥得到晶型XI产品。In some embodiments, Aforana is dissolved in isopropyl acetate, the solution is slowly added dropwise to n-heptane until crystals are precipitated, filtered and dried to obtain the crystalline form XI product.
本发明提供了所述阿福拉纳晶型XII的制备方法。The present invention provides a method for preparing the Aforana crystal form XII.
本发明所述晶型XII的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型XII的方法，包括：将阿福拉纳溶于乙酸乙酯中，将溶清液向甲苯中缓慢滴加至析出晶体，过滤、干燥得到晶型XII产品。A method for preparing the crystal form XII of aforana includes: dissolving the aforana in ethyl acetate, slowly dripping the clear solution into toluene until the crystals are precipitated, filtering and drying to obtain the crystal form XII product.
本发明提供了所述阿福拉纳晶型XIII的制备方法。The present invention provides a preparation method of the Aforana crystal form XIII.
本发明所述晶型XIII的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XIII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型XIII的方法，包括：将阿福拉纳溶于乙二醇二甲醚中，将溶清液向纯化水中缓慢滴加至析出晶体，过滤、干燥，得到晶型XIII产品。A method for preparing Aforana crystal form XIII, including: dissolving Aforana in ethylene glycol dimethyl ether, slowly adding the dissolved clear liquid to purified water until crystals are precipitated, filtering and drying to obtain crystals Type XIII products.
在一些实施方式中，将阿福拉纳于乙二醇二甲醚和纯化水的二元溶剂中于室温下混悬2h-24h，过滤、干燥，得到晶型XIII产品。In some embodiments, aforana is suspended in a binary solvent of ethylene glycol dimethyl ether and purified water for 2-24 hours at room temperature, filtered and dried to obtain the crystal form XIII product.
本发明提供了所述阿福拉纳晶型XIV的制备方法。The present invention provides a method for preparing the Aforana crystal form XIV.
本发明所述晶型XIV的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XIV of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型XIV的方法，包括：将阿福拉纳溶于甲苯中，降温析出固体，过滤得到晶型XIV产品。根据本发明所述实施例，所述阿福拉纳和所用甲苯体积的比例为10mg/mL～200mg/mL；根据本发明所述实施例，溶解温度为40℃～80℃；根据本发明所述实施例，冷却温度为-20℃～10℃。A method for preparing crystal form XIV of aforana includes: dissolving aforana in toluene, cooling to precipitate a solid, and filtering to obtain crystal form XIV product. According to the embodiment of the present invention, the ratio of the aforana to the volume of toluene used is 10 mg/mL to 200 mg/mL; according to the embodiment of the present invention, the dissolution temperature is 40° C. to 80° C.; according to the present invention In the foregoing embodiment, the cooling temperature is -20°C to 10°C.
本发明提供了所述阿福拉纳晶型XV的制备方法。The present invention provides a method for preparing the Aforana crystal form XV.
本发明所述晶型XV的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XV of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型XV的方法，包括：将阿福拉纳溶于甲醇有机溶剂中，析出固体，过滤、干燥得到晶型XV产品。根据本发明所述实施例，所述有机溶剂为甲醇、1,4-二氧六环中的一种或多种。在一些具体实施方式中，所述有机溶剂为1,4-二氧六环和水的混合溶剂；在一些具体实施方式中，所述析出固体操作步骤为挥发；在一些具体实施方式中，所述析出固体操作步骤为降温。A method for preparing the crystal form XV of Aforana includes: dissolving Aforana in a methanol organic solvent to precipitate a solid, filtering and drying to obtain the crystal form XV product. According to the embodiment of the present invention, the organic solvent is one or more of methanol and 1,4-dioxane. In some specific embodiments, the organic solvent is a mixed solvent of 1,4-dioxane and water; in some specific embodiments, the solid precipitation operation step is volatilization; in some specific embodiments, the The operation step for the precipitation of solids is cooling.
在一些实施方式中，将阿福拉纳溶于1,4-二氧六环中，溶清后缓慢滴加纯化水至析出固体，过滤、干 燥，得到晶型XV产品。In some embodiments, Aforana is dissolved in 1,4-dioxane, and purified water is slowly added dropwise to precipitate a solid after the solution is cleared, filtered and dried to obtain the crystalline form XV product.
本发明提供了所述阿福拉纳晶型XVI的制备方法。The present invention provides a preparation method of the Aforana crystal form XVI.
本发明所述晶型XVI的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XVI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrialized production.
一种制备阿福拉纳晶型XVI的方法，包括：将阿福拉纳溶于1-己醇中，降温析出固体，过滤、干燥，得到晶型XVI产品。A method for preparing crystal form XVI of Aforana includes: dissolving Aforana in 1-hexanol, cooling to precipitate a solid, filtering and drying to obtain crystal form XVI product.
本发明提供了所述阿福拉纳晶型XVII的制备方法。The present invention provides a method for preparing the Aforana crystal form XVII.
本发明所述晶型XVII的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XVII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型XVII的方法，包括：将阿福拉纳溶于有机溶剂中，降温析出固体，过滤、干燥，得到晶型XVII产品。根据本发明所述实施例，所述有机溶剂为正丙醇、三氟乙醇、乙醇中的一种或多种；根据本发明所述实施例，所述有机溶剂为正丙醇、三氟乙醇、乙醇与水的混合溶剂。A method for preparing crystal form XVII of Aforana includes: dissolving Aforana in an organic solvent, cooling to precipitate a solid, filtering and drying to obtain crystal form XVII product. According to the embodiment of the present invention, the organic solvent is one or more of n-propanol, trifluoroethanol, and ethanol; according to the embodiment of the present invention, the organic solvent is n-propanol, trifluoroethanol , A mixed solvent of ethanol and water.
在一些实施方式中，将阿福拉纳溶于三氟乙醇中，溶清后缓慢滴加纯化水至固体析出，过滤、干燥，得到晶型XVII产品。根据本发明所述实施例，滴加方式还可以是反滴。In some embodiments, Aforana is dissolved in trifluoroethanol, and purified water is slowly added dropwise until the solid precipitates out, filtered and dried to obtain the crystal form XVII product. According to the embodiment of the present invention, the dripping method may also be reverse dripping.
本发明提供了所述阿福拉纳晶型XVIII的制备方法。The present invention provides a preparation method of the Aforana crystal form XVIII.
本发明所述晶型XVIII的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XVIII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型XVIII的方法，包括：将阿福拉纳溶于丙酮和水的混合溶剂中，降温析出固体，过滤，干燥，得到晶型XVIII产品。A method for preparing crystal form XVIII of aforana comprises: dissolving aforana in a mixed solvent of acetone and water, cooling to precipitate a solid, filtering, and drying to obtain a product of crystal form XVIII.
本发明提供了所述阿福拉纳晶型XIX的制备方法。The present invention provides a method for preparing the Aforana crystal form XIX.
本发明所述晶型XIX的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XIX of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型XIX的方法，包括：将阿福拉纳溶于甲醇中，降温析出固体，过滤，干燥，得到晶型XIX产品。A method for preparing the crystal form XIX of aforana includes: dissolving aforana in methanol, cooling to precipitate a solid, filtering, and drying to obtain the crystal form XIX product.
在一些实施方式中，将阿福拉纳溶于N-甲基吡咯烷酮中，将溶清液向纯化水中缓慢滴加至析出固体，过滤，干燥，得到晶型XIX产品。In some embodiments, Aforana is dissolved in N-methylpyrrolidone, the solution is slowly added dropwise to purified water until a solid precipitates, filtered, and dried to obtain the crystal form XIX product.
本发明提供了所述阿福拉纳晶型XX的制备方法。The present invention provides a preparation method of the Aforana crystal form XX.
本发明所述晶型XX的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XX of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrialized production.
一种制备阿福拉纳晶型XX的方法，包括：将阿福拉纳晶型XIV产品在50℃条件下真空干燥20h，得到晶型XX产品。A method for preparing Aforana crystal form XX includes: vacuum drying Aforana crystal form XIV product at 50° C. for 20 hours to obtain crystal form XX product.
本发明提供了所述阿福拉纳晶型XXI的制备方法。The present invention provides a preparation method of the Aforana crystal form XXI.
本发明所述晶型XXI的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XXI of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型XXI的方法，包括：在一定温度条件下，将阿福拉纳溶于有机醇类溶剂中，然后与水混合，搅拌析出固体，过滤，在55℃-65℃条件下真空干燥，得到晶型XXI。A method for preparing Aforana crystal form XXI includes: dissolving Aforana in an organic alcohol solvent under certain temperature conditions, then mixing with water, stirring to precipitate solids, filtering, and heating at 55℃-65℃. Vacuum drying at ℃ to obtain crystal form XXI.
在一些实施例中，一种制备阿福拉纳晶型XXI的方法，包括：在一定温度下，将阿福拉纳溶于有机醇类溶剂中，加水，搅拌析出固体，过滤，在60℃条件下真空干燥，得到晶型XXI。In some embodiments, a method for preparing Aforana Form XXI includes: dissolving Aforana in an organic alcohol solvent at a certain temperature, adding water, stirring to precipitate solids, filtering, and heating at 60°C. Under vacuum drying conditions, the crystal form XXI was obtained.
在一些实施例中，所述水包括纯化水。在一些实施例中，所述水为纯化水。In some embodiments, the water includes purified water. In some embodiments, the water is purified water.
根据本发明所述实施例，所述有机醇类溶剂包括甲醇或者乙醇。在一些实施例中，所述有机醇类溶剂包括甲醇；在一些实施例中，所述有机醇类溶剂包括乙醇。在一些实施例中，所述有机醇类溶剂为乙醇和 /或甲醇。According to the embodiment of the present invention, the organic alcohol solvent includes methanol or ethanol. In some embodiments, the organic alcohol solvent includes methanol; in some embodiments, the organic alcohol solvent includes ethanol. In some embodiments, the organic alcohol solvent is ethanol and/or methanol.
根据本发明所述实施例，按照体积比，水的用量是醇类溶剂的1-10倍。在一些实施例中，水的用量是醇类溶剂的2-10倍；在一些实施例中，水的用量是醇类溶剂的3-10倍；在一些实施例中，水的用量是醇类溶剂的4-10倍；在一些实施例中，水的用量是醇类溶剂的5-10倍；在一些实施例中，水的用量是醇类溶剂的6-10倍；在一些实施例中，水的用量是醇类溶剂的7-10倍；在一些实施例中，水的用量是醇类溶剂的8-10倍；在一些实施例中，水的用量是醇类溶剂的9-10倍；在一些实施例中，水的用量是醇类溶剂的1倍；在一些实施例中，水的用量是醇类溶剂的2倍；在一些实施例中，水的用量是醇类溶剂的3倍；在一些实施例中，水的用量是醇类溶剂的4倍；在一些实施例中，水的用量是醇类溶剂的5倍；在一些实施例中，水的用量是醇类溶剂的6倍；在一些实施例中，水的用量是醇类溶剂的7倍；在一些实施例中，水的用量是醇类溶剂的8倍；在一些实施例中，水的用量是醇类溶剂的9倍；在一些实施例中，水的用量是醇类溶剂的10倍。According to the embodiment of the present invention, according to the volume ratio, the amount of water is 1-10 times that of the alcohol solvent. In some embodiments, the amount of water used is 2-10 times that of alcoholic solvents; in some embodiments, the amount of water used is 3-10 times that of alcoholic solvents; in some embodiments, the amount of water used is alcoholic solvents. 4-10 times the solvent; in some embodiments, the amount of water is 5-10 times that of alcohol solvents; in some embodiments, the amount of water is 6-10 times that of alcohol solvents; in some embodiments , The amount of water is 7-10 times that of alcohol solvents; in some embodiments, the amount of water is 8-10 times that of alcohol solvents; in some embodiments, the amount of water is 9-10 times that of alcohol solvents Times; In some embodiments, the amount of water is 1 times that of alcohol solvents; in some embodiments, the amount of water is twice that of alcohol solvents; in some embodiments, the amount of water is that of alcohol solvents 3 times; in some embodiments, the amount of water used is 4 times that of alcohol solvents; in some embodiments, the amount of water used is 5 times that of alcohol solvents; in some embodiments, the amount of water used is alcohol solvents In some embodiments, the amount of water is 7 times that of alcohol solvents; in some embodiments, the amount of water is 8 times that of alcohol solvents; in some embodiments, the amount of water is alcohol 9 times the solvent; in some embodiments, the amount of water is 10 times the alcohol solvent.
根据本发明所述实施例，所述搅拌时间为4h-24h。在一些实施例中，所述搅拌时间为4h-20h；在一些实施例中，所述搅拌时间为4h-16h；在一些实施例中，所述搅拌时间为4h-12h；在一些实施例中，所述搅拌时间为4h-8h；在一些实施例中，所述搅拌时间为4h；在一些实施例中，所述搅拌时间为8h；在一些实施例中，所述搅拌时间为12h；在一些实施例中，所述搅拌时间为16h；在一些实施例中，所述搅拌时间为24h。According to the embodiment of the present invention, the stirring time is 4h-24h. In some embodiments, the stirring time is 4h-20h; in some embodiments, the stirring time is 4h-16h; in some embodiments, the stirring time is 4h-12h; in some embodiments , The stirring time is 4h-8h; in some embodiments, the stirring time is 4h; in some embodiments, the stirring time is 8h; in some embodiments, the stirring time is 12h; In some embodiments, the stirring time is 16h; in some embodiments, the stirring time is 24h.
根据本发明所述实施例，所述真空干燥时间为16h-40h。在一些实施例中，所述真空干燥时间为16h-36h；在一些实施例中，所述真空干燥时间为16h-30h；在一些实施例中，所述真空干燥时间为16h-24h；在一些实施例中，所述真空干燥时间为16h；在一些实施例中，所述真空干燥时间为24h；在一些实施例中，所述真空干燥时间为30h；在一些实施例中，所述真空干燥时间为36h；在一些实施例中，所述真空干燥时间为40h。According to the embodiment of the present invention, the vacuum drying time is 16h-40h. In some embodiments, the vacuum drying time is 16h-36h; in some embodiments, the vacuum drying time is 16h-30h; in some embodiments, the vacuum drying time is 16h-24h; in some embodiments, the vacuum drying time is 16h-24h; In an embodiment, the vacuum drying time is 16h; in some embodiments, the vacuum drying time is 24h; in some embodiments, the vacuum drying time is 30h; in some embodiments, the vacuum drying The time is 36h; in some embodiments, the vacuum drying time is 40h.
根据本发明所述实施例，所述温度为室温到80℃。在一些实施例中，所述温度为室温-80℃。在一些实施例中，所述温度为20℃-80℃。在一些实施例中，所述温度为室温到70℃；在一些实施例中，所述温度为室温-60℃；在一些实施例中，所述温度为室温-50℃；在一些实施例中，所述温度为室温-40℃；在一些实施例中，所述温度为80℃；在一些实施例中，所述温度为75℃；在一些实施例中，所述温度为70℃；在一些实施例中，所述温度为65℃；在一些实施例中，所述温度为60℃；在一些实施例中，所述温度为55℃；在一些实施例中，所述温度为50℃；在一些实施例中，所述温度为45℃；在一些实施例中，所述温度为40℃；在一些实施例中，所述温度为室温。According to the embodiment of the present invention, the temperature is room temperature to 80°C. In some embodiments, the temperature is between room temperature and 80°C. In some embodiments, the temperature is 20°C-80°C. In some embodiments, the temperature is from room temperature to 70°C; in some embodiments, the temperature is from room temperature to 60°C; in some embodiments, the temperature is from room temperature to 50°C; in some embodiments , The temperature is room temperature-40°C; in some embodiments, the temperature is 80°C; in some embodiments, the temperature is 75°C; in some embodiments, the temperature is 70°C; In some embodiments, the temperature is 65°C; in some embodiments, the temperature is 60°C; in some embodiments, the temperature is 55°C; in some embodiments, the temperature is 50°C In some embodiments, the temperature is 45°C; in some embodiments, the temperature is 40°C; in some embodiments, the temperature is room temperature.
在一些具体实施例中，一种制备阿福拉纳晶型XXI的方法，包括：在60℃条件下将阿福拉纳溶于乙醇，加纯化水，搅拌得到晶型XXI。在一些具体实施例中，一种制备阿福拉纳晶型XXI的方法，包括：在室温下将阿福拉纳溶于甲醇，加纯化水，搅拌得到晶型XXI。In some specific embodiments, a method for preparing the crystal form XXI of aforana includes: dissolving aforana in ethanol at 60° C., adding purified water, and stirring to obtain the crystal form XXI. In some specific embodiments, a method for preparing the crystal form XXI of Aforana includes: dissolving Aforana in methanol at room temperature, adding purified water, and stirring to obtain the crystal form XXI.
本发明提供了所述阿福拉纳晶型XXII的制备方法。The present invention provides a preparation method of the Aforana crystal form XXII.
本发明所述晶型XXII的制备方法简单，操作方便，条件温和，适用于工业化生产。The preparation method of the crystal form XXII of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳晶型XXII的方法，包括：将阿福拉纳晶型VI在50℃-70℃条件下真空干燥16h-48h，得到晶型XXII。A method for preparing crystal form XXII of Aforana includes: drying crystal form VI of Aforana in vacuum at 50°C-70°C for 16h-48h to obtain crystal form XXII.
在一些实施例中，一种制备阿福拉纳晶型XXII的方法，包括：将阿福拉纳晶型VI在60℃条件下真空干燥24h，得到晶型XXII。In some embodiments, a method for preparing the crystal form of Aforana XXII includes: drying the crystal form of Aforana VI under vacuum at 60° C. for 24 hours to obtain the crystal form XXII.
本发明提供了所述阿福拉纳无定型的制备方法。The invention provides a preparation method of the amorphous Aforana.
本发明所述无定型的制备方法简单，操作方便，条件温和，适用于工业化生产。The amorphous preparation method of the present invention is simple, convenient to operate, and mild in conditions, and is suitable for industrial production.
一种制备阿福拉纳无定型的方法，包括：将阿福拉纳溶于良溶剂中，溶清后滴加纯化水，析出固体，过滤、干燥，得到无定型产品；根据本发明所述实施例，所述良溶剂为甲醇、乙醇、二甲基甲酰胺、二甲亚砜中的一种或多种。在一些具体实施方式中，所述滴加方式为正滴；在一些具体实施方式中，所述滴加方式为反滴。A method for preparing amorphous afrana, comprising: dissolving afrana in a good solvent, adding purified water dropwise after dissolving, separating solids, filtering and drying to obtain an amorphous product; according to the present invention In an embodiment, the good solvent is one or more of methanol, ethanol, dimethylformamide, and dimethyl sulfoxide. In some specific embodiments, the dripping method is forward dripping; in some specific embodiments, the dripping method is reverse dripping.
在一些实施方式中，将阿福拉纳溶于二氯甲烷中，降温，析出无定型。In some embodiments, Aforana is dissolved in dichloromethane, the temperature is lowered, and an amorphous form is precipitated.
在一些实施方式中，将阿福拉纳溶于有机溶剂中，挥干，得到无定型产品。根据本发明所述实施例，所述有机溶剂为甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇、丙酮、丁酮、乙酸乙酯、甲酸丁酯、甲酸乙酯、乙酸异丙酯、四氢呋喃、乙腈、乙二醇单甲醚、乙二醇二甲醚、二氯甲烷、甲基异丁酮环己烷、甲苯中的一种或多种。在一些具体实施方式中，所述挥干过程为旋转蒸发；在一些具体实施方式中，所述挥干过程为挥发。In some embodiments, Aforana is dissolved in an organic solvent and evaporated to dryness to obtain an amorphous product. According to the embodiment of the present invention, the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, acetone, butanone, ethyl acetate, butyl formate, One or more of ethyl formate, isopropyl acetate, tetrahydrofuran, acetonitrile, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, dichloromethane, methyl isobutyl ketone cyclohexane, and toluene. In some specific embodiments, the volatilization process is rotary evaporation; in some specific embodiments, the volatilization process is volatilization.
术语定义Definition of Terms
晶型或无定形可以通过多种技术手段进行鉴别，例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。Crystal form or amorphous form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) ), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.
X-射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施方案中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本试验所用仪器状况，衍射峰存在±0.2°的误差容限。X-ray powder diffraction (XRPD) can detect the change of crystal form, crystallinity, crystal structure state and other information, and it is a common method to identify crystal form. The peak position of the XRPD spectrum mainly depends on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the drawings of the present invention. At the same time, the 2θ measurement of the XRPD pattern may have experimental errors. The 2θ measurement of the XRPD pattern may be slightly different between different instruments and different samples, so the 2θ value cannot be regarded as absolute. According to the condition of the instrument used in this experiment, the diffraction peak has an error tolerance of ±0.2°.
差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al 2O 3)之间的能量差随温度变化的一种技术。DSC曲线的熔化峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本试验所用仪器状况，熔化峰存在±3℃的误差容限。 Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (commonly used α-Al 2 O 3) with temperature changes under program control through continuous heating or cooling. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, and the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline form of the present invention is characterized by a DSC chart with characteristic peak positions, which is substantially as shown in the DSC chart provided in the accompanying drawings of the present invention. At the same time, the DSC spectrum may have experimental errors. The peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute. According to the condition of the instrument used in this experiment, the melting peak has an error tolerance of ±3°C.
热重分析(TGA)是在程序控制下，测定物质的质量随温度变化的一种技术，适用于检查晶体中溶剂的丧失或样品升华、分解的过程，可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间，TGA检测的质量变化略有差别。根据本试验所用的仪器状况，质量变化存在±0.1％的误差容限。Thermogravimetric analysis (TGA) is a technique for measuring the quality of a substance with temperature changes under program control. It is suitable for checking the loss of solvent in the crystal or the process of sample sublimation and decomposition. It can be inferred that the crystal contains crystal water or crystal solvent. Case. The quality change displayed by the TGA curve depends on many factors such as sample preparation and instrument; the quality change of TGA detection varies slightly between different instruments and different samples. According to the condition of the instrument used in this experiment, there is an error tolerance of ±0.1% for the mass change.
术语“基本上如图所示”是指基本上纯净的某种“晶型”其X-射线粉末衍射图中至少50％，或至少60％， 或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰出现在所给出的X-射线粉末衍射图中。当样品中某种晶型的含量逐渐降低时，其X-射线粉末衍射图中的一些归属于该晶型的衍射峰可能会由于仪器的检测灵敏度的因素而变少。The term "substantially as shown in the figure" refers to a certain "crystal form" that is substantially pure and has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least in the X-ray powder diffraction pattern. 90%, or at least 95%, or at least 99% of the peaks appear in the X-ray powder diffraction pattern given. When the content of a certain crystal form in the sample gradually decreases, some diffraction peaks attributable to the crystal form in the X-ray powder diffraction pattern may be reduced due to the detection sensitivity of the instrument.
在本发明的上下文中，X-射线粉末衍射图中的衍射角2θ(又称2theta或衍射峰)值均以度(°)为单位。In the context of the present invention, the diffraction angle 2θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).
当提及图谱和/或图中数据，术语“衍射峰”是指本领域的技术人员不会归属于背景噪音的一个特征。When referring to a spectrum and/or data in the graph, the term "diffraction peak" refers to a feature that is not attributed to background noise by those skilled in the art.
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现1％，2％，或5％等差异。当大约用来形容X-射线粉末衍射峰的2θ(又称2theta或衍射峰)值时，大约表示所述2θ值可能有+/-0.2个单位或+/-0.1个单位或+/-0.05个单位差异。In the context of the present invention, regardless of whether the words "about" or "about" are used, all numbers disclosed herein are approximate values. The value of each number may differ by 1%, 2%, or 5%. When approximately used to describe the 2θ (also known as 2theta or diffraction peak) value of an X-ray powder diffraction peak, it roughly means that the 2θ value may have +/-0.2 units or +/-0.1 units or +/-0.05 Unit difference.
术语“室温”是指温度在大约20℃-35℃或大约23℃-28℃或大约25℃。The term "room temperature" refers to a temperature of about 20°C to 35°C or about 23°C to 28°C or about 25°C.
本发明中，mg/mL表示毫克/毫升，h表示小时，g表示克，ml表示毫升，℃表示摄氏度，mL/min表示毫升/分钟。In the present invention, mg/mL means milligram/ml, h means hour, g means gram, ml means milliliter, °C means degrees Celsius, and mL/min means milliliters/minute.
附图说明Description of the drawings
图1显示了晶型I的XRPD谱图。Figure 1 shows the XRPD spectrum of Form I.
图2显示了晶型II的XRPD谱图。Figure 2 shows the XRPD spectrum of Form II.
图3显示了晶型III的XRPD谱图。Figure 3 shows the XRPD spectrum of Form III.
图4显示了晶型IV的XRPD谱图。Figure 4 shows the XRPD spectrum of Form IV.
图5显示了晶型V的XRPD谱图。Figure 5 shows the XRPD spectrum of Form V.
图6显示了晶型VI的XRPD谱图。Figure 6 shows the XRPD spectrum of Form VI.
图7显示了晶型VIII的XRPD谱图。Figure 7 shows the XRPD spectrum of Form VIII.
图8显示了晶型IX的XRPD谱图。Figure 8 shows the XRPD spectrum of Form IX.
图9显示了晶型X的XRPD谱图。Figure 9 shows the XRPD spectrum of Form X.
图10显示了晶型XI的XRPD谱图。Figure 10 shows the XRPD spectrum of Form XI.
图11显示了晶型XII的XRPD谱图。Figure 11 shows the XRPD spectrum of Form XII.
图12显示了晶型XIII的XRPD谱图。Figure 12 shows the XRPD spectrum of Form XIII.
图13显示了晶型XIV的XRPD谱图。Figure 13 shows the XRPD spectrum of Form XIV.
图14显示了晶型XV的XRPD谱图。Figure 14 shows the XRPD spectrum of Form XV.
图15显示了晶型XVI的XRPD谱图。Figure 15 shows the XRPD spectrum of Form XVI.
图16显示了晶型XVII的XRPD谱图。Figure 16 shows the XRPD spectrum of Form XVII.
图17显示了晶型XVIII的XRPD谱图。Figure 17 shows the XRPD spectrum of Form XVIII.
图18显示了晶型XIX的XRPD谱图。Figure 18 shows the XRPD spectrum of Form XIX.
图19显示了晶型XX的XRPD谱图。Figure 19 shows the XRPD spectrum of Form XX.
图20显示了晶型XXI的XRD谱图。Figure 20 shows the XRD spectrum of the crystalline form XXI.
图21显示了晶型XXI的DSC谱图。Figure 21 shows the DSC spectrum of the crystalline form XXI.
图22显示了晶型XXI的TGA谱图。Figure 22 shows the TGA spectrum of Form XXI.
图23显示了晶型XXII的XRD谱图。Figure 23 shows the XRD spectrum of Form XXII.
图24显示了晶型XXII的DSC谱图。Figure 24 shows the DSC spectrum of Form XXII.
图25显示了晶型XXII的TGA谱图。Figure 25 shows the TGA spectrum of Form XXII.
图26显示了无定型的XRPD谱图。Figure 26 shows the XRPD spectrum of the amorphous form.
具体实施方式detailed description
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。The reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
实施例1：晶型I的制备Example 1: Preparation of Form I
称取600mg阿福拉纳，在室温条件下溶于2mL丁酮，降至0℃析出固体，过滤、干燥，得到562mg晶型I。经检测，其XRD图谱与图1基本一致。Weigh 600 mg of Aforana, and dissolve it in 2 mL of methyl ethyl ketone at room temperature, drop to 0° C. to precipitate a solid, filter and dry to obtain 562 mg of crystal form I. After testing, its XRD pattern is basically consistent with Figure 1.
实施例2：晶型II的制备Example 2: Preparation of Form II
称取30mg阿福拉纳，溶于0.5mL乙腈中，滴加2mL纯化水析出固体，过滤、干燥，得到20mg晶型II。经检测，其XRD图谱与图2基本一致。Weigh 30 mg of Aforana and dissolve it in 0.5 mL of acetonitrile, add dropwise 2 mL of purified water to precipitate a solid, filter and dry to obtain 20 mg of crystal form II. After testing, its XRD pattern is basically consistent with Figure 2.
实施例3：晶型III的制备Example 3: Preparation of Form III
称取2g阿福拉纳，在50℃下于20mL碳酸二甲酯中打浆8h后过滤、干燥，得到1.65g晶型III产品。经检测，其XRD图谱与图3基本一致。Weigh 2 g of Aforana, beat it in 20 mL of dimethyl carbonate at 50° C. for 8 hours, filter and dry to obtain 1.65 g of crystal form III product. After testing, its XRD pattern is basically consistent with Figure 3.
实施例4：晶型IV的制备Example 4: Preparation of Form IV
称取300mg阿福拉纳，在60℃下溶于5mL正丁醇中，溶清后缓慢地向20mL正庚烷中滴加，析出固体，过滤、干燥，得到254mg晶型IV。经检测，其XRD图谱与图4基本一致。Weigh 300 mg aforana, and dissolve it in 5 mL n-butanol at 60° C., after dissolving, slowly add dropwise to 20 mL n-heptane to precipitate a solid, filter and dry to obtain 254 mg crystal form IV. After testing, its XRD pattern is basically consistent with Figure 4.
实施例5：晶型V的制备Example 5: Preparation of Form V
称取60mg阿福拉纳溶于1mL 1,4-二氧六环中，溶清后缓慢地向4mL纯化水中滴加，析出固体，过滤、干燥，得到45mg晶型V。经检测，其XRD图谱与图5基本一致。Weigh 60 mg of Aforana and dissolve it in 1 mL of 1,4-dioxane, and slowly add dropwise to 4 mL of purified water after dissolving it. The solid is precipitated, filtered and dried to obtain 45 mg of crystal form V. After testing, its XRD pattern is basically consistent with Figure 5.
实施例6：晶型VI的制备Example 6: Preparation of Form VI
称取300mg阿福拉纳，室温下溶于5mL甲酸丁酯中，溶清后缓慢滴加20mL正庚烷，析出固体，过滤、干燥，得到274mg晶型VI。经检测，其XRD图谱与图6基本一致。Weigh 300 mg of Aforana and dissolve it in 5 mL of butyl formate at room temperature. After dissolving, add 20 mL of n-heptane slowly to precipitate a solid, which is filtered and dried to obtain 274 mg of crystal form VI. After testing, its XRD pattern is basically consistent with Figure 6.
实施例7：晶型VI的制备Example 7: Preparation of Form VI
称取100mg阿福拉纳，室温下溶于1mL甲酸丁酯中，溶清后在室温下缓慢挥发，析出固体，干燥得到74mg晶型VI。经检测，其XRD图谱与图6基本一致。Weigh 100 mg of Aforana, and dissolve it in 1 mL of butyl formate at room temperature. After dissolving, slowly evaporate at room temperature to precipitate a solid and dry to obtain 74 mg of crystalline form VI. After testing, its XRD pattern is basically consistent with Figure 6.
实施例8：晶型VIII的制备Example 8: Preparation of Form VIII
称取50mg阿福拉纳，室温下下溶于1mL乙腈中，溶清后在室温下缓慢挥发，析出固体，过滤、干燥，得到40mg晶型VIII。经检测，其XRD图谱与图7基本一致。Weigh 50 mg of Aforana, and dissolve it in 1 mL of acetonitrile at room temperature. After dissolving, slowly evaporate at room temperature to precipitate a solid, which is filtered and dried to obtain 40 mg of crystal form VIII. After testing, its XRD pattern is basically consistent with Figure 7.
实施例9：晶型IX的制备Example 9: Preparation of Form IX
称取300mg阿福拉纳，50℃下溶于5mL纯化水和10mL异丙醇的混合溶剂中，降至0℃析出固体， 过滤、干燥，得到280mg晶型IX。经检测，其XRD图谱与图8基本一致。Weigh 300 mg of Aforana, and dissolve it in a mixed solvent of 5 mL of purified water and 10 mL of isopropanol at 50°C, drop to 0°C to precipitate a solid, filter and dry to obtain 280 mg of crystal form IX. After testing, its XRD pattern is basically consistent with Figure 8.
实施例10：晶型IX的制备Example 10: Preparation of Form IX
称取200mg阿福拉纳，室温下于4.5mL纯化水和1.5mL N-甲基吡咯烷酮的混合溶剂中混悬搅拌24h后，过滤、干燥，得到166mg晶型IX产品。经检测，其XRD图谱与图8基本一致。Weigh 200 mg of Aforana, suspend it in a mixed solvent of 4.5 mL of purified water and 1.5 mL of N-methylpyrrolidone at room temperature and stir for 24 hours, then filter and dry to obtain 166 mg of crystal form IX product. After testing, its XRD pattern is basically consistent with Figure 8.
实施例11：晶型X的制备Example 11: Preparation of Form X
称取60mg阿福拉纳，室温下于1.5mL纯化水和0.5mL乙二醇二甲醚的混合溶剂中混悬搅拌22h后，过滤，得到40mg晶型X。经检测，其XRD图谱与图9基本一致。Weigh 60 mg of Aforana, and suspend it in a mixed solvent of 1.5 mL of purified water and 0.5 mL of ethylene glycol dimethyl ether at room temperature and stir for 22 hours, and then filter to obtain 40 mg of crystal form X. After testing, its XRD pattern is basically consistent with Figure 9.
实施例12：晶型XI的制备Example 12: Preparation of Form XI
称取600mg阿福拉纳，50℃下溶于2mL乙酸异丙酯中，降至0℃析出固体，过滤、干燥，得到545mg晶型XI。经检测，其XRD图谱与图10基本一致。Weigh 600 mg of Aforana, and dissolve it in 2 mL of isopropyl acetate at 50°C, drop it to 0°C to precipitate a solid, filter and dry to obtain 545 mg of crystalline form XI. After testing, its XRD pattern is basically consistent with Figure 10.
实施例13：晶型XII的制备Example 13: Preparation of Form XII
称取150mg阿福拉纳，于室温下溶于2mL乙酸乙酯中，溶清后缓慢地向10mL甲苯中滴加，析出固体，过滤、干燥，得到120mg晶型XII。经检测，其XRD图谱与图11基本一致。Weigh 150 mg of Aforana, and dissolve it in 2 mL of ethyl acetate at room temperature. After dissolving, slowly add dropwise to 10 mL of toluene to precipitate a solid, which is filtered and dried to obtain 120 mg of crystal form XII. After testing, its XRD pattern is basically consistent with Figure 11.
实施例14：晶型XIII的制备Example 14: Preparation of Form XIII
称取300mg阿福拉纳，室温下溶于5mL乙二醇二甲醚中，溶清后缓慢地向20mL纯化水中滴加，析出固体，过滤、干燥，得到263mg晶型XIII。经检测，其XRD图谱与图12基本一致。Weigh 300 mg of Aforana, and dissolve it in 5 mL of ethylene glycol dimethyl ether at room temperature. After the solution is clear, it is slowly added dropwise to 20 mL of purified water to precipitate a solid, which is filtered and dried to obtain 263 mg of crystal form XIII. After testing, its XRD pattern is basically consistent with Figure 12.
实施例15：晶型XIV的制备Example 15: Preparation of Form XIV
称取300mg阿福拉纳，60℃下溶于10mL甲苯中，降至0℃析出固体，过滤、干燥，得到190mg晶型XIV。经检测，其XRD图谱与图13基本一致。Weigh 300 mg of Aforana, and dissolve it in 10 mL of toluene at 60°C, drop to 0°C to precipitate a solid, filter and dry to obtain 190 mg of crystal form XIV. After testing, its XRD pattern is basically consistent with Figure 13.
实施例16：晶型XV的制备Example 16: Preparation of Form XV
称取300mg阿福拉纳，在50℃下溶于5mL 1,4-二氧六环和3mL纯化水的混合溶剂中，降至0℃析出固体，过滤、干燥，得到238mg晶型XV。经检测，XRD图谱与图14基本一致。Weigh 300 mg of Aforana, and dissolve it in a mixed solvent of 5 mL 1,4-dioxane and 3 mL purified water at 50°C, drop it to 0°C to precipitate a solid, filter and dry to obtain 238 mg of crystalline form XV. After testing, the XRD pattern is basically consistent with Figure 14.
实施例17：晶型XVI的制备Example 17: Preparation of Form XVI
称取30mg阿福拉纳，于50℃下溶于0.5mL 1-己醇中，溶清后缓慢降至0℃后析出固体，过滤、干燥，得到晶型XVI。经检测，XRD图谱与图15基本一致。Weigh 30 mg of Aforana and dissolve it in 0.5 mL 1-hexanol at 50°C. After the solution is clear, the solid is slowly reduced to 0°C, and then a solid is precipitated, filtered and dried to obtain crystal form XVI. After testing, the XRD pattern is basically consistent with Figure 15.
实施例18：晶型XVII的制备Example 18: Preparation of Form XVII
称取150mg阿福拉纳，于50℃下溶于2.5mL正丙醇中，溶清后缓慢降至0℃后析出固体，过滤、干燥，得到120mg晶型XVII。经检测，XRD图谱与图16基本一致。Weigh 150 mg of Aforana and dissolve it in 2.5 mL of n-propanol at 50°C. After the solution is clear, the solid is slowly reduced to 0°C, and then a solid is precipitated, filtered and dried to obtain 120 mg of crystalline form XVII. After testing, the XRD pattern is basically consistent with Figure 16.
实施例19：晶型XVIII的制备Example 19: Preparation of Form XVIII
称取90mg阿福拉纳，室温下溶于2mL丙酮和1mL纯化水的混合溶剂中，溶清后缓慢降至0℃析出 固体，过滤、干燥，得到74mg晶型XVIII。经检测，XRD图谱与图17基本一致。Weigh 90 mg of Aforana and dissolve it in a mixed solvent of 2 mL of acetone and 1 mL of purified water at room temperature. After dissolving, the solid is slowly reduced to 0°C to precipitate a solid, which is filtered and dried to obtain 74 mg of crystal form XVIII. After testing, the XRD pattern is basically consistent with Figure 17.
实施例20：晶型XIX的制备Example 20: Preparation of Form XIX
称取60mg阿福拉纳，室温下溶于0.5mL N-甲基吡咯烷酮中，溶清后缓慢地向2mL纯化水中滴加，析出固体，过滤、干燥，得到45mg晶型XIX。经检测，其XRD图谱与图18基本一致。Weigh 60 mg of Aforana, and dissolve it in 0.5 mL of N-methylpyrrolidone at room temperature. After dissolving, slowly add dropwise to 2 mL of purified water to precipitate a solid, filter and dry to obtain 45 mg of crystal form XIX. After testing, its XRD pattern is basically consistent with Figure 18.
实施例21：晶型XX的制备Example 21: Preparation of Form XX
称取100mg阿福拉纳的晶型XIV，在50℃下真空干燥12h，得到97mg晶型XX。经检测，其XRD图谱与图19基本一致。Weigh 100 mg of the crystal form XIV of Aforana, and vacuum-dry it at 50° C. for 12 h to obtain 97 mg of crystal form XX. After testing, its XRD pattern is basically consistent with Figure 19.
实施例22：晶型XXI的制备Example 22: Preparation of Form XXI
称取3g阿福拉纳，在室温下溶于24mL甲醇，滴加8mL纯化水析出固体，搅拌23h，过滤，60℃真空干燥20h，得到2.7g晶型XXI。经检测，其XRD、DSC、TGA图谱分别与图20、21和22基本一致。Weigh 3 g of Aforana and dissolve it in 24 mL of methanol at room temperature, add 8 mL of purified water dropwise to precipitate a solid, stir for 23 hours, filter, and vacuum dry at 60° C. for 20 hours to obtain 2.7 g of crystalline form XXI. After testing, its XRD, DSC, TGA patterns are basically consistent with Figures 20, 21 and 22, respectively.
实施例23：晶型XXI的制备Example 23: Preparation of Form XXI
称取200mg阿福拉纳，在60℃下溶于1mL乙醇，滴加4mL纯化水析出固体，搅拌28h，过滤，60℃真空干燥10h，得到180mg晶型XXI。经检测，其XRD、DSC、TGA图谱分别与图20、21和22基本一致。Weigh 200 mg of Aforana and dissolve it in 1 mL of ethanol at 60°C, add 4 mL of purified water dropwise to precipitate a solid, stir for 28 hours, filter, and vacuum dry at 60°C for 10 hours to obtain 180 mg of crystal form XXI. After testing, its XRD, DSC, TGA patterns are basically consistent with Figures 20, 21 and 22, respectively.
实施例24：晶型XXI的制备Example 24: Preparation of Form XXI
称取400mg阿福拉纳，在60℃下溶于2mL乙醇，滴加8mL纯化水后添加40mgXXI晶种，搅拌4h，过滤，60℃真空干燥16h，得到380mg晶型XXI。经检测，其XRD、DSC、TGA图谱分别与图20、21和22基本一致。Weigh 400 mg of Aforana and dissolve it in 2 mL of ethanol at 60° C., add 8 mL of purified water dropwise and add 40 mg of XXI seed crystals, stir for 4 hours, filter, and vacuum dry at 60° C. for 16 hours to obtain 380 mg of crystal form XXI. After testing, its XRD, DSC, TGA patterns are basically consistent with Figures 20, 21 and 22, respectively.
实施例25：晶型XXII的制备Example 25: Preparation of Form XXII
称取5g阿福拉纳的晶型VI，在60℃下真空干燥24h，得到4.5g晶型XXII。经检测，其XRD、DSC、TGA图谱分别与图23、24和25基本一致。Weigh 5 g of Aforana's crystal form VI and vacuum-dried at 60° C. for 24 hours to obtain 4.5 g of crystal form XXII. After testing, its XRD, DSC, TGA patterns are basically consistent with Figures 23, 24 and 25, respectively.
实施例26：无定型的制备Example 26: Preparation of amorphous
称取800mg阿福拉纳，于室温下溶于10mL甲醇中，溶清后滴加40mL纯化水析出固体，搅拌5h后过滤、干燥得到725mg无定型。经检测，其XRD图谱与图26基本一致。Weigh 800 mg of Aforana and dissolve it in 10 mL of methanol at room temperature. After the solution is clear, 40 mL of purified water is added dropwise to precipitate a solid. After stirring for 5 hours, it is filtered and dried to obtain 725 mg of amorphous form. After testing, its XRD pattern is basically consistent with Figure 26.
实施例27：Example 27:
根据药物制剂稳定性试验指导原则，对晶型IX、XIX、XXI和XXII进行影响因素实验考察，包括高温试验、高湿试验和强光照射试验，考察其晶型的稳定性。According to the guidelines for stability testing of pharmaceutical preparations, the influencing factors of crystal forms IX, XIX, XXI and XXII were investigated, including high temperature test, high humidity test and strong light irradiation test, to investigate the stability of the crystal form.
高温试验：分别取上述晶型样品适量，平铺置称量瓶中，在60℃±5℃、RH 75±5％恒温恒湿箱中放置，然后分别于0、5和15天取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)测试其晶型情况，结果如表1所示。High temperature test: Take appropriate amounts of the above crystal samples, lay them flat in a weighing bottle, and place them in a constant temperature and humidity box at 60°C±5°C, RH 75±5%, and then take the samples in 0, 5, and 15 days. About 100 mg, the crystal form was tested by powder X-ray powder diffraction (XRPD), and the results are shown in Table 1.
高湿试验：分别取上述晶型样品适量，平铺置称量瓶中，在25℃、RH 92.5±5％恒温恒湿箱中放置，然后分别于0、5和15天取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)测试其晶型情况，结果如表1所示。High humidity test: Take appropriate amounts of the above-mentioned crystal samples, and place them in a weighing bottle, place them in a constant temperature and humidity box at 25°C, RH 92.5±5%, and then take about 100mg of the above samples on 0, 5, and 15 days. , Using powder X-ray powder diffraction (XRPD) to test its crystal form, the results are shown in Table 1.
光照试验：分别取上述晶型样品适量，平铺至称量瓶中，在可见光4500Lux±500Lux(VIS)、紫外光1.7W*h/m2(UV)的恒温恒湿箱(25℃、RH 60％±5％)条件下放置，然后分别于0、5和15天取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)测试其晶型情况，结果如表1所示。Illumination test: Take appropriate amounts of the above crystal samples and spread them in a weighing bottle. Place them in a constant temperature and humidity box (25℃, RH 60) with visible light 4500Lux±500Lux(VIS) and ultraviolet light %±5%), and then about 100 mg of the above sample was taken at 0, 5, and 15 days, and the crystal form was tested by powder X-ray powder diffraction (XRPD). The results are shown in Table 1.
表1：晶型IX、XIX、XXI和XXII的稳定性试验结果Table 1: Stability test results of crystal forms IX, XIX, XXI and XXII
Figure PCTCN2021100649-appb-000002
Figure PCTCN2021100649-appb-000002
实施例28：Example 28:
为了考察晶型之间的相对稳定性，将等质量的晶型XXI、晶型XXII和CN102947278B公开的晶型A、晶型B分别在水中于室温、37℃及60℃高温下混合搅拌24h，过滤、干燥并测试所得固体的晶型，结果如下表2所示。In order to investigate the relative stability between the crystal forms, the crystal form XXI, the crystal form XXII and the crystal form A and the crystal form B disclosed in CN102947278B were mixed and stirred in water at room temperature, 37°C and 60°C for 24 hours, respectively. The crystal form of the obtained solid was filtered, dried and tested, and the results are shown in Table 2 below.
表2：新晶型在水中的稳定性考察Table 2: Investigation of the stability of the new crystal form in water
实验编号Experiment number 原料晶型Raw material crystal form 室温下搅拌24hStir at room temperature for 24h 37℃下搅拌24hStir at 37°C for 24h 60℃下搅拌24hStir at 60℃ for 24h
0101 XXI+XXIIXXI+XXII XXIXXI XXI，结晶度差XXI, poor crystallinity XXI，结晶度高XXI, high crystallinity
0202 XXI+BXXI+B XXI+BXXI+B XXI+BXXI+B XXI，结晶度高XXI, high crystallinity
0303 XXI+AXXI+A XXIXXI XXI，结晶度差XXI, poor crystallinity XXI，结晶度高XXI, high crystallinity
0404 XXII+BXXII+B XXII+BXXII+B XXII+BXXII+B BB
0505 XXII+AXXII+A XXIIXXII XXIIXXII XXIIXXII
0606 A+BA+B A+BA+B A+BA+B BB
结果：由上表可知，四种晶型分别在三种温度下于水中相互竞争，其中在室温和37℃下，晶型A竞争不过晶型XXII，晶型XXII竞争不过晶型XXI，可以得出结论，稳定性晶型XXI>晶型XXII>晶型A，但晶型B与晶型XXI的稳定性尚不好判断。而升温至60℃后，晶型A和晶型XXII都无法与晶型B竞争，但晶型B竞争不过晶型XXI，60℃下晶型B转化为高结晶度的晶型XXI，说明晶型XXI的稳定性高于晶 型A和晶型B，即稳定性顺序为：晶型XXI>晶型B>晶型XXII>晶型A。Result: It can be seen from the above table that the four crystal forms compete with each other in water at three temperatures. Among them, at room temperature and 37°C, the crystal form A cannot compete with the crystal form XXII, and the crystal form XXII cannot compete with the crystal form XXI. It is concluded that the stability of crystal form XXI>crystal form XXII>crystal form A, but the stability of crystal form B and crystal form XXI is still not easy to judge. After the temperature is raised to 60°C, neither crystal form A nor crystal form XXII can compete with crystal form B, but crystal form B cannot compete with crystal form XXI. At 60°C, crystal form B transforms into crystal form XXI with high crystallinity, indicating that the crystal The stability of Form XXI is higher than that of Form A and Form B, that is, the order of stability is: Form XXI>Form B>Form XXII>Form A.
实施例29：Example 29:
参照2020版中国药典，测量晶型B、XXI、XXII的堆密度和振实密度，计算相应的卡尔指数。堆密度测量方法：取待测粉末样品100g，缓慢倾入玻璃刻度量筒，小心刮平顶部，避免压紧粉末，以最接近的刻度线，记录表观体积，按公式ρ B＝M/V B计算堆密度，式中V B为表观体积，同一批样品平行测量3次取平均值。振实密度测量方法：将已填充松散状态粉末(100g)的量筒固定于托架上，振实多次并记录对应的体积，直至两次连续记录的体积之差小于2mL，按公式ρ T＝M/V T计算振实密度，式中V T为振实体积，同一批样品平行测量3次取平均值。卡尔指数的计算公式为C＝(ρ T-ρ B)/ρ T。测量结果如下表3所示。 Refer to the 2020 Chinese Pharmacopoeia to measure the bulk density and tap density of crystal forms B, XXI, and XXII, and calculate the corresponding Carr index. Bulk density measurement method: Take 100g of the powder sample to be tested, slowly pour it into the glass graduated cylinder, carefully scrape the top, avoid compacting the powder, record the apparent volume with the closest scale line, according to the formula ρ B ＝M/V B Calculate the bulk density, where V B is the apparent volume, and the same batch of samples are measured in parallel for 3 times and the average value is taken. Tap density measurement method: Fix the measuring cylinder filled with loose powder (100g) on the bracket, tap several times and record the corresponding volume until the difference between the two consecutive records is less than 2mL, according to the formula ρ T ＝ M/V T calculates the tap density, where V T is the tap volume, and the same batch of samples is measured in parallel for 3 times and the average value is taken. The calculation formula of Karl's index is C=(ρ T -ρ B )/ρ T. The measurement results are shown in Table 3 below.
表3：晶型B与晶型XXI、XXII样品的堆密度、振实密度和卡尔指数Table 3: Bulk density, tap density and Carr index of crystal form B and crystal form XXI and XXII samples
晶型种类Crystal type 堆密度ρ B/(g/mL) Bulk density ρ B /(g/mL) 振实密度ρ T/(g/mL) Tap density ρ T /(g/mL) 卡尔指数CCarr Index C
晶型BForm B 0.2460.246 0.3920.392 37.237.2
晶型XXICrystal Form XXI 0.6920.692 1.0041.004 31.131.1
晶型XXIICrystal Form XXII 0.1540.154 0.3880.388 60.360.3
结果：由上表可知，流动性大小顺序为：XXI>B>XXII，晶型XXI的堆密度和振实密度都是最大的，且其卡尔指数最小，说明晶型XXI的流动性最好。Result: It can be seen from the above table that the order of fluidity is: XXI>B>XXII, the bulk density and tap density of crystal form XXI are both the largest, and its Carr index is the smallest, indicating that crystal form XXI has the best fluidity.
仪器参数，测试条件及表征结果Instrument parameters, test conditions and characterization results
仪器信息：Instrument information:
1)X射线粉末衍射分析仪(PXRD)--PANalytical1) X-ray powder diffraction analyzer (PXRD)--PANalytical
2)差示扫描量热仪(DSC)--TA Q20002) Differential Scanning Calorimeter (DSC)--TA Q2000
3)热重分析仪(TGA)--TA Q5003) Thermogravimetric Analyzer (TGA)--TA Q500
测试方法：Test Methods:
1)PXRD方法1) PXRD method
Figure PCTCN2021100649-appb-000003
Figure PCTCN2021100649-appb-000003
2)DSC方法2) DSC method
DSC方法参数如下：The DSC method parameters are as follows:
30-300℃，10℃/min；N 2(50mL/min)。 30-300°C, 10°C/min; N 2 (50 mL/min).
3)TGA方法3) TGA method
TGA方法参数如下：The TGA method parameters are as follows:
30-300℃，10℃/min；N 2(60mL/min)。 30-300°C, 10°C/min; N 2 (60 mL/min).
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。The method of the present invention has been described through the preferred embodiments. It is obvious that relevant persons can make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention. . Those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.

Claims (13)

  1. 一种阿福拉纳晶型，其特征在于，所述晶型为阿福拉纳晶型XXI，其X-射线粉末衍射图中包含2θ角为15.8，18.0，18.4，19.6和21.8度的衍射峰。A crystal form of Aforana, characterized in that the crystal form is Aforana crystal form XXI, and its X-ray powder diffraction pattern contains diffractions with 2θ angles of 15.8, 18.0, 18.4, 19.6 and 21.8 degrees. peak.
  2. 根据权利要求1所述的阿福拉纳晶型，其特征在于，其X-射线粉末衍射图中包含2θ角为4.7，15.8，16.8，18.0，18.4，19.3，19.6和21.8度的衍射峰；或者其X-射线粉末衍射图中包含2θ角为4.7，9.3，11.2，15.8，16.8，18.0，18.4，19.3，19.6，19.9，20.8，21.2，21.4，21.8，23.0，23.6，24.0，26.4，28.0和29.7度的衍射峰；或者其X-射线粉末衍射图中包含2θ角为4.7，5.7，9.3，10.8，11.2，12.1，12.8，13.8，14.0，15.1，15.8，16.8，18.0，18.4，19.3，19.6，19.9，20.8，21.2，21.4，21.8，23.0，23.6，24.0，24.5，25.3，26.0，26.4，27.2，28.0，29.7和31.4度的衍射峰。The Aforana crystal form according to claim 1, wherein the X-ray powder diffraction pattern contains diffraction peaks with 2θ angles of 4.7, 15.8, 16.8, 18.0, 18.4, 19.3, 19.6 and 21.8 degrees; Or its X-ray powder diffraction pattern contains 2θ angles of 4.7, 9.3, 11.2, 15.8, 16.8, 18.0, 18.4, 19.3, 19.6, 19.9, 20.8, 21.2, 21.4, 21.8, 23.0, 23.6, 24.0, 26.4, 28.0 And 29.7 degrees diffraction peak; or its X-ray powder diffraction pattern contains 2θ angles of 4.7, 5.7, 9.3, 10.8, 11.2, 12.1, 12.8, 13.8, 14.0, 15.1, 15.8, 16.8, 18.0, 18.4, 19.3, 19.6, 19.9, 20.8, 21.2, 21.4, 21.8, 23.0, 23.6, 24.0, 24.5, 25.3, 26.0, 26.4, 27.2, 28.0, 29.7 and 31.4 degree diffraction peaks.
  3. 根据权利要求1或2所述的阿福拉纳晶型，其特征在于，其X-射线粉末衍射图基本上如图20所示。The Aforana crystal form according to claim 1 or 2, characterized in that its X-ray powder diffraction pattern is basically as shown in FIG. 20.
  4. 根据权利要求1-3任一项所述的阿福拉纳晶型，其特征在于，所述晶型XXI的差示扫描量热曲线在116℃-126℃处具有吸热峰。The Aforana crystal form according to any one of claims 1 to 3, wherein the differential scanning calorimetry curve of the crystal form XXI has an endothermic peak at 116°C-126°C.
  5. 根据权利要求1-4任一项所述的阿福拉纳晶型，其特征在于，其热重分析曲线显示晶型XXI在30℃-150℃失重小于1.0％。The Aforana crystal form according to any one of claims 1 to 4, wherein the thermogravimetric analysis curve shows that the crystal form XXI has a weight loss of less than 1.0% at 30°C to 150°C.
  6. 根据权利要求1-4任一项所述的阿福拉纳晶型，其特征在于，所述晶型XXI含水，阿福拉纳与水的摩尔比约为4:1。The crystal form of Aforana according to any one of claims 1 to 4, wherein the crystal form XXI contains water, and the molar ratio of aforana to water is about 4:1.
  7. 一种制备如权利要求1-6任一项所述阿福拉纳晶型的方法，其特征在于，包括：在一定温度条件下，将阿福拉纳溶于有机醇类溶剂中，然后与水混合，搅拌析出固体，过滤，在55℃-65℃条件下真空干燥，得到晶型XXI。A method for preparing the crystal form of Aforana as claimed in any one of claims 1 to 6, characterized in that it comprises: dissolving Aforana in an organic alcohol solvent under a certain temperature condition, and then mixing it with The water was mixed, stirred to precipitate a solid, filtered, and dried under vacuum at 55°C-65°C to obtain crystal form XXI.
  8. 根据权利要求7所述的方法，其特征在于，所述有机醇类溶剂包括甲醇或者乙醇。The method according to claim 7, wherein the organic alcohol solvent comprises methanol or ethanol.
  9. 根据权利要求7或8所述的方法，其特征在于，按照体积比，所述水的用量是醇类溶剂的1-10倍。The method according to claim 7 or 8, characterized in that, according to the volume ratio, the amount of water is 1-10 times that of the alcohol solvent.
  10. 根据权利要求7-9任一项所述的方法，其特征在于，所述搅拌时间为4h-24h。The method according to any one of claims 7-9, wherein the stirring time is 4h-24h.
  11. 根据权利要求7-10任一项所述的方法，其特征在于，所述温度为室温到80℃。The method according to any one of claims 7-10, wherein the temperature is room temperature to 80°C.
  12. 一种阿福拉纳晶型，其特征在于，所述晶型为阿福拉纳晶型XXII，其X-射线粉末衍射图中包含2θ角为4.4，10.7，13.2，17.5，19.3和25.2度的衍射峰；或者其X-射线粉末衍射图中包含2θ角为4.4，10.7，12.6，13.2，15.7，17.5，19.3，19.9，23.2，25.2和26.5度的衍射峰；或者其X-射线粉末衍射图中包含2θ角为4.4，6.6，7.6，8.7，10.7，12.6，13.2，14.2，15.7，16.7，17.5，18.1，19.3，19.9，21.4，23.2，25.2，26.5和27.4度的衍射峰峰。A crystal form of Aforana, characterized in that the crystal form is Aforana crystal form XXII, and its X-ray powder diffraction pattern contains 2θ angles of 4.4, 10.7, 13.2, 17.5, 19.3 and 25.2 degrees. Or its X-ray powder diffraction pattern contains diffraction peaks with 2θ angles of 4.4, 10.7, 12.6, 13.2, 15.7, 17.5, 19.3, 19.9, 23.2, 25.2 and 26.5 degrees; or its X-ray powder diffraction The figure contains diffraction peaks with 2θ angles of 4.4, 6.6, 7.6, 8.7, 10.7, 12.6, 13.2, 14.2, 15.7, 16.7, 17.5, 18.1, 19.3, 19.9, 21.4, 23.2, 25.2, 26.5 and 27.4 degrees.
  13. 一种制备如权利要求12所述晶型的方法，其特征在于，包括：将阿福拉纳溶于甲酸丁酯中，溶清后加入正庚烷或异丙醚至析出晶体，过滤、干燥，得到晶型VI；或者将阿福拉纳溶于甲酸丁酯中，挥发，得到晶型VI；再将所得晶型VI在50℃-70℃条件下真空干燥16h-48h，得到晶型XXII；所述晶型VI的X-射线粉末衍射图谱中包含2θ角为3.9，11.5，12.6，13.2，14.8，15.8，16.5，17.5，18.1，19.1，19.4，20.2，21.3，22.0，22.3，22.5，22.8，23.4，23.9，25.4，25.7，26.3，26.9，27.4，29.2，29.9和30.3度的衍射峰。A method for preparing the crystal form according to claim 12, characterized in that it comprises: dissolving aforana in butyl formate, dissolving it, adding n-heptane or isopropyl ether to precipitate crystals, filtering and drying , Obtain crystal form VI; or dissolve aforana in butyl formate and volatilize to obtain crystal form VI; then vacuum dry the obtained crystal form VI at 50℃-70℃ for 16h-48h to obtain crystal form XXII The X-ray powder diffraction pattern of the crystal form VI contains 2θ angles of 3.9, 11.5, 12.6, 13.2, 14.8, 15.8, 16.5, 17.5, 18.1, 19.1, 19.4, 20.2, 21.3, 22.0, 22.3, 22.5, 22.8, 23.4, 23.9, 25.4, 25.7, 26.3, 26.9, 27.4, 29.2, 29.9 and 30.3 degree diffraction peaks.
PCT/CN2021/100649 2020-06-19 2021-06-17 Crystal form of gaba inhibitor and preparation method therefor WO2021254445A1 (en)

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CN109195955A (en) * 2016-04-06 2019-01-11 梅里亚股份有限公司 The method of the crystallization toluene solvate for isoxazoline compound-(the S)-afoxolaner being enriched with being used to prepare enantiomerism
CN111032634A (en) * 2017-04-05 2020-04-17 勃林格殷格翰动物保健美国公司 Crystalline forms of (S) -Aforana
CN112457267A (en) * 2020-11-27 2021-03-09 麦蒂辛生物医药科技成都有限公司 Preparation method of isoxazoline insecticide

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CN102947278A (en) * 2010-05-27 2013-02-27 杜邦公司 Crystalline form of 4- [5 - [3 -chloro-5 - (trifluoromethyl) phenyl] -4, 5 - dihydro - 5 - (trifluoromethyl) -3 - isoxazolyl] -n- [2-0x0-2- [ ( 2, 2, 2 - trifluoroethyl) amino] ethyl] -1- naphthalenecarboxamide
CN109195955A (en) * 2016-04-06 2019-01-11 梅里亚股份有限公司 The method of the crystallization toluene solvate for isoxazoline compound-(the S)-afoxolaner being enriched with being used to prepare enantiomerism
CN111032634A (en) * 2017-04-05 2020-04-17 勃林格殷格翰动物保健美国公司 Crystalline forms of (S) -Aforana
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