WO2024067784A1 - Forme amorphe et solide cristallin de composé bicyclique et son procédé de préparation - Google Patents

Forme amorphe et solide cristallin de composé bicyclique et son procédé de préparation Download PDF

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Publication number
WO2024067784A1
WO2024067784A1 PCT/CN2023/122465 CN2023122465W WO2024067784A1 WO 2024067784 A1 WO2024067784 A1 WO 2024067784A1 CN 2023122465 W CN2023122465 W CN 2023122465W WO 2024067784 A1 WO2024067784 A1 WO 2024067784A1
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ray powder
diffraction pattern
powder diffraction
crystalline form
present
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PCT/CN2023/122465
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English (en)
Chinese (zh)
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张勇
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上海济煜医药科技有限公司
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Publication of WO2024067784A1 publication Critical patent/WO2024067784A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and in particular, relates to an amorphous form, a polymorphic form and applications of a bicyclic compound.
  • the present invention provides a crystalline form A of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2 ⁇ angles: 3.76 ⁇ 0.2°, 5.2 ⁇ 0.2°, 13.75 ⁇ 0.2°, 16.97 ⁇ 0.2°, 17.67 ⁇ 0.2°, and 19.75 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2 ⁇ angles: 3.76 ⁇ 0.2°, 5.2 ⁇ 0.2°, 5.82 ⁇ 0.2°, 13.75 ⁇ 0.2°, 14.7 ⁇ 0.2°, 16.97 ⁇ 0.2°, 17.67 ⁇ 0.2°, 18.41 ⁇ 0.2°, 19.75 ⁇ 0.2°, and 21.09 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2 ⁇ angles: 3.76 ⁇ 0.2°, 5.2 ⁇ 0.2°, 5.82 ⁇ 0.2°, 13.07 ⁇ 0.2°, 13.75 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.85 ⁇ 0.2°, 16.97 ⁇ 0.2°, 17.67 ⁇ 0.2°, 18.41 ⁇ 0.2°, 19.23 ⁇ 0.2°, 19.75 ⁇ 0.2°, 21.09 ⁇ 0.2°, 21.87 ⁇ 0.2°, and 22.92 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the X-ray powder diffraction pattern analysis data of the crystal form A is shown in Table 1 below.
  • the present invention also proposes a crystalline form B of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2 ⁇ angles: 11.92 ⁇ 0.2°, 16.31 ⁇ 0.2°, 17.75 ⁇ 0.2°, 18.74 ⁇ 0.2°, 19.56 ⁇ 0.2°, and 21.72 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.88 ⁇ 0.2°, 11.92 ⁇ 0.2°, 16.31 ⁇ 0.2°, 17.19 ⁇ 0.2°, 17.75 ⁇ 0.2°, 18.74 ⁇ 0.2°, 19.56 ⁇ 0.2°, 20.59 ⁇ 0.2°, 21.72 ⁇ 0.2°, and 23.68 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.88 ⁇ 0.2°, 10.89 ⁇ 0.2°, 11.92 ⁇ 0.2°, 13.11 ⁇ 0.2°, 14.84 ⁇ 0.2°, 16.31 ⁇ 0.2°, 17.19 ⁇ 0.2°, 17.75 ⁇ 0.2°, 18.74 ⁇ 0.2°, 19.56 ⁇ 0.2°, 20.59 ⁇ 0.2°, 21.27 ⁇ 0.2°, 21.72 ⁇ 0.2°, 22.84 ⁇ 0.2°, and 23.68 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form B has an X-ray powder diffraction pattern substantially as shown in FIG. 3 .
  • the X-ray powder diffraction pattern analysis data of the crystal form B is shown in Table 2 below.
  • the present invention also discloses a crystalline form C of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2 ⁇ angles: 10.15 ⁇ 0.2°, 11.26 ⁇ 0.2°, 18.24 ⁇ 0.2°, 20.34 ⁇ 0.2°, 20.92 ⁇ 0.2°, and 22.59 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2 ⁇ angles: 10.15 ⁇ 0.2°, 11.26 ⁇ 0.2°, 14.27 ⁇ 0.2°, 16.57 ⁇ 0.2°, 17.75 ⁇ 0.2°, 18.24 ⁇ 0.2°, 20.34 ⁇ 0.2°, 20.92 ⁇ 0.2°, 22.59 ⁇ 0.2°, and 27.33 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form C has characteristic diffraction peaks at the following 2 ⁇ angles: 7.04 ⁇ 0.2°, 10.15 ⁇ 0.2°, 10.97 ⁇ 0.2°, 11.26 ⁇ 0.2°, 14.27 ⁇ 0.2°, 16.57 ⁇ 0.2°, 17.75 ⁇ 0.2°, 18.24 ⁇ 0.2°, 20.34 ⁇ 0.2°, 20.92 ⁇ 0.2°, 22.59 ⁇ 0.2°, 23.78 ⁇ 0.2°, 24.87 ⁇ 0.2°, 25.97 ⁇ 0.2°, and 27.33 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
  • the X-ray powder diffraction pattern analysis data of the crystal form C is shown in Table 3 below.
  • the present invention provides a crystalline form D of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.96 ⁇ 0.2°, 6.65 ⁇ 0.2°, 8.93 ⁇ 0.2°, 13.11 ⁇ 0.2°, 13.85 ⁇ 0.2°, and 17.19 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.34 ⁇ 0.2°, 4.96 ⁇ 0.2°, 6.65 ⁇ 0.2°, 8.93 ⁇ 0.2°, 13.11 ⁇ 0.2°, 13.85 ⁇ 0.2°, 17.19 ⁇ 0.2°, 17.95 ⁇ 0.2°, 18.84 ⁇ 0.2°, and 20.01 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form D has characteristic diffraction peaks at the following 2 ⁇ angles: 4.34 ⁇ 0.2°, 4.96 ⁇ 0.2°, 6.65 ⁇ 0.2°, 8.93 ⁇ 0.2°, 13.11 ⁇ 0.2°, 13.85 ⁇ 0.2°, 14.54 ⁇ 0.2°, 15.89 ⁇ 0.2°, 17.19 ⁇ 0.2°, 17.95 ⁇ 0.2°, 18.84 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.01 ⁇ 0.2°, 22.16 ⁇ 0.2°, and 22.86 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form D has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
  • the X-ray powder diffraction pattern analysis data of the crystal form D is shown in Table 4 below.
  • the present invention provides a crystalline form E of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2 ⁇ angles: 10.42 ⁇ 0.2°, 12.6 ⁇ 0.2°, 16.59 ⁇ 0.2°, 18.24 ⁇ 0.2°, 20.22 ⁇ 0.2°, and 22.42 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2 ⁇ angles: 10.42 ⁇ 0.2°, 12.6 ⁇ 0.2°, 13.5 ⁇ 0.2°, 16.59 ⁇ 0.2°, 17.71 ⁇ 0.2°, 18.24 ⁇ 0.2°, 20.22 ⁇ 0.2°, 20.88 ⁇ 0.2°, 22.42 ⁇ 0.2°, and 24.11 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form E has characteristic diffraction peaks at the following 2 ⁇ angles: 3.76 ⁇ 0.2°, 10.42 ⁇ 0.2°, 12.6 ⁇ 0.2°, 13.5 ⁇ 0.2°, 14.51 ⁇ 0.2°, 15.23 ⁇ 0.2°, 16.59 ⁇ 0.2°, 17.71 ⁇ 0.2°, 18.24 ⁇ 0.2°, 20.22 ⁇ 0.2°, 20.88 ⁇ 0.2°, 21.44 ⁇ 0.2°, 22.42 ⁇ 0.2°, 23.5 ⁇ 0.2°, and 24.11 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form E has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .
  • the X-ray powder diffraction pattern analysis data of the crystal form E is shown in Table 5 below.
  • the present invention also proposes a crystalline form F of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2 ⁇ angles: 11.94 ⁇ 0.2°, 15.75 ⁇ 0.2°, 18.06 ⁇ 0.2°, 19.27 ⁇ 0.2°, 20.47 ⁇ 0.2°, and 21.39 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2 ⁇ angles: 3.35 ⁇ 0.2°, 4.11 ⁇ 0.2°, 10.09 ⁇ 0.2°, 11.24 ⁇ 0.2°, 11.94 ⁇ 0.2°, 15.75 ⁇ 0.2°, 18.06 ⁇ 0.2°, 19.27 ⁇ 0.2°, 20.47 ⁇ 0.2°, and 21.39 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form F has characteristic diffraction peaks at the following 2 ⁇ angles: 3.35 ⁇ 0.2°, 4.11 ⁇ 0.2°, 5.18 ⁇ 0.2°, 5.7 ⁇ 0.2°, 10.09 ⁇ 0.2°, 11.24 ⁇ 0.2°, 11.94 ⁇ 0.2°, 15.75 ⁇ 0.2°, 16.59 ⁇ 0.2°, 18.06 ⁇ 0.2°, 19.27 ⁇ 0.2°, 20.47 ⁇ 0.2°, 21.39 ⁇ 0.2°, 22.46 ⁇ 0.2°, and 24.24 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form F has an X-ray powder diffraction pattern substantially as shown in FIG. 11 .
  • the X-ray powder diffraction pattern analysis data of the crystal form F is shown in Table 6 below.
  • the present invention also proposes a crystalline form G of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2 ⁇ angles: 5.62 ⁇ 0.2°, 10.58 ⁇ 0.2°, 11.65 ⁇ 0.2°, 14.62 ⁇ 0.2°, 17.67 ⁇ 0.2°, and 21.13 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2 ⁇ angles: 5.62 ⁇ 0.2°, 10.58 ⁇ 0.2°, 11.65 ⁇ 0.2°, 14.62 ⁇ 0.2°, 15.34 ⁇ 0.2°, 17.67 ⁇ 0.2°, 19.95 ⁇ 0.2°, 20.51 ⁇ 0.2°, 21.13 ⁇ 0.2°, and 21.66 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form G has characteristic diffraction peaks at the following 2 ⁇ angles: 5.62 ⁇ 0.2°, 9.34 ⁇ 0.2°, 9.8 ⁇ 0.2°, 10.58 ⁇ 0.2°, 11.65 ⁇ 0.2°, 14.62 ⁇ 0.2°, 15.34 ⁇ 0.2°, 17.67 ⁇ 0.2°, 18.61 ⁇ 0.2°, 19.95 ⁇ 0.2°, 20.51 ⁇ 0.2°, 21.13 ⁇ 0.2°, 21.66 ⁇ 0.2°, 23.33 ⁇ 0.2°, and 25.02 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form G has an X-ray powder diffraction pattern substantially as shown in FIG. 13 .
  • the X-ray powder diffraction pattern analysis data of the sulfate crystal form G is shown in Table 7 below.
  • the present invention also provides a crystalline form H of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2 ⁇ angles: 10.46 ⁇ 0.2°, 12.47 ⁇ 0.2°, 16.29 ⁇ 0.2°, 18.41 ⁇ 0.2°, 20.26 ⁇ 0.2°, and 21.02 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2 ⁇ angles: 10.46 ⁇ 0.2°, 11.34 ⁇ 0.2°, 12.47 ⁇ 0.2°, 16.29 ⁇ 0.2°, 17.89 ⁇ 0.2°, 18.41 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.26 ⁇ 0.2°, 21.02 ⁇ 0.2°, and 22.42 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form H has characteristic diffraction peaks at the following 2 ⁇ angles: 10.46 ⁇ 0.2°, 11.34 ⁇ 0.2°, 12.47 ⁇ 0.2°, 13.53 ⁇ 0.2°, 16.29 ⁇ 0.2°, 16.97 ⁇ 0.2°, 17.89 ⁇ 0.2°, 18.41 ⁇ 0.2°, 19.07 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.26 ⁇ 0.2°, 21.02 ⁇ 0.2°, 22.42 ⁇ 0.2°, 24.01 ⁇ 0.2°, and 25.53 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form H has an X-ray powder diffraction pattern substantially as shown in FIG. 15 .
  • the X-ray powder diffraction pattern analysis data of the crystal form H is shown in Table 8 below.
  • the present invention also provides a crystalline form I of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2 ⁇ angles: 9.84 ⁇ 0.2°, 10.37 ⁇ 0.2°, 11.51 ⁇ 0.2°, 20.24 ⁇ 0.2°, 20.71 ⁇ 0.2°, and 22.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2 ⁇ angles: 9.84 ⁇ 0.2°, 10.37 ⁇ 0.2°, 11.51 ⁇ 0.2°, 14.27 ⁇ 0.2°, 17.95 ⁇ 0.2°, 18.3 ⁇ 0.2°, 20.24 ⁇ 0.2°, 20.71 ⁇ 0.2°, 21.25 ⁇ 0.2°, and 22.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form I has an X-ray powder diffraction pattern substantially as shown in Figure 17.
  • the X-ray powder diffraction pattern analysis data of the crystalline form I is shown in Table 9 below.
  • the present invention also proposes a crystalline form J of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form J has characteristic diffraction peaks at the following 2 ⁇ angles: 11.67 ⁇ 0.2°, 16.08 ⁇ 0.2°, 16.68 ⁇ 0.2°, 18.86 ⁇ 0.2°, 19.35 ⁇ 0.2°, and 23.74 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form J has characteristic diffraction peaks at the following 2 ⁇ angles: 9.67 ⁇ 0.2°, 10.91 ⁇ 0.2°, 11.67 ⁇ 0.2°, 16.08 ⁇ 0.2°, 16.68 ⁇ 0.2°, 17.21 ⁇ 0.2°, 18.86 ⁇ 0.2°, 19.35 ⁇ 0.2°, 21.27 ⁇ 0.2°, and 23.74 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form J has characteristic diffraction peaks at the following 2 ⁇ angles: 5.49 ⁇ 0.2°, 6.3 ⁇ 0.2°, 9.67 ⁇ 0.2°, 10.91 ⁇ 0.2°, 11.67 ⁇ 0.2°, 12.87 ⁇ 0.2°, 14.68 ⁇ 0.2°, 16.08 ⁇ 0.2°, 16.68 ⁇ 0.2°, 17.21 ⁇ 0.2°, 18.86 ⁇ 0.2°, 19.35 ⁇ 0.2°, 20.32 ⁇ 0.2°, 21.27 ⁇ 0.2°, and 23.74 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form J has an X-ray powder diffraction pattern substantially as shown in FIG. 19 .
  • the X-ray powder diffraction pattern analysis data of the crystal form J is shown in Table 10 below.
  • the present invention also proposes a crystalline form K of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form K has characteristic diffraction peaks at the following 2 ⁇ angles: 12.04 ⁇ 0.2°, 15.85 ⁇ 0.2°, 18.18 ⁇ 0.2°, 19.31 ⁇ 0.2°, 19.56 ⁇ 0.2°, 21.48 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form K has characteristic diffraction peaks at the following 2 ⁇ angles: 11.42 ⁇ 0.2°, 12.04 ⁇ 0.2°, 15.85 ⁇ 0.2°, 16.64 ⁇ 0.2°, 18.18 ⁇ 0.2°, 19.31 ⁇ 0.2°, 19.56 ⁇ 0.2°, 20.57 ⁇ 0.2°, 21.48 ⁇ 0.2°, and 24.28 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form K has characteristic diffraction peaks at the following 2 ⁇ angles: 5.76 ⁇ 0.2°, 10.17 ⁇ 0.2°, 11.42 ⁇ 0.2°, 12.04 ⁇ 0.2°, 15.85 ⁇ 0.2°, 16.64 ⁇ 0.2°, 18.18 ⁇ 0.2°, 18.72 ⁇ 0.2°, 19.31 ⁇ 0.2°, 19.56 ⁇ 0.2°, 20.57 ⁇ 0.2°, 21.48 ⁇ 0.2°, 22.51 ⁇ 0.2°, 24.28 ⁇ 0.2°, and 25.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form K has an X-ray powder diffraction pattern substantially as shown in Figure 21.
  • the X-ray powder diffraction pattern analysis data of the crystal form K is shown in Table 11 below.
  • the present invention also proposes a crystalline form L of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2 ⁇ angles: 10.42 ⁇ 0.2°, 12.43 ⁇ 0.2°, 16.27 ⁇ 0.2°, 18.18 ⁇ 0.2°, 20.08 ⁇ 0.2°, 21 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2 ⁇ angles: 10.42 ⁇ 0.2°, 11.28 ⁇ 0.2°, 12.43 ⁇ 0.2°, 13.48 ⁇ 0.2°, 16.27 ⁇ 0.2°, 18.18 ⁇ 0.2°, 20.08 ⁇ 0.2°, 21 ⁇ 0.2°, 22.36 ⁇ 0.2°, and 23.91 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2 ⁇ angles: 3.08 ⁇ 0.2°, 10.42 ⁇ 0.2°, 11.28 ⁇ 0.2°, 12.43 ⁇ 0.2°, 13.48 ⁇ 0.2°, 14.47 ⁇ 0.2°, 16.27 ⁇ 0.2°, 16.82 ⁇ 0.2°, 18.18 ⁇ 0.2°, 20.08 ⁇ 0.2°, 21 ⁇ 0.2°, 22.36 ⁇ 0.2°, 23.91 ⁇ 0.2°, 25.47 ⁇ 0.2°, and 28.15 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form L has an X-ray powder diffraction pattern substantially as shown in Figure 23.
  • the X-ray powder diffraction pattern analysis data of the crystal form L is shown in Table 12 below.
  • the present invention also proposes a crystalline form M of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form M has characteristic diffraction peaks at the following 2 ⁇ angles: 5.33 ⁇ 0.2°, 7.04 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.85 ⁇ 0.2°, 18.43 ⁇ 0.2°, and 21.11 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form M has characteristic diffraction peaks at the following 2 ⁇ angles: 4.38 ⁇ 0.2°, 5.33 ⁇ 0.2°, 7.04 ⁇ 0.2°, 14.06 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.85 ⁇ 0.2°, 17.38 ⁇ 0.2°, 18.43 ⁇ 0.2°, 19.11 ⁇ 0.2°, and 21.11 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form M has characteristic diffraction peaks at the following 2 ⁇ angles: 4.38 ⁇ 0.2°, 4.87 ⁇ 0.2°, 5.33 ⁇ 0.2°, 7.04 ⁇ 0.2°, 10.6 ⁇ 0.2°, 14.06 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.85 ⁇ 0.2°, 17.38 ⁇ 0.2°, 18.43 ⁇ 0.2°, 19.11 ⁇ 0.2°, 19.58 ⁇ 0.2°, 21.11 ⁇ 0.2°, 21.78 ⁇ 0.2°, and 27.78 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form N has an X-ray powder diffraction pattern substantially as shown in Figure 27.
  • the X-ray powder diffraction pattern analysis data of the crystal form N is shown in Table 14 below.
  • the present invention also proposes a crystalline form O of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2 ⁇ angles: 5.02 ⁇ 0.2°, 10.29 ⁇ 0.2°, 12.54 ⁇ 0.2°, 16.72 ⁇ 0.2°, 17.62 ⁇ 0.2°, and 20.45 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2 ⁇ angles: 5.02 ⁇ 0.2°, 10.29 ⁇ 0.2°, 12.54 ⁇ 0.2°, 13.59 ⁇ 0.2°, 15.34 ⁇ 0.2°, 16.72 ⁇ 0.2°, 17.62 ⁇ 0.2°, 19.75 ⁇ 0.2°, 20.45 ⁇ 0.2°, and 25.37 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form O has characteristic diffraction peaks at the following 2 ⁇ angles: 5.02 ⁇ 0.2°, 10.29 ⁇ 0.2°, 12.54 ⁇ 0.2°, 13.59 ⁇ 0.2°, 14.25 ⁇ 0.2°, 15.34 ⁇ 0.2°, 16.72 ⁇ 0.2°, 17.62 ⁇ 0.2°, 19.75 ⁇ 0.2°, 20.45 ⁇ 0.2°, 20.9 ⁇ 0.2°, 22.61 ⁇ 0.2°, 23.33 ⁇ 0.2°, 25.37 ⁇ 0.2°, and 26.79 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form O has an X-ray powder diffraction pattern substantially as shown in Figure 29.
  • the X-ray powder diffraction pattern analysis data of the crystal form O is shown in Table 15 below.
  • the present invention also proposes a crystalline form P of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the crystalline form P has characteristic diffraction peaks at the following 2 ⁇ angles: 11.53 ⁇ 0.2°, 14.72 ⁇ 0.2°, 15.98 ⁇ 0.2°, 17.01 ⁇ 0.2°, 17.54 ⁇ 0.2°, and 19.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 9.57 ⁇ 0.2°, 11.05 ⁇ 0.2°, 11.53 ⁇ 0.2°, 12.82 ⁇ 0.2°, 14.72 ⁇ 0.2°, 15.98 ⁇ 0.2°, 17.01 ⁇ 0.2°, 17.54 ⁇ 0.2°, 19.09 ⁇ 0.2°, and 19.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form P has characteristic diffraction peaks at the following 2 ⁇ angles: 9.57 ⁇ 0.2°, 11.05 ⁇ 0.2°, 11.53 ⁇ 0.2°, 12.82 ⁇ 0.2°, 14.72 ⁇ 0.2°, 15.98 ⁇ 0.2°, 17.01 ⁇ 0.2°, 17.54 ⁇ 0.2°, 19.09 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.24 ⁇ 0.2°, 20.88 ⁇ 0.2°, 21.43 ⁇ 0.2°, 22.14 ⁇ 0.2°, and 23.89 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form P has an X-ray powder diffraction pattern substantially as shown in Figure 31.
  • the X-ray powder diffraction pattern analysis data of the crystal form P is shown in Table 16 below.
  • API or “free state” refers to the free base form of the compound represented by formula (I).
  • Crystal form or “crystalline form” refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, inclusion compounds, co-crystals, salts, solvates of salts, hydrates of salts of compounds.
  • the crystalline form of a substance can be obtained by many methods known in the art.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, for example, in a nanopore or capillary, crystallization on a surface or template, for example, on a polymer, crystallization in the presence of an additive such as a co-crystallization countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, grinding and solvent drop grinding, etc.
  • an additive such as a co-crystallization countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, grinding and solvent drop grinding, etc.
  • Amorphous or “amorphous form” refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and is characterized by a diffuse X-ray powder diffraction pattern without peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline substances.
  • the amorphous form of a substance can be obtained by many methods known in the art. This method includes, but is not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion technology, etc.
  • Solvent refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
  • Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, tolu
  • Anti-solvent refers to a fluid that promotes precipitation of a product (or a product precursor) from a solvent.
  • the anti-solvent may include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid from the solvent.
  • Solidvate means that the crystal has a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice, wherein the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof
  • a specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice is water.
  • the hydrate On the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice, the hydrate may or may not have other solvents except water.
  • Crystalline or amorphous forms 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, solution calorimetry, scanning electron microscopy (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
  • solution calorimetry scanning electron microscopy
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect information such as changes in crystal forms, crystallinity, and crystal structure states, and is a common means of identifying crystal forms.
  • the peak position of the XRPD spectrum depends mainly on the structure of the crystal form, is relatively insensitive to experimental details, and its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal 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 accompanying drawings of the present invention.
  • the measurement of 2 ⁇ of the XRPD spectrum may have experimental errors, and the measurement of 2 ⁇ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2 ⁇ cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, there is an error tolerance of ⁇ 0.2° for the diffraction peak.
  • DSC Differential scanning calorimetry
  • an inert reference material usually ⁇ -Al 2 O 3
  • the height of the melting peak of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form of the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention.
  • DSC spectra may have experimental errors, and the peak positions and peak values of DSC spectra may vary slightly between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
  • the melting peak has an error tolerance of ⁇ 3°C.
  • Glass transition refers to the transition of amorphous materials between a highly elastic state and a glassy state, which is an inherent property of the material; its corresponding transition temperature is the glass transition temperature (Tg), which is an important physical property of amorphous materials. Glass transition is a phenomenon related to molecular motion, and therefore, the glass transition temperature (Tg) mainly depends on the structure of the material, and is relatively insensitive to experimental details.
  • the glass transition temperature (Tg) of the amorphous material of the present invention is measured by differential scanning calorimetry (DSC), characterized in that it has a glass transition temperature of 66°C. According to the instrument conditions used in the test of the present invention, the glass transition temperature has an error tolerance of ⁇ 3°C.
  • DSC Differential scanning calorimetry
  • Solids with the same chemical composition often form isomers with different crystal structures, or variants, under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase phenomenon.
  • crystal transformation When the temperature and pressure conditions change, the variants will transform into each other, which is called crystal transformation. Due to the crystal transformation, the mechanical, electrical, magnetic and other properties of the crystal will change greatly.
  • DSC differential scanning calorimetry
  • this transformation process can be observed on the differential scanning calorimetry (DSC) graph, characterized in that the DSC graph has an exothermic peak reflecting this transformation process, and at the same time has two or more endothermic peaks, which are the characteristic endothermic peaks of different crystal forms before and after the transformation.
  • the crystal form or amorphous form of the compound of the present invention can undergo crystal transformation under appropriate conditions.
  • Thermogravimetric analysis is a technique for measuring the mass change of a substance with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition, and can infer the presence of crystal water or crystallization solvent in the crystals.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. According to the instrument conditions used in the test of the present invention, the mass change has an error tolerance of ⁇ 0.3%.
  • the moisture adsorption/desorption isotherm measurement is a measurement method that measures the adsorption and desorption behavior of moisture by measuring the weight change of a solid object under various relative humidity conditions.
  • a peak refers to a feature that can be identified by one skilled in the art and which cannot be attributed to background noise.
  • substantially as shown means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or the DSC pattern or the TGA results are shown in its pattern.
  • substantially pure means that one crystalline form is substantially free of one or more other crystalline forms, that is, the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystalline form contains other crystalline forms, and the percentage of the other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • substantially free means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • “Relative intensity” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.
  • FIG1 is an XRPD diagram of Form A according to an embodiment of the present invention.
  • FIG2 is an NMR diagram of Form A according to an embodiment of the present invention.
  • FIG3 is an XRPD diagram of Form B according to an embodiment of the present invention.
  • FIG4 is an NMR diagram of Form B according to an embodiment of the present invention.
  • FIG5 is an XRPD diagram of Form C according to an embodiment of the present invention.
  • FIG6 is an NMR diagram of Form C according to an embodiment of the present invention.
  • FIG7 is an XRPD diagram of Form D according to an embodiment of the present invention.
  • FIG8 is an NMR diagram of Form D according to an embodiment of the present invention.
  • FIG9 is an XRPD diagram of Form E according to an embodiment of the present invention.
  • FIG10 is an NMR diagram of Form E according to an embodiment of the present invention.
  • FIG11 is an XRPD diagram of Form F according to an embodiment of the present invention.
  • FIG12 is an NMR diagram of Form F according to an embodiment of the present invention.
  • FIG13 is an XRPD diagram of Form G according to an embodiment of the present invention.
  • FIG14 is an NMR diagram of Form G according to an embodiment of the present invention.
  • FIG15 is an XRPD diagram of Form H according to an embodiment of the present invention.
  • FIG16 is an NMR diagram of Form H according to an embodiment of the present invention.
  • FIG17 is an XRPD diagram of Form I according to an embodiment of the present invention.
  • FIG18 is an NMR diagram of Form I according to an embodiment of the present invention.
  • FIG19 is an XRPD diagram of Form J according to an embodiment of the present invention.
  • FIG20 is an NMR diagram of Form J according to an embodiment of the present invention.
  • FIG21 is an XRPD diagram of Form K according to an embodiment of the present invention.
  • FIG22 is an NMR diagram of Form K according to an embodiment of the present invention.
  • FIG23 is an XRPD diagram of Form L according to an embodiment of the present invention.
  • FIG24 is an NMR diagram of Form L according to an embodiment of the present invention.
  • FIG25 is an XRPD diagram of Form M according to an embodiment of the present invention.
  • FIG26 is an NMR diagram of Form M according to an embodiment of the present invention.
  • FIG27 is an XRPD diagram of Form N according to an embodiment of the present invention.
  • FIG28 is an NMR diagram of Form N according to an embodiment of the present invention.
  • FIG29 is an XRPD diagram of Form O according to an embodiment of the present invention.
  • FIG30 is an NMR diagram of Form O according to an embodiment of the present invention.
  • FIG31 is an XRPD diagram of Form P according to an embodiment of the present invention.
  • FIG32 is an NMR diagram of Form P according to an embodiment of the present invention.
  • FIG33 is (a) a DVS curve of Form P according to an embodiment of the present invention. (b) an XRPD diagram before and after the DVS test;
  • FIG34 is a PLM image of a crystal form P according to an embodiment of the present invention.
  • FIG35 is an XRPD pattern of an amorphous form according to an embodiment of the present invention.
  • FIG36 is an NMR graph of an amorphous form according to an embodiment of the present invention.
  • Figure 37 is an amorphous (a) DVS curve according to an embodiment of the present invention. (b) XRPD diagram before and after DVS test;
  • FIG38 is an amorphous PLM image according to an embodiment of the present invention.
  • FIG39 is an XRPD diagram of amorphous stability study according to an embodiment of the present invention.
  • FIG40 is an XRPD diagram of a stability study of Form P according to an embodiment of the present invention.
  • FIG41 is a comparison diagram of XRPD of the remaining solid after the amorphous phase was shaken in a medium for 24 hours according to an embodiment of the present invention
  • Figure 42 is a comparison chart of XRPD of the solid remaining after the crystal form P according to an embodiment of the present invention was oscillated in a medium for 24 hours.
  • the solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Bruker D8Advance (Bruker, GER). The 2 ⁇ scanning angle was from 3° to 45°, the scanning step was 0.02°, and the exposure time was 0.08 seconds.
  • the test method was Cu target K ⁇ 1 radiation, voltage 40kV, current 40mA, and the sample pan was a zero background sample pan.
  • thermogravimetric analyzer is TA Discovery 550 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, and the nitrogen purge rate at the sample was 60 mL/min and the nitrogen purge rate at the balance was 40 mL/min.
  • the model of the differential scanning calorimeter was TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a DSC Tzero sample pan with holes and heated to the final temperature at a rate of 10 °C/min, with nitrogen purge rate of 50 mL/min in the furnace.
  • Dynamic moisture adsorption and desorption analysis was performed using DVS Intrinsic (SMS, UK). The test used a gradient mode, with humidity changes of 50%-95%-0%-50%. The humidity change for each gradient in the range of 0% to 90% was 10%. The gradient endpoint was determined using the dm/dt method, with dm/dt less than 0.002% and maintained for 10 minutes as the gradient endpoint. After the test was completed, the sample was subjected to XRPD analysis to confirm whether the solid morphology had changed.
  • the model of polarizing microscope is Nikon Ci-POL (Nikon, JP). Place a small amount of sample on a glass slide and select a suitable lens to observe the sample morphology.
  • HPLC model was SHIMADZU LC-2030C (Shimadzu, JP).
  • the test conditions were shown in Tables 17 and 18.
  • the clear solution obtained from the raw material solubility test (general test method 1) or about 20 mg of the sample is weighed to prepare a clear solution (filter the system with solid precipitation), and it is left to stand at room temperature in an open air until the solvent is completely evaporated to obtain a solid.
  • Different crystal forms are used as raw materials, a certain amount of sample is added to a selected single solvent or binary solvent until a suspension is formed, and after being suspended and stirred at room temperature for a certain period of time, the suspension is centrifuged and the solid is vacuum dried at room temperature.
  • amorphous as raw material Using amorphous as raw material, a certain amount of sample is added to the selected solvent until a suspension is formed. After suspension and stirring at 50° C. for 24 hours, the suspension is centrifuged and the solid is vacuum dried at room temperature.
  • Thermal crystallization was performed using an Instec HCS424GXY hot stage (Instec Inc., US). 6-8 mg of sample was placed on a glass slide on the hot stage and heated to the target temperature at a rate of 10°C/min. The temperature was kept constant for 10 min, and then the sample was naturally cooled to room temperature to obtain a solid.
  • sample amorphous: about 10 mg; crystalline form P: about 20 mg
  • high temperature 60°C
  • high humidity 25°C/92.5% RH
  • light 25°C/4500Lux
  • acceleration 40°C/75% RH
  • pH buffer solution The preparation process of pH buffer solution is shown in Table 19. Samples of different crystal forms were added to pH buffer solution and shaken at a constant temperature of 25°C for 24 hours before sampling. The sampled solution was filtered with a 0.22 ⁇ m water filter membrane, and some samples with higher concentrations were appropriately diluted with diluents. The signal peak area of the solution was measured by HPLC, and finally the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution multiple. In addition, the remaining liquid was centrifuged and the remaining supernatant was taken to test its pH value.
  • the preparation process of the biological medium is shown in Table 20. Samples of different crystal forms were added to the biological medium and water and shaken at a constant temperature of 37°C for 24 hours. Samples were taken at 0.5h, 2h and 24h, respectively. The sampled solutions were filtered with a 0.22 ⁇ m water filter membrane. Some samples with higher concentrations were appropriately diluted with diluents. The signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material and the dilution multiple. In addition, the pH value of the supernatant after 24h was tested, and the remaining solid was tested by XRPD.
  • reaction solution was filtered, and the crude filtrate was purified by preparative separation (preparation method: chromatographic column: Agilent 10Prep-C18 250x21.2 mm; column temperature: 25°C; mobile phase: water (0.1% TFA)-acetonitrile; mobile phase acetonitrile ratio 50%-70% in 12 min; flow rate 30 mL/min) to obtain the title compound 51 (62 mg, yield: 62%, containing two pairs of enantiomers).
  • RPMI1640 culture medium Brand: Gibco, Product No.: 31800-014
  • Amphotericin B Brand: Abcam, Catalog Number: ab141199
  • Liquid culture medium RPMI is prepared with pure water, and 0.165 mol/L MOPS is added and the pH is adjusted to 7.0. After sterilization by filtering with a 0.22 um filter membrane, it is stored at 4°C (no more than 3 months). After high temperature sterilization at 121°C for 30 minutes with 0.85% saline, it is stored at room temperature (no more than 1 week). The compound is dissolved in DMSO to 12.8 mg/mL and stored at -20°C.
  • yeast pick 3-5 colonies from the SDA plate on the day of the test and fully suspend them in 5 mL of sterilized 0.85% saline. Measure the turbidity of the bacterial solution with a turbidity meter and adjust the turbidity to about 0.2. Dilute the bacterial solution 50 times and 20 times (a total of 1000 times) with RPMI1640 medium as the inoculum. The final inoculum concentration is 500-2500 CFU/mL.
  • Aspergillus For Aspergillus, take 5 mL of saline to cover the hyphae, gently scrape off the spores with a spreader, and then transfer the spore suspension to a sterile test tube. Take an appropriate amount of spore suspension and count it under a microscope using a hemocytometer. Use RPMI1640 medium to adjust the spore concentration to about 0.4-5x 10 4 spores/mL.
  • the compound was diluted with DMSO to a maximum of 800 ⁇ g/mL (or 400 ⁇ g/mL) and 10 two-fold serial dilutions were performed, for a total of 11 concentrations.
  • 2 ⁇ L of serially diluted compounds were transferred to the corresponding wells of a 96-well plate, and 198 ⁇ L of inoculum was transferred to the test plate and incubated at 35 degrees for 24 hours (48 and 72 hours for Aspergillus fumigatus and Cryptococcus neoformans, respectively).
  • Form P is easily soluble in ethanol, acetone and ethyl acetate (>100 mg/mL); soluble in acetonitrile, dichloromethane and tetrahydrofuran (>10 mg/mL).
  • Form P was basically soluble in 0.1 mL of ethanol, acetone, ethyl acetate, acetonitrile and tetrahydrofuran, respectively, and there were granular substances attached to the EP tube wall in the solution.
  • Form P was basically soluble in 1.1 mL of dichloromethane, and dichloromethane was continued to be added, and no signs of reduction of flocculent substances in the solution were observed.
  • the stability of amorphous and crystalline P was studied under high temperature (60°C), high humidity (25°C/92.5%RH), light (25°C/4500Lux), and accelerated (40°C/75%RH) conditions.
  • Samples were taken for XRPD characterization and HPLC testing at 7 days and 17 days, respectively. The results are shown in Table 24, Figure 39, and Figure 40.
  • the XRPD results showed that the amorphous and crystalline P were stable under high temperature, high humidity, light, and accelerated conditions for 17 days, and no crystal transformation occurred. Deliquescence was observed under accelerated conditions.
  • the HPLC results showed that the chemical purity of the amorphous and crystalline P did not change significantly after being placed under the above conditions for 17 days.
  • the solubility of amorphous and crystalline P was measured in different pH buffers.
  • the experimental method is shown in General Test Method 11.1, and the corresponding results are shown in Table 27.
  • the results show that the solubility of amorphous and crystalline P in different pH buffers is very low and is not detected.
  • the dynamic solubility of amorphous and crystalline P in three biological media (FaSSIF, FeSSIF and FaSSGF) and water was determined.
  • the experimental method is shown in General Test Method 11.2, and the corresponding results are shown in Table 28 and Figures 41 and 42.
  • the results show that the solubility of amorphous in FaSSIF and FeSSIF and crystalline P in FeSSIF has a downward trend over time.
  • the 24h solubility of amorphous and crystalline P in FeSSIF is greater than that in FaSSIF, and it is not detected in FaSSGF and water. After the solubility test, the remaining solid crystalline in the biological medium and water has no change.

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Abstract

L'invention concerne une forme amorphe et 16 formes cristallines d'un composé représenté par la formule (I). Les formes cristallines sont nommées dans l'ordre de la forme cristalline A à la forme cristalline P. L'invention concerne également un procédé de préparation de la forme amorphe et des polymorphes du composé représenté par la formule (I).
PCT/CN2023/122465 2022-09-30 2023-09-28 Forme amorphe et solide cristallin de composé bicyclique et son procédé de préparation WO2024067784A1 (fr)

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