WO2023078440A1 - 吡嗪类衍生物的盐的晶型及其制备方法 - Google Patents

吡嗪类衍生物的盐的晶型及其制备方法 Download PDF

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WO2023078440A1
WO2023078440A1 PCT/CN2022/130227 CN2022130227W WO2023078440A1 WO 2023078440 A1 WO2023078440 A1 WO 2023078440A1 CN 2022130227 W CN2022130227 W CN 2022130227W WO 2023078440 A1 WO2023078440 A1 WO 2023078440A1
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compound
salt
crystal form
suspension
crystalline form
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French (fr)
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郑骏浩
章杜前
胡海文
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杭州中美华东制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms

Definitions

  • the invention relates to a crystal form and a preparation method of compound 3,6-diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine and a salt thereof.
  • 3,6-diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine is a kind of excellent photophysical properties and other chemical and Physical properties of fluorescent compounds.
  • patents US 8,155,000, US 8,664,392, US 8,697,033, US 8,722,685, US 8,778,309, US 9,005,581, US 9,114,160, US 9,283,288, US 9,376,399 and US 9,480,687 It is disclosed that this compound is known for renal function monitoring.
  • 3,6-Diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine is being developed as a real-time GFR ( GFR) measured fluorescent agent. It emits a strong fluorescent signal at 556nm when excited at 434nm. Human clinical research is currently in progress.
  • GFR GFR
  • 3,6-diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyridine can be measured transcutaneously in real time in the patient's bloodstream. The clearance rate of oxazine was calculated to obtain the patient's glomerular filtration rate.
  • the crystal structure of pharmaceutical active ingredients often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystal forms.
  • the bioavailability of different crystal forms of the same drug may also be different; in addition, its stability, fluidity, and compressibility may also be different. These physical and chemical properties have a certain impact on the application of the drug, thereby affecting the drug. curative effect.
  • a first aspect of the present invention provides 3,6-diamino-2,5-bis ⁇ N-[(1R)-1-carboxy-2-hydroxyethyl]carbamoyl ⁇ pyrazine (hereinafter referred to as "the compound I”) and the crystalline forms of salts thereof as described below:
  • Crystal form I of hydrochloride Including crystal form I of hydrochloride, crystal form I of sulfate, crystal form I of p-toluenesulfonate, crystal form II of p-toluenesulfonate, crystal form I of mesylate, and crystal form of sodium salt I.
  • the crystal form can satisfy the reproducibility and controllability of the crystallization process in the industrial production process at the same time, and has good properties in aspects such as solid state stability and dynamic solubility.
  • the second aspect of the present invention provides the crystalline form I of the hydrochloride, the crystalline form I of the sulfate, the crystalline form I of the p-toluenesulfonate, the crystalline form II of the p-toluenesulfonate, and the crystalline form of the mesylate Form I, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt or crystal form A of compound I.
  • the third aspect of the present invention provides a pharmaceutical composition, which comprises an effective amount of crystal form I selected from the hydrochloride salt, crystal form I sulfate, crystal form I p-toluenesulfonate, p-toluenesulfonate Any of the crystalline form II of the mesylate salt, the crystalline form I of the sodium salt, the crystalline form II of the sodium salt, the crystalline form I of the ethanolamine salt, or the crystalline form A of compound I and one or Various pharmaceutically acceptable carriers.
  • the fourth aspect of the present invention provides the crystalline form I of the hydrochloride, the crystalline form I of the sulfate, the crystalline form I of the p-toluenesulfonate, the crystalline form II of the p-toluenesulfonate, and the crystalline form of the mesylate Any one of Form I, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt, or crystal form A of compound I, or the pharmaceutical composition, which is used for monitoring renal function, wherein The renal function monitoring is GFR monitoring, especially real-time GFR monitoring.
  • the fifth aspect of the present invention provides the crystalline form I of the hydrochloride, the crystalline form I of the sulfate, the crystalline form I of the p-toluenesulfonate, the crystalline form II of the p-toluenesulfonate, and the crystalline form of the mesylate
  • Any one of type I, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt, or crystal form A of compound I or the pharmaceutical composition is used in the preparation of drugs for renal function monitoring Use in , wherein the renal function monitoring is GFR monitoring, particularly real-time GFR monitoring.
  • a sixth aspect of the present invention provides a method for monitoring renal function in an individual, the method comprising administering to the individual an effective amount of the crystalline form I of the hydrochloride, the crystalline form I of the sulfate, the p-toluenesulfonic acid Crystal form I of salt, crystal form II of p-toluenesulfonate, crystal form I of mesylate salt, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt or crystal form of compound I Any one of type A or the pharmaceutical composition, wherein the renal function monitoring is GFR monitoring, especially real-time GFR monitoring.
  • the seventh aspect of the present invention provides a method for preparing the crystalline form of the salt of Compound I described above, the method comprising forming the crystalline form of Compound I with a suitable acidic/basic compound in a suitable solvent.
  • Figure 1 XRPD pattern of Form I of the hydrochloride salt of Compound I.
  • FIG. 1 Thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of crystalline form I of the hydrochloride salt of compound I.
  • Figure 3 1 H NMR spectra of the crystal form I of the hydrochloride salt of compound I and the crystal form A of compound I.
  • Figure 4 XRPD patterns of the crystalline form I of the hydrochloride salt of compound I before and after dynamic water sorption (DVS) tests.
  • FIG. 5 PLM image of Form I of the hydrochloride salt of Compound I.
  • Figure 6 XRPD pattern of Form I of the sulfate salt of Compound I.
  • Figure 7 TGA and DSC profiles of Form I of the sulfate salt of Compound I.
  • Figure 8 1 H NMR spectra of the crystal form I of the sulfate salt of compound I and the crystal form A of compound I.
  • FIG. 11 1 H NMR spectra of the crystal form I of the mesylate salt of compound I and the crystal form A of compound I.
  • Figure 12 XRPD pattern of Form I of p-toluenesulfonate salt of Compound I.
  • Figure 13 TGA and DSC spectra of Form I of p-toluenesulfonate salt of Compound I.
  • Figure 14 XRPD pattern of Form II of p-toluenesulfonate salt of Compound I.
  • Figure 15 TGA and DSC spectra of Form II of p-toluenesulfonate salt of compound I.
  • Figure 16 1 H NMR spectra of Form II of p-toluenesulfonate salt of Compound I and Form A of Compound I.
  • Figure 17 XRPD patterns of Form II of p-toluenesulfonate salt of compound I before and after DVS test.
  • Figure 18 PLM image of Form II of the p-toluenesulfonate salt of Compound I.
  • Figure 19 XRPD pattern of Form III of p-toluenesulfonate salt of Compound I.
  • Figure 20 XRPD pattern of Form I of the sodium salt of Compound I.
  • Figure 22 XRPD pattern of Form II of the sodium salt of Compound I.
  • Figure 24 1 H NMR spectra of the crystalline form II of the sodium salt of compound I and the crystalline form A of compound I.
  • Figure 25 XRPD pattern of Form I of Compound I ethanolamine salt.
  • Figure 27 1 H NMR spectra of the crystal form I of the ethanolamine salt of compound I and the crystal form A of compound I.
  • Figure 28 XRPD pattern of the crystalline form I of ethanolamine salt of compound I before and after DVS test.
  • Figure 29 PLM image of Form I of the ethanolamine salt of Compound I.
  • FIG. 32 1 H NMR spectrum of Form A of Compound I.
  • Figure 33 PLM image of Form A of Compound I.
  • the term "about" used when describing XRPD diffraction angles means that those of ordinary skill in the art believe that within an acceptable standard error of the stated value, for example ⁇ 0.05, ⁇ 0.1, ⁇ 0.2, ⁇ 0.3 , ⁇ 1, ⁇ 2 or ⁇ 3, etc.
  • the term "optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that description includes that said event or circumstance occurs and that it does not.
  • crystalline form or “crystal” refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • X-ray powder diffraction pattern or "XRPD pattern” refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. XRPD patterns are usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
  • the term "diffraction angle" or “2 ⁇ ” refers to the peak position expressed in degrees (°) based on the setup in an X-ray diffraction experiment, and is usually the abscissa unit in a diffraction pattern. If reflections are diffracted when the incident beam forms an angle ⁇ with a lattice plane, the experimental setup requires recording the reflected beam at 2 ⁇ angles. It should be understood that reference herein to a particular 2 ⁇ value for a particular crystalline form is intended to represent the 2 ⁇ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-K ⁇ (K ⁇ 1 1.5406) monochromatic radiation.
  • the XRPD pattern herein is preferably collected on a Bruker D8 Advance (Bruker, GER) X-ray powder diffraction analyzer, and the transmission mode is preferably collected on a Bruker D8 Advance (Bruker, GER) X-ray powder diffraction analyzer.
  • the terms "substantially the same” or “substantially as shown in Figure X" for X-ray diffraction peaks mean that representative peak positions and intensity variations are taken into consideration. For example, those skilled in the art will understand that peak position (2 ⁇ ) will show some variation, typically by as much as 0.1 to 0.2 degrees, and that the instrumentation used to measure diffraction will also cause some variation. In addition, those skilled in the art will appreciate that relative peak intensities will vary due to instrument-to-instrument variation, as well as the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art.
  • the NMR spectra in the present application are preferably collected on a Bruker AVANCE-III (Bruker, GER) NMR instrument, unless otherwise specified, using DMSO-d6 as a solvent.
  • Polarized light microscopy data in this application is preferably collected by a Motic BA310Met (Motic, CN) polarized light microscope.
  • the term “good solvent” means a solvent in which Compound I can dissolve or have a relatively higher solubility.
  • the term “anti-solvent” means a solvent in which Compound I is not or substantially insoluble or has relatively lower solubility.
  • the terms “good solvent” and “anti-solvent” may also be relative terms, and do not represent the absolute solubility of Compound I therein.
  • the same solvent can act as a good solvent in some cases and as an anti-solvent in other cases.
  • water or toluene can be used as a good solvent in some cases, such as when used alone to dissolve compound I, but can be used as an anti-solvent in some cases, such as when used in combination with DMF.
  • room temperature refers to 20°C ⁇ 5°C.
  • the present invention provides the crystal form I of the hydrochloride salt of compound I, the crystal form I of the sulfate salt, the crystal form I of the p-toluenesulfonate salt, the crystal form II of the p-toluenesulfonate salt, and the mesylate salt
  • Form I of compound I form I of sodium salt, form II of sodium salt, form I of ethanolamine salt and form A of compound I in free state.
  • the present invention provides crystalline Form I of the hydrochloride salt of Compound I having the following formula:
  • the XRPD pattern of Form I of the hydrochloride salt of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity .
  • the XRPD pattern of Form I of the hydrochloride salt of Compound 1 comprises diffraction angles (2 ⁇ ) at the diffraction peak.
  • the XRPD pattern of the crystalline form I of the hydrochloride salt further comprises diffraction angles (2 ⁇ ) at the diffraction peak.
  • the XRPD pattern of the crystalline form I of the hydrochloride salt also includes a temperature at about 7.4 ⁇ 0.2°, 12.8 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.2 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.9 ⁇ 0.2°, 23.6 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.3 ⁇ 0.2°, 27.1 ⁇ 0.2°, 27.4 ⁇ 0.2°, 28.2 ⁇ 0.2°, 29.1 ⁇ 0.2°, 33.5 ⁇ 0.2° / or a diffraction peak at a diffraction angle (2 ⁇ ) of 40.4 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form I of the hydrochloride salt is substantially as shown in FIG. 1 , more preferably as shown in FIG. 1 .
  • the crystalline form I of the hydrochloride loses about 4.0% of its weight when heated to 130 ⁇ 5°C (preferably about 130 ⁇ 2°C), and continues to heat to about 200 ⁇ 5°C (preferably about 200 ⁇ 2°C) with a further weight loss of about 8.2%, decomposition may occur at about 210 ⁇ 5°C (preferably about 210 ⁇ 2°C), as measured using TGA.
  • the TGA spectrum of the crystalline form I of the hydrochloride is substantially as shown in FIG. 2 , more preferably as shown in FIG. 2 .
  • the crystalline form I of the hydrochloride salt has endothermic peaks at about 91 ⁇ 5°C (preferably about 91 ⁇ 2°C) and about 192 ⁇ 5°C (preferably about 192 ⁇ 2°C).
  • the DSC spectrum of the crystalline form I of the hydrochloride is substantially as shown in FIG. 2 , more preferably as shown in FIG. 2 .
  • the NMR spectrum of the crystalline form I of the hydrochloride salt is substantially as shown in (a) of FIG. 3 , preferably as shown in (a) of FIG. 3 .
  • the comparison of the NMR spectrum (a) with the NMR spectrum (b) of compound I shows that the amino peak position of the crystalline form I of the hydrochloride salt changes, indicating that the hydrochloride salt sample tested is indeed a salt.
  • the XRPD pattern of the crystalline form I of the hydrochloride after the DVS test is consistent with that before the test, and there is no crystal form change.
  • the PLM image of the crystalline form I of the hydrochloride salt is substantially as shown in FIG. 5 , preferably as shown in FIG. 5 .
  • the crystal form I of the hydrochloride salt generally has a particle size of less than about 20 ⁇ m and agglomerates.
  • the present invention also provides crystalline form I of the sulfate salt of compound I having the following formula:
  • the XRPD pattern of Form I of the sulfate salt of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of the crystalline form I of the sulfate salt of Compound 1 comprises a temperature at about 14.9 ⁇ 0.2°, 20.9 ⁇ 0.2°, 23.2 ⁇ 0.2°, 27.9 ⁇ 0.2° and/or 30.8 ⁇ 0.2° Diffraction peaks at diffraction angle (2 ⁇ ).
  • the XRPD pattern of the crystalline sulfate salt form I also includes diffraction angles (2 ⁇ ) at about 7.3 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.1 ⁇ 0.2°, 22.5 ⁇ 0.2° and/or 27.4 ⁇ 0.2° diffraction peaks.
  • the XRPD pattern of the sulfate crystal form I also includes a range at about 5.9 ⁇ 0.2°, 8.0 ⁇ 0.2°, 10.2 ⁇ 0.2°, 10.6 ⁇ 0.2°, 11.4 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.0 ⁇ 0.2°, 19.4 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.3 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.4 ⁇ 0.2°, 24.7 ⁇ Diffraction angles (2 ⁇ ) of 0.2°, 25.2 ⁇ 0.2°, 26.2 ⁇ 0.2°, 27.0 ⁇ 0.2°, 28.4 ⁇ 0.2°, 28.9 ⁇ 0.2°, 29.5 ⁇ 0.2°, 29.7 ⁇ 0.2° and/or 35.1 ⁇ 0.2° diffraction peaks at .
  • the XRPD pattern of the crystal form I of the sulfate salt is substantially as shown in FIG. 6 , more preferably as shown in FIG. 6 .
  • the crystalline form I of the sulfate salt loses about 6.5% of its weight during heating to about 120 ⁇ 5°C (preferably about 120 ⁇ 2°C), and continues to heat to about 210 ⁇ 5°C (preferably A further weight loss of about 7.6% is obtained over the course of about 210 ⁇ 2° C., and decomposition may occur above about 210 ⁇ 5° C. (preferably about 210 ⁇ 2° C.), as measured using TGA.
  • the TGA spectrum of the crystal form I of the sulfate salt is substantially as shown in FIG. 7 , more preferably as shown in FIG. 7 .
  • the crystalline form I of the sulfate salt has two endothermic peaks, specifically, there is a very broad endothermic peak between about 25-120°C and about 120-210°C, which are respectively compared with TGA The weight loss phenomenon in the corresponding temperature range is consistent.
  • the DSC spectrum of the crystal form I of the sulfate salt is substantially as shown in FIG. 7 , more preferably as shown in FIG. 7 .
  • the NMR spectrum of the crystal form I of the sulfate salt is substantially as shown in (a) of FIG. 8 , preferably as shown in (a) of FIG. 8 .
  • a comparison of the NMR spectrum (a) with that of Compound I (b) shows a change in the peak at about 6.79 ppm, indicating that the sulfate sample tested is indeed a salt.
  • the present invention also provides crystalline form I of the mesylate salt of compound I having the following formula:
  • the XRPD pattern of Form I of the mesylate salt of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (° ).
  • the XRPD pattern of the crystalline form I of the mesylate salt of Compound 1 includes an XRPD pattern at about 4.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.0 ⁇ 0.2° and/or 27.8 ⁇ 0.2 The diffraction peak at the diffraction angle (2 ⁇ ) of °.
  • the XRPD pattern of the crystalline form I of the mesylate salt further comprises diffraction angles at about 14.8 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.2 ⁇ 0.2°, 27.2 ⁇ 0.2° and/or 30.7 ⁇ 0.2° ( Diffraction peaks at 2 ⁇ ).
  • the XRPD pattern of the crystalline form I of the mesylate salt further includes a temperature range of about 7.3 ⁇ 0.2°, 8.0 ⁇ 0.2°, 10.2 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.0 ⁇ 0.2°, 19.5 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.4 ⁇ 0.2°, 23.6 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.1 ⁇ 0.2°, 26.1 ⁇ 0.2°, 26.8 ⁇ 0.2°, 28.3 ⁇ 0.2°, Diffraction peaks at diffraction angles (2 ⁇ ) of 28.9 ⁇ 0.2°, 29.4 ⁇ 0.2°, 29.5 ⁇ 0.2°, 29.9 ⁇ 0.2°, 34.0 ⁇ 0.2° and/or 41.8 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form I of the mesylate salt is substantially as shown in FIG. 9 , more preferably as shown in FIG. 9 .
  • the crystalline form I of the mesylate salt loses about 19.0% of its weight when heated to about 100 ⁇ 5°C (preferably about 100 ⁇ 2°C), and loses about 19.0% at about 150 ⁇ 5°C (preferably about 150 ⁇ 2°C), decomposition may occur above, as measured using TGA.
  • the TGA spectrum of the crystalline form I of the mesylate salt is substantially as shown in FIG. 10 , more preferably as shown in FIG. 10 .
  • the DSC spectrum of the crystalline form I of the mesylate salt is substantially as shown in FIG. 10 , preferably as shown in FIG. 10 .
  • the crystalline form I of the mesylate salt has an endothermic peak corresponding to the TGA weight loss signal at about 84 ⁇ 5°C (preferably about 84 ⁇ 2°C); The thermal peak, combined with the onset of TGA and sustained weight loss, probably corresponds to a melting process accompanied by decomposition.
  • the NMR spectrum of the crystalline form I of the mesylate salt is substantially as shown in (a) of FIG. 11 , preferably as shown in (a) of FIG. 11 .
  • a comparison of (a) of the NMR spectrum with the NMR spectrum of methanesulfonic acid (b) and the NMR spectrum of compound I (c) shows a change in the peak at about 6.79 ppm, indicating that the mesylate salt sample tested It is indeed a salt, and the integral result shows that the molar ratio of compound 1 to methanesulfonic acid in the salt is 1:2.
  • the present invention also provides crystalline form I, crystalline form II and crystalline form III of the p-toluenesulfonate salt of compound I having the following formula:
  • the XRPD pattern of Form I of the p-toluenesulfonate salt of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ ( °).
  • the XRPD pattern of Form I of the p-toluenesulfonate salt of Compound I comprises a temperature range of about 5.6 ⁇ 0.2°, 15.1 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.0 ⁇ 0.2° and/or 22.8 ⁇ 0.2°
  • the diffraction peak at the diffraction angle (2 ⁇ ) of °
  • the XRPD pattern of the crystalline form I of the p-toluenesulfonate salt further includes diffraction angles (2 ⁇ ) at about 19.9 ⁇ 0.2°, 21.4 ⁇ 0.2°, 25.8 ⁇ 0.2° and/or 27.1 ⁇ 0.2° Diffraction peaks.
  • the XRPD pattern of the crystalline form I of p-toluenesulfonate further includes , 16.0 ⁇ 0.2°, 17.3 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.3 ⁇ 0.2°, 20.4 ⁇ 0.2°, 21.6 ⁇ 0.2°, 21.9 ⁇ 0.2°, 24.1 ⁇ 0.2° , 24.5 ⁇ 0.2°, 25.2 ⁇ 0.2°, 28.8 ⁇ 0.2°, 31.6 ⁇ 0.2°, 34.7 ⁇ 0.2° and/or 43.6 ⁇ 0.2° diffraction angle (2 ⁇ ) of the diffraction peaks.
  • the XRPD pattern of the crystalline form I of the p-toluenesulfonate salt is substantially as shown in FIG. 12 , more preferably as shown in FIG. 12 .
  • the crystalline form I of p-toluenesulfonate loses about 5.5% of its weight when heated to about 150 ⁇ 5°C (preferably about 150 ⁇ 2°C), and loses about 5.5% at about 200 ⁇ 5°C (preferably about 200 ⁇ 2°C) decomposition may occur as measured using TGA.
  • the TGA spectrum of the crystalline form I of p-toluenesulfonate is substantially as shown in Figure 13, more preferably as shown in Figure 13.
  • the DSC spectrum of the crystalline form I of the p-toluenesulfonate salt is substantially as shown in FIG. 13 , preferably as shown in FIG. 13 .
  • the crystalline form I of p-toluenesulfonate has a broad endothermic signal between about 25-100°C, which is consistent with the TGA weight loss signal, and has a melting endotherm at about 216 ⁇ 5°C (preferably about 216 ⁇ 2°C) peak.
  • the XRPD pattern of Form II of the p-toluenesulfonate salt of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ ( °).
  • the XRPD pattern of Form II of the p-toluenesulfonate salt of Compound I comprises an XRPD pattern at about 4.9 ⁇ 0.2°, 5.7 ⁇ 0.2°, 15.2 ⁇ 0.2°, 17.1 ⁇ 0.2° and/or 22.8 ⁇ 0.2° Diffraction peak at a diffraction angle (2 ⁇ ) of 0.2°.
  • the XRPD pattern of the crystalline form II of p-toluenesulfonate further comprises diffraction angles at about 11.4 ⁇ 0.2°, 17.4 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.4 ⁇ 0.2° and/or 28.7 ⁇ 0.2° Diffraction peak at (2 ⁇ ).
  • the XRPD pattern of the crystalline form II of the p-toluenesulfonate salt further includes , 24.6 ⁇ 0.2°, 29.9 ⁇ 0.2°, 30.6 ⁇ 0.2°, 31.7 ⁇ 0.2° and/or 40.0 ⁇ 0.2° diffraction angle (2 ⁇ ) of the diffraction peaks.
  • the XRPD pattern of the crystalline form II of the p-toluenesulfonate salt is substantially as shown in FIG. 14 , more preferably as shown in FIG. 14 .
  • the crystalline form II of the p-toluenesulfonate salt continues to lose weight during heating, and loses about 3.4% in the process of heating to about 128 ⁇ 5°C (preferably about 128 ⁇ 2°C). Decomposition may occur above 200 ⁇ 5°C, preferably about 200 ⁇ 2°C, as measured using TGA.
  • the TGA spectrum of the crystalline form II of p-toluenesulfonate is substantially as shown in Figure 15, more preferably as shown in Figure 15.
  • the DSC spectrum of the crystalline form II of the p-toluenesulfonate salt is substantially as shown in FIG. 15 , preferably as shown in FIG. 15 .
  • the crystalline form II of p-toluenesulfonate has a broad endothermic signal between about 25-100°C, which is consistent with the TGA weight loss signal, and has melting with decomposition at about 224 ⁇ 5°C (preferably about 224 ⁇ 2°C) signal of.
  • the NMR spectrum of the crystalline form II of the p-toluenesulfonate salt is substantially as shown in (a) of FIG. 16 , preferably as shown in (a) of FIG. 16 .
  • the comparison of (a) of the NMR spectrum with the NMR spectrum (b) of p-toluenesulfonic acid and the NMR spectrum (c) of compound I shows that the amino peak position of the crystal form II of the p-toluenesulfonic acid salt has a change, indicating that the The tested p-toluenesulfonic acid salt sample is indeed a salt, and the integral result shows that the molar ratio of compound I to p-toluenesulfonic acid in the salt is 1:1.5.
  • the XRPD pattern of the crystalline form II of the p-toluenesulfonate salt after the DVS test is consistent with that before the test, and there is no crystal form change.
  • the PLM image of Form II of the p-toluenesulfonate salt is substantially as shown in Figure 18, preferably as shown in Figure 18.
  • the crystalline form II of p-toluenesulfonate is a rod-shaped crystal, and the particle size is generally less than 20 ⁇ m.
  • the XRPD pattern of Form III of the p-toluenesulfonate salt of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ ( °).
  • the XRPD pattern of Form III of the p-toluenesulfonate salt of Compound I comprises diffraction angles at about 3.6 ⁇ 0.2°, 7.2 ⁇ 0.2°, 20.4 ⁇ 0.2°, and/or 25.7 ⁇ 0.2° Diffraction peak at (2 ⁇ ).
  • the XRPD pattern of the crystalline form III of p-toluenesulfonate further comprises Diffraction peak at a diffraction angle (2 ⁇ ) of 0.2°.
  • the XRPD pattern of the p-toluenesulfonate salt crystal form III also includes at about 5.0 ⁇ 0.2°, 13.1 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.7 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.8 ⁇ 0.2° , 22.0 ⁇ 0.2° and/or 28.8 ⁇ 0.2° diffraction angle (2 ⁇ ) diffraction peaks.
  • the XRPD pattern of the crystalline form III of the p-toluenesulfonate salt is substantially as shown in FIG. 19 , more preferably as shown in FIG. 19 .
  • the present invention also provides crystalline form I and crystalline form II of the sodium salt of compound I having the following formula:
  • the XRPD pattern of Form I of the sodium salt of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form I of the sodium salt of Compound 1 comprises diffraction angles (2 ⁇ ) at about 8.8 ⁇ 0.2°, 17.9 ⁇ 0.2°, 27.1 ⁇ 0.2°, and/or 26.9 ⁇ 0.2° diffraction peaks at .
  • the XRPD pattern of the crystalline form I of the sodium salt further comprises a diffraction angle (2 ⁇ ) at about 16.8 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.7 ⁇ 0.2°, 28.0 ⁇ 0.2° and/or 30.9 ⁇ 0.2° diffraction peaks at .
  • the XRPD pattern of the crystalline form I of the sodium salt also includes a range at about 12.5 ⁇ 0.2°, 19.1 ⁇ 0.2°, 20.0 ⁇ 0.2°, 24.7 ⁇ 0.2°, 25.2 ⁇ 0.2°, 27.6 ⁇ 0.2°, 31.6 ⁇ Diffraction peaks at diffraction angles (2 ⁇ ) of 0.2°, 32.2 ⁇ 0.2° and/or 36.0 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form I of the sodium salt is substantially as shown in FIG. 20 , more preferably as shown in FIG. 20 .
  • the crystalline form I of the sodium salt continues to lose weight during heating, and loses about 6.1% of its weight during heating to about 120 ⁇ 5°C (preferably about 120 ⁇ 2°C). Decomposition may occur above (preferably about 200 ⁇ 2°C) as measured using TGA.
  • the TGA spectrum of the crystalline form I of the sodium salt is substantially as shown in FIG. 21 , more preferably as shown in FIG. 21 .
  • the DSC spectrum of the crystalline form I of the sodium salt is substantially as shown in FIG. 21 , preferably as shown in FIG. 21 .
  • the crystalline form I of the sodium salt has a broad endothermic signal at about 25-127°C, consistent with the TGA weight loss signal, and has an endothermic peak at about 150 ⁇ 5°C (preferably about 150 ⁇ 2°C).
  • the XRPD pattern of Form II of the sodium salt of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form II of the sodium salt of Compound I comprises diffraction angles (2 ⁇ ) at about 12.2 ⁇ 0.2°, 14.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, and/or 23.3 ⁇ 0.2° diffraction peaks at .
  • the XRPD pattern of the crystalline form II of the sodium salt further comprises a diffraction angle (2 ⁇ ) at about 7.0 ⁇ 0.2°, 17.9 ⁇ 0.2°, 33.2 ⁇ 0.2°, 21.8 ⁇ 0.2° and/or 22.6 ⁇ 0.2° diffraction peaks at .
  • the XRPD pattern of the crystalline form II of the sodium salt also includes a temperature range of about 16.2 ⁇ 0.2°, 18.4 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.3 ⁇ 0.2°, 24.0 ⁇ 0.2°, 24.5 ⁇ 0.2°, 25.4 ⁇ 0.2°, 25.7 ⁇ 0.2°, 27.9 ⁇ 0.2°, 28.4 ⁇ 0.2°, 28.7 ⁇ 0.2°, 29.3 ⁇ 0.2°, 30.1 ⁇ 0.2°, 30.7 ⁇ 0.2°, 33.0 ⁇ 0.2° and/or Diffraction peak at a diffraction angle (2 ⁇ ) of 40.3 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form II of the sodium salt is substantially as shown in FIG. 22 , more preferably as shown in FIG. 22 .
  • the crystalline form II of the sodium salt continues to lose weight during the heating process, and loses about 4.2% in the process of heating to about 100 ⁇ 5°C (preferably about 100 ⁇ 2°C), and continues to heat to about 200 Weight loss of about 3.4% over the course of ⁇ 5°C (preferably about 200 ⁇ 2°C), decomposition may occur above 220 ⁇ 5°C (preferably about 220 ⁇ 2°C), as measured using TGA.
  • the TGA spectrum of the crystalline form II of the sodium salt is substantially as shown in FIG. 23 , more preferably as shown in FIG. 23 .
  • the DSC spectrum of the crystalline form II of the sodium salt is substantially as shown in FIG. 23 , preferably as shown in FIG. 23 .
  • the crystalline form II of the sodium salt has a broad endothermic peak at about 25-100°C and about 100-200°C respectively, which coincides with the TGA weight loss signal.
  • the NMR spectrum of the crystalline form II of the sodium salt is substantially as shown in (a) of FIG. 24 , preferably as shown in (a) of FIG. 24 .
  • the comparison of the NMR spectrum (a) and the NMR spectrum (b) of compound I shows that there is a significant shift in the peak position at about 4.4-4.5ppm, indicating that the tested sodium salt sample is indeed a salt.
  • the present invention also provides crystalline form I of the ethanolamine salt of compound I having the following formula:
  • the XRPD pattern of Form I of the ethanolamine salt of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form I of the ethanolamine salt of Compound 1 comprises diffraction angles (2 ⁇ ) at about 10.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 23.6 ⁇ 0.2°, and/or 28.2 ⁇ 0.2° diffraction peaks at .
  • the XRPD pattern of the crystalline form I of the ethanolamine salt further comprises a diffraction angle (2 ⁇ ) at about 9.9 ⁇ 0.2°, 20.0 ⁇ 0.2°, 22.8 ⁇ 0.2°, 24.5 ⁇ 0.2° and/or 29.8 ⁇ 0.2° diffraction peaks at .
  • the XRPD pattern of the crystal form I of the ethanolamine salt further includes Diffraction peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 24.9 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.6 ⁇ 0.2°, 28.8 ⁇ 0.2°, 34.8 ⁇ 0.2° and/or 35.9 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form I of the ethanolamine salt is substantially as shown in Figure 25, more preferably as shown in Figure 25;
  • the crystalline form I of the ethanolamine salt continues to lose weight during the heating process, and loses about 3.9% in the process of heating to about 100 ⁇ 5°C (preferably about 100 ⁇ 2°C), Above about 160 ⁇ 2° C.), decomposition may occur as measured using TGA.
  • the TGA spectrum of the crystalline form I of the ethanolamine salt is substantially as shown in FIG. 26 , more preferably as shown in FIG. 26 .
  • the crystalline form I of the ethanolamine salt has a broad endothermic signal at about 25-100°C, which is consistent with the TGA weight loss signal, and has a broad endothermic signal at about 209 ⁇ 5°C (preferably about 209 ⁇ 2°C). Endothermic melting peak.
  • the DSC spectrum of the crystalline form I of the ethanolamine salt is substantially as shown in FIG. 26 , more preferably as shown in FIG. 26 .
  • the NMR spectrum of the crystalline form I of the ethanolamine salt is substantially as shown in (a) of FIG. 27 , preferably as shown in (a) of FIG. 27 .
  • the comparison of (a) of the NMR spectrum with the NMR spectrum (b) of ethanolamine and the NMR spectrum (c) of Compound I shows that the peak positions at about 2.5-4.5ppm are significantly shifted, at about 2.8ppm and about 3.5ppm The characteristic peak of ethanolamine can be seen at ppm, indicating that the measured ethanolamine salt sample is indeed a salt.
  • the XRPD pattern of the crystalline form I of the ethanolamine salt after the DVS test is consistent with that before the test, and there is no crystal form change.
  • the PLM image of the crystalline form I of the ethanolamine salt is substantially as shown in Figure 29, preferably as shown in Figure 29.
  • the crystal form I of the ethanolamine salt is a rod-shaped crystal, and the particle size is generally less than 20 ⁇ m.
  • the XRPD pattern of Form A of Compound I exhibits at least two, at least three, at least four, at least five, or at least six diffraction angles 2 ⁇ (°) at maximum intensity.
  • the XRPD pattern of Form A of Compound I includes diffraction at diffraction angles (2 ⁇ ) of about 6.7 ⁇ 0.2°, 18.2 ⁇ 0.2°, 27.4 ⁇ 0.2°, and/or 28.2 ⁇ 0.2° peak.
  • the XRPD pattern of the crystal form A further includes diffraction at a diffraction angle (2 ⁇ ) of about 16.9 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.0 ⁇ 0.2° and/or 21.8 ⁇ 0.2° peak.
  • the XRPD pattern of the crystalline form A also includes a temperature at about 14.0 ⁇ 0.2°, 15.1 ⁇ 0.2°, 17.3 ⁇ 0.2°, 19.1 ⁇ 0.2°, 19.7 ⁇ 0.2°, 20.5 ⁇ 0.2°, 22.4 ⁇ 0.2° , 23.1 ⁇ 0.2°, 24.4 ⁇ 0.2°, 24.8 ⁇ 0.2°, 26.9 ⁇ 0.2°, 28.5 ⁇ 0.2°, 29.2 ⁇ 0.2°, 30.6 ⁇ 0.2°, 30.8 ⁇ 0.2°, 32.8 ⁇ 0.2°, 33.5 ⁇ 0.2° , 34.2 ⁇ 0.2°, 41.2 ⁇ 0.2° and/or 43.5 ⁇ 0.2° diffraction angles (2 ⁇ ) of the diffraction peaks.
  • the XRPD pattern of the crystalline form A is substantially as shown in FIG. 30 , more preferably as shown in FIG. 30 .
  • the onset temperature of the endothermic peak of the crystalline form A is about 185 ⁇ 5°C, preferably about 185 ⁇ 2°C.
  • the DSC spectrum of the crystal form A is substantially as shown in FIG. 31 , more preferably as shown in FIG. 31 .
  • the crystal form A loses about 2.24% of its weight when heated to about 100 ⁇ 5°C (preferably about 100 ⁇ 2°C), and may Decomposition started, as measured using TGA.
  • the TGA spectrum of the crystal form A is substantially as shown in FIG. 31 , more preferably as shown in FIG. 31 .
  • the NMR spectrum of Form A is substantially as shown in Figure 32, preferably as shown in Figure 32.
  • the NMR spectrum shows no obvious organic solvent characteristic peaks.
  • the Form A is not a solvate, more preferably an anhydrate.
  • the PLM image of Form A is substantially as shown in Figure 34, preferably as shown in Figure 34.
  • the crystalline form A is tabular particles, the particle size of which is generally less than about 20 ⁇ m.
  • the present invention provides a process for the preparation of a crystalline form of the salt of Compound I as described above, said process comprising:
  • An antisolvent is added to the resulting suspension for crystallization, and crystals obtained by solid-liquid separation (for example, by centrifugation) are dried to obtain the crystal form.
  • the Compound I is Form A of Compound I.
  • the acidic compounds include, but are not limited to, hydrochloric acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the alkaline compound includes but not limited to sodium hydroxide, sodium isooctanoate or other alkaline sodium reagents (such as sodium isocaproate, sodium isovalerate), ethanolamine.
  • the solvent includes water, ethyl acetate, tetrahydrofuran, methanol and a combination of two or more thereof.
  • the present invention provides a method for the preparation of Form I of the hydrochloride salt as described above, the method comprising:
  • the Compound I is Form A of Compound I.
  • the solution containing hydrogen chloride is dilute hydrochloric acid.
  • the present invention provides a method for the preparation of crystalline form I of the sulfate salt described above, the method comprising:
  • the Compound I is Form A of Compound I.
  • the solution containing sulfuric acid is dilute aqueous sulfuric acid.
  • the present invention provides a process for the preparation of Form I of the p-toluenesulfonate salt described above, the process comprising:
  • the Compound I is Form A of Compound I.
  • the p-toluenesulfonic acid can be added by itself, or in the form of a solution in a suitable solvent.
  • the present invention provides a process for the preparation of Form II of the p-toluenesulfonate salt described above, the process comprising:
  • the Compound I is Form A of Compound I.
  • the p-toluenesulfonic acid can be added by itself, or in the form of a solution in a suitable solvent.
  • the present invention provides a method for preparing Form I of the mesylate salt described above, the method comprising:
  • the Compound I is Form A of Compound I.
  • the methanesulfonic acid can be added by itself or as a solution in a suitable solvent.
  • the present invention provides a method for preparing Form I of the sodium salt described above, the method comprising:
  • Compound I shown is Form A of Compound I.
  • the sodium hydroxide may be added by itself, or in the form of a solution in a suitable solvent.
  • the present invention provides a method for preparing the crystalline form II of the sodium salt described above, the method comprising:
  • the Compound I is Form A of Compound I.
  • the sodium isooctanoate or other basic sodium reagent can be added as such, or as a solution in a suitable solvent.
  • the other basic sodium reagents include, but are not limited to, sodium isocaproate and sodium isovalerate.
  • the present invention provides a method for preparing the crystalline form I of the ethanolamine salt described above, the method comprising:
  • Compound I shown is Form A of Compound I.
  • the ethanolamine can be added by itself or as a solution in a suitable solvent.
  • the present invention provides a method for the preparation of Form A described above, the method comprising:
  • a1) providing a suspension of Compound I in a suitable solvent, preferably the content of Compound I in said suspension is about 1-200 mg/ml;
  • the suitable solvent is selected from DMF, DMSO, methanol, ethanol, n-propanol, isopropanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate Esters, ethyl formate, butyl formate, n-heptane, cyclohexane, dioxane, diethyl ether, methyl tert-butyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, water, acetonitrile, toluene , dichloromethane, chloroform, tetrahydrofuran and mixtures thereof.
  • the stirring at room temperature in step a2), lasts for about 3-7 days.
  • the stirring at room temperature in a pilot experiment, the stirring at room temperature lasts for about 7 days; in scale-up production, the stirring at room temperature lasts for about 3 days.
  • the present invention provides a method for preparing the free form A, the method comprising:
  • step b2) adding an appropriate acid to the filtrate obtained in step b1), to precipitate a solid to obtain the crystal form A;
  • the good solvent is water, isopropyl ether, n-heptane or toluene, more preferably water.
  • the base is ethanolamine.
  • the acid is hydrochloric acid, sulfuric acid or phosphoric acid.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of crystalline form I of hydrochloride, crystalline form I of sulfate, crystalline form I of p-toluenesulfonate, p-toluenesulfonate, p- Any of the crystalline form II of the tosylate salt, the crystalline form I of the mesylate salt, the crystalline form I of the sodium salt, the crystalline form II of the sodium salt, the crystalline form I of the ethanolamine salt, and the crystalline form A of the compound I and one or more pharmaceutically acceptable carriers.
  • the present invention provides crystalline form I of hydrochloride, crystalline form I of sulfate, crystalline form I of p-toluenesulfonate, crystalline form II of p-toluenesulfonate, methanesulfonate as described above
  • the present invention provides crystalline form I of hydrochloride, crystalline form I of sulfate, crystalline form I of p-toluenesulfonate, crystalline form II of p-toluenesulfonate, methanesulfonate as described above
  • Any one of the crystal form I of salt salt, the crystal form I of sodium salt, the crystal form II of sodium salt, the crystal form I of ethanolamine salt and the crystal form A of compound I or the pharmaceutical composition is used in the preparation of kidney Use in a drug for functional monitoring ("tracer"), wherein said renal function monitoring is GFR monitoring, in particular real-time GFR monitoring.
  • the present invention provides a method for renal function monitoring in an individual, said method comprising administering to said individual an effective amount of crystalline form I of the hydrochloride salt, crystalline form I of the sulfate salt, Crystal form I of p-toluenesulfonate salt, crystal form II of p-toluenesulfonate salt, crystal form I of mesylate salt, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt and Any one of the crystal forms A of Compound I or the pharmaceutical composition, wherein the renal function monitoring is GFR monitoring, especially real-time GFR monitoring.
  • the crystal form I of the hydrochloride, the crystal form I of the sulfate salt, the crystal form I of the p-toluenesulfonate salt, the crystal form II of the p-toluenesulfonate salt, the crystal form I of the mesylate salt, and the crystal form of the sodium salt Form I, crystalline form II of sodium salt, crystalline form I of ethanolamine salt, and crystalline form A of compound I, or the pharmaceutical composition or drug can be administered by various routes, including but not limited to oral, parenteral, transdermal, Administration is subcutaneous, enteral or intravenous.
  • Compound I forms stable salts with hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, sodium hydroxide, ethanolamine, and the like.
  • the crystal form A of compound I in the free state, the crystal form I of its hydrochloride, the crystal form II of p-toluenesulfonate, and the crystal form I of ethanolamine salt have good properties in terms of solid state stability and dynamic solubility.
  • the crystal form I of ethanolamine salt has better solubility and can meet the requirements of oral administration and other routes of administration.
  • the crystal form A of compound I in the free state has advantages in stability under conditions of light, high temperature and high humidity, and can meet the pharmaceutical requirements for production, transportation and storage.
  • the production process is stable, repeatable and controllable, and can be adapted to industrial production.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • 1 H NMR nuclear magnetic resonance
  • PLM polarized light microscope analysis
  • Samples were analyzed with an X-ray powder diffractometer Bruker D8 Advance (Bruker, GER).
  • the scanning 2 ⁇ range is from 3° to 45° (Cu-K ⁇ (K ⁇ 1 1.5406)), the scan step size is 0.02°, and the exposure time is 0.2 seconds (for the crystal forms of various salts) or 0.12 seconds (for the crystal form A of the compound I in the free state).
  • the light tube voltage and current of the test sample are 40kV and 40mA respectively, and the sample disk is a zero background sample disk.
  • thermogravimetric analyzer TA Discovery 55 (TA, US) was used. 2 to 5 mg of sample is placed in a balanced open aluminum sample pan and automatically weighed in a TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, the nitrogen purging rate at the sample was 60 ml/min, and the nitrogen purging rate at the balance was 40 ml/min.
  • a differential scanning calorimeter TA Discovery 2500 (TA, US) was used. 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan, heated to the final temperature at a rate of 10°C/min, and the nitrogen purging rate in the furnace was 50ml/min.
  • Polarizing microscope Motic BA310Met (Motic, CN) was used. Place a small amount of sample on a glass slide, and select a suitable lens to observe the shape of the sample.
  • Dynamic moisture sorption analysis was performed using DVSIntrinsic (SMS, UK). The test adopts the gradient mode, the humidity change is 50%-95%-0%-50%, the humidity change of each gradient is 10% within the range of 0% to 90%, and the gradient end point is judged by the dm/dt method. dm/dt is less than 0.002% and maintained for 10 minutes as the end point of the gradient. After the test is complete, XRPD analysis is performed on the sample to confirm whether the solid form has changed.
  • the solution without solid precipitation in the solution suspension method was placed in a refrigerator at 5°C or -15°C to cool for 1 day, and the solution with solid precipitation was centrifuged to separate the solid and dried in vacuum at room temperature.
  • the anti-solvent methyl tert-butyl ether was added dropwise at room temperature until a small amount of turbidity was generated and stirred overnight, and then the solution with solid precipitation was centrifuged to separate the solid and vacuum at room temperature dry.
  • the XRPD spectrum of the crystal form I of the hydrochloride salt is shown in Figure 1; the XRPD spectrum of the crystal form I of the sulfate salt is shown in Figure 6; the XRPD spectrum of the crystal form I of the mesylate salt is shown in Figure 9
  • the XRPD spectrum of the crystal form I of p-toluenesulfonate is shown in Figure 12; the XRPD spectrum of the crystal form I of the sodium salt is shown in Figure 20; the XRPD spectrum of the crystal form II of the sodium salt is shown in Figure 22; ethanolamine
  • the XRPD pattern of Form I of the salt is shown in FIG. 25 .
  • Embodiment 2 the preparation of the crystal form I of the hydrochloride of compound I
  • XRPD results showed that the crystal form I of the hydrochloride was a crystal with relatively high crystallinity.
  • the TGA results are shown in Figure 2, showing that the crystal form I of the hydrochloride salt has a weight loss step of about 4.0% in the process of heating to about 130°C, and a weight loss of about 8.2% in the process of 130-200°C; after 200°C Vigorous weight loss, indicating possible decomposition.
  • the DSC results are shown in Figure 2, showing that the crystal form I of hydrochloride has endothermic signals at about 90°C and about 195°C, which are consistent with the weight loss signal of TGA; there is a signal of melting with decomposition at about 212°C.
  • the NMR results are shown in Figure 3, showing that the amino peak position of the hydrochloride has changed, indicating that the tested sample is indeed a salt; there is a broad signal at 4.0-5.0ppm, indicating that the sample contains water.
  • the ion chromatography test results showed that the chloride ion content of the sample was 6.52%, indicating that the molar ratio of compound 1 and HCl in the salt was 1:1.
  • the XRPD pattern of the sample after the DVS test is consistent with that before the test, and there is no crystal form change.
  • Microscope image as shown in Figure 5 shows that the crystalline form I particle of hydrochloride is smaller, and agglomeration phenomenon is obvious.
  • the crystal form I of hydrochloride may be an anhydrate or a hydrate containing adsorbed water.
  • the obtained crystal form I of ethanolamine salt was characterized by XRPD, DSC, TGA, NMR, DVS, and PLM.
  • the TGA results are shown in Figure 26, which shows that the crystalline form I of ethanolamine salt continues to lose weight during the heating process, and the weight loss is about 3.9% in the process of heating to 100°C, and decomposition may occur above 160°C.
  • the DSC results are shown in Figure 26, showing that the crystal form I of ethanolamine salt has a broad endothermic signal between 25-100°C, which is consistent with the TGA weight loss signal; there is an endothermic melting peak at about 209°C.
  • the NMR results are shown in Figure 27, showing that there is a significant shift in the peak position at 2.5-4.5ppm, and the characteristic peaks of ethanolamine can be seen at 2.8ppm and 3.5ppm, indicating that the measured sample is indeed a salt, and the integration results show that the salt
  • the molar ratio of compound to ethanolamine is 1:2; there is a broad signal at about 3.3ppm, which may correspond to the water in the sample.
  • the XRPD pattern of the sample after the DVS test is generally consistent with that before the test.
  • the microscope image is shown in Figure 29, which shows that the crystalline form I particles of ethanolamine salt are smaller and the agglomeration phenomenon is obvious. Based on the above information, the crystal form I of ethanolamine salt may be an anhydrous substance containing adsorbed water.
  • Form A of compound I (532.1mg), p-toluenesulfonic acid (568.2mg) and tetrahydrofuran (56mL) were mixed, stirred at room temperature for 3 days, centrifuged, and the obtained solid was vacuum-dried at room temperature to obtain a yellow powder solid (630mg) .
  • the XRPD pattern is substantially as shown in Figure 14, indicating that the solid is Form II of the p-toluenesulfonate salt.
  • XRPD results showed that the crystalline form II of p-toluenesulfonate was a crystal with higher crystallinity.
  • the TGA results are shown in Figure 15, showing that the crystalline form II of p-toluenesulfonate continues to lose weight during heating, and loses about 3.4% in the process of heating to 128°C, and may decompose above 200°C.
  • the DSC results are shown in Figure 15, showing that the crystal form II of p-toluenesulfonate has a broad endothermic signal between 25-100°C, which is consistent with the TGA weight loss signal; there is a signal of melting with decomposition at 224°C.
  • the NMR results are shown in Figure 16, showing that the amino peak position of the crystal form II of the p-toluenesulfonate salt has changed, indicating that the sample tested is indeed a salt, and the integral result is the mole of compound 1 and p-toluenesulfonic acid in the salt.
  • the ratio is 1:1.5; there is a broad signal at about 5ppm, probably corresponding to the water in the sample.
  • the XRPD pattern of the sample after the DVS test is generally consistent with that before the test.
  • the microscope image is shown in Figure 18, which shows that the crystalline form II particles of p-toluenesulfonate are rod-shaped crystals with a small particle size and agglomeration.
  • the crystalline form II of p-toluenesulfonate may be an anhydrous substance containing adsorbed water.
  • FaSSIF is a simulated intestinal fluid in a fasting state, which is prepared as follows: (1) Weigh 0.042g sodium hydroxide, 0.3438g sodium dihydrogen phosphate and 0.6186g sodium chloride, add 90mL of purified water and mix well, then wash with 1N hydrochloric acid or 1N Adjust the pH to 6.5 with sodium hydroxide, and dilute to 100mL with purified water; (2) Take 50mL of the buffer solution prepared in (1) above, add 0.224g of FaSSIF/FeSSIF/FaSSGF commercially available powder (Biorelevant.com) , stir until dissolved, and then dilute to 100 mL with the buffer prepared in (1). Place the prepared buffer solution at room temperature, and observe that the buffer solution is slightly milky white after standing for two hours, and it can be used immediately.
  • FeSSIF is a simulated intestinal juice in a fed state, which is prepared as follows: (1) Weigh 0.404g sodium hydroxide, 0.865g glacial acetic acid and 1.1874g sodium chloride, add 90mL of pure water and mix well, then oxidize with 1N hydrochloric acid or 1N hydroxide Adjust the pH to 5.0 with sodium, and dilute to 100 mL with purified water; (2) Take 50 mL of the buffer solution prepared in (1) above, add 1.12 g of FaSSIF/FeSSIF/FaSSGF commercially available powder (Biorelevant.com), and stir Until dissolved, then dilute to 100mL with the buffer solution prepared in (1). Place the prepared buffer solution at room temperature, and observe that the buffer solution is a transparent liquid after standing for two hours, and it can be used immediately.
  • SGF FaSSGF
  • solubility value is calculated based on the free compound I, calculated according to the standard curve of the free compound I.
  • the crystal form I of hydrochloride, the crystal form II of p-toluenesulfonate, the crystal form I of ethanolamine salt and the crystal form A of free compound I all have good properties in FaSSIF, FeSSIF and FaSSGF.
  • Solubility, especially the crystal form I of the ethanolamine salt can therefore have a considerable dissolution advantage in the prepared preparation, which is beneficial to the dissolution and bioavailability under different biological media conditions during application.

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Abstract

3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪(化合物I)及其盐的晶型及制备方法，具体地涉及8种盐型晶型：盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II和乙醇胺盐的晶型I及其制备方法。盐酸盐的晶型I、对甲苯磺酸盐的晶型II、乙醇胺盐的晶型I在固态稳定性和动态溶解度等方面具有良好的性质，乙醇胺盐的晶型I具有较好的溶解度，能够满足口服等给药途径的要求。

Description

吡嗪类衍生物的盐的晶型及其制备方法 技术领域
本发明涉及化合物3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪及其盐的晶型及制备方法。
背景技术
3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪，是一种具有优异的光物理性质和其他化学和物理特性的荧光化合物。如专利US 8,155,000、US 8,664,392、US 8,697,033、US 8,722,685、US 8,778,309、US 9,005,581、US 9,114,160、US 9,283,288、US 9,376,399和US 9,480,687所公开的，该化合物已知用于肾功能监测。3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪正在被开发作为用于实时肾小球滤过率(GFR)测定的荧光剂。当在434nm激发时，它在556nm处发出强荧光信号。目前人体临床研究正在进行中。值得注意的是，可以经皮实时测量在患者血流中3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪的清除速率，从而换算得到患者的肾小球滤过率。
药用活性成分的晶型结构往往影响到药物的化学稳定性。结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。同一种药物的不同晶型的生物利用度也可能会存在差别；另外，其稳定性、流动性、可压缩性也可能会不同，这些理化性质对药物的应用产生一定的影响，从而影响药物的疗效。
尚未发现公开3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪及其盐的晶型的报道。为了满足3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪制剂开发所选用的原料形态，同时满足工业化生产过程中结晶工艺的重现性和可控性，满足生产、运输、储存的药用要求，需要开发3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪及其盐的晶型及相应的适用于工业化生产的制备方法。
发明内容
本发明的第一方面提供3,6-二氨基-2,5-双{N-[(1R)-1-羧基-2-羟基乙基]氨基甲酰基}吡嗪(在下文中称作“化合物I”)及其如下文所述的盐的晶型：
Figure PCTCN2022130227-appb-000001
包括盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I或化合物I的晶型A。所述晶型能同时满足工业化生产过程中结晶工艺的重现性和可控性，在固态稳定性 和动态溶解度等方面具有良好的性质。
本发明的第二方面提供所述盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I或化合物I的晶型A的制备方法。
本发明的第三方面提供药物组合物，其包含有效量的选自所述盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I或化合物I的晶型A中的任一种以及一种或多种药学上可接受的载体。
本发明的第四方面提供所述盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I或化合物I的晶型A中的任一种或所述药物组合物，其用于肾功能监测，其中所述肾功能监测是GFR监测，特别是实时GFR监测。
本发明的第五方面提供所述盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I或化合物I的晶型A中的任一种或所述药物组合物在制备用于肾功能监测的药物中的用途，其中所述肾功能监测是GFR监测，特别是实时GFR监测。
本发明的第六方面提供用于个体的肾功能监测的方法，所述方法包括向所述个体施用有效量的所述盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I或化合物I的晶型A中的任一种或所述药物组合物，其中所述肾功能监测是GFR监测，特别是实时GFR监测。
本发明的第七方面提供制备上文所述的化合物I的盐的晶型的方法，所述方法包括使化合物I与适当的酸性/碱性化合物在适当的溶剂中形成所述晶型。
附图说明
图1：化合物I的盐酸盐的晶型I的XRPD图谱。
图2：化合物I的盐酸盐的晶型I的热重量分析(TGA)图谱和差示扫描量热(DSC)图谱。
图3：化合物I的盐酸盐的晶型I与化合物I的晶型A的 1H NMR图谱。
图4：化合物I的盐酸盐的晶型I在动态水分吸附(DVS)测试前后的XRPD图谱。
图5：化合物I的盐酸盐的晶型I的PLM图像。
图6：化合物I的硫酸盐的晶型I的XRPD图谱。
图7：化合物I的硫酸盐的晶型I的TGA和DSC图谱。
图8：化合物I的硫酸盐的晶型I与化合物I的晶型A的 1H NMR图谱。
图9：化合物I的甲磺酸盐的晶型I的XRPD图谱。
图10：化合物I的甲磺酸盐的晶型I的TGA和DSC图谱。
图11：化合物I的甲磺酸盐的晶型I与化合物I的晶型A的 1H NMR图谱。
图12：化合物I的对甲苯磺酸盐的晶型I的XRPD图谱。
图13：化合物I的对甲苯磺酸盐的晶型I的TGA和DSC图谱。
图14：化合物I的对甲苯磺酸盐的晶型II的XRPD图谱。
图15：化合物I的对甲苯磺酸盐的晶型II的TGA和DSC图谱。
图16：化合物I的对甲苯磺酸盐的晶型II与化合物I的晶型A的 1H NMR图谱。
图17：化合物I的对甲苯磺酸盐的晶型II在DVS测试前后的XRPD图谱。
图18：化合物I的对甲苯磺酸盐的晶型II的PLM图像。
图19：化合物I的对甲苯磺酸盐的晶型III的XRPD图谱。
图20：化合物I的钠盐的晶型I的XRPD图谱。
图21：化合物I的钠盐的晶型I的TGA和DSC图谱。
图22：化合物I的钠盐的晶型II的XRPD图谱。
图23：化合物I的钠盐的晶型II的TGA和DSC图谱。
图24：化合物I的钠盐的晶型II与化合物I的晶型A的 1H NMR图谱。
图25：化合物I的乙醇胺盐的晶型I的XRPD图谱。
图26：化合物I的乙醇胺盐的晶型I的TGA和DSC图谱。
图27：化合物I的乙醇胺盐的晶型I与化合物I的晶型A的 1H NMR图谱。
图28：化合物I的乙醇胺盐的晶型I在DVS测试前后的XRPD图谱。
图29：化合物I的乙醇胺盐的晶型I的PLM图像。
图30：化合物I的晶型A的XRPD图谱。
图31：化合物I的晶型A的TGA和DSC图谱。
图32：化合物I的晶型A的 1H NMR图谱。
图33：化合物I的晶型A的PLM图像。
具体实施方式
以下对本发明进一步解释说明，应理解，所述用语旨在描述目的，而非限制本发明。
定义
除非另有说明，本文使用的所有技术术语和科学术语均具有与本发明所属领域技术人员通常所理解的相同的含义。若存在矛盾，则以本文中的定义为准。当以范围、优选范围或者优选的数值上限及优选的数值下限的形式表述某个量、浓度或其他值或参数时，应当理解相当于具体揭示了通过将任意一对范围上限或优选数值与任意范围下限或优选数值结合起来的任何范围。除非另有说明，本文所列出的数值范围旨在包括范围的端点和该范围内的所有整数和分数(小数)。
术语“约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±20％、±10％、±5％或±2％的范围内。
如本文中，在描述XRPD衍射角时所使用的术语“约”是指本领域的普通技术人员认为在所述值的可接受的标准误差内，例如±0.05、±0.1、±0.2、±0.3、±1、±2或±3等。
术语“包含”或与其同义的类似表述“包括”、“含有”和“具有”等是开放性的，不排除额外的未列举的元素、步骤或成分。表述“由……组成”排除未指明的任何元素、步骤或成分。术语“基本上由……组成”指范围限制在指定的元素、步骤或成分，加上任选存在的不会实质上影响所要求保护的主题的基本和新的特征的元素、步骤或成分。应当理解，术语“包含”、“包括”及类似术语涵盖术语“基本上由……组成”和“由……组成”。
本文所使用的术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不 发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
除非另有说明，本文的百分比、份数等都按重量计。
如本文中所使用，术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定形固体物质相反，其产生具有边界清楚的峰的特征性XRPD图谱。
如本文中所使用，术语“X射线粉末衍射图谱”或“XRPD图谱”是指实验观察的衍射图或源于其的参数、数据或值。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。
如本文中所使用，术语“衍射角”或“2θ”是指基于X射线衍射实验中设置的以度数(°)表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶型的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。例如，如本文所述，使用Cu-Kα(Kα1
Figure PCTCN2022130227-appb-000002
1.5406)单色辐射。本文中的XRPD图谱优选在Bruker D8 Advance(Bruker，GER)X射线粉末衍射分析仪上采集，透射模式优选在Bruker D8 Advance(Bruker，GER)X射线粉末衍射分析仪上采集。
如本文中所使用，对于X射线衍射峰的术语“基本上相同”或“基本上如图×所示”意指将代表性峰位和强度变化考虑在内。例如，本领域技术人员会理解峰位(2θ)会显示一些变化，通常多达0.1至0.2度，并且用于测量衍射的仪器也会导致一些变化。另外，本领域技术人员会理解相对峰强度会因仪器间的差异以及结晶性程度、择优取向、制备的样品表面以及本领域技术人员已知的其它因素而出现变化。
类似地，如本文中所使用，对于DSC图谱和TGA图谱所述的“基本上如图×所示”也意图涵盖本领域技术人员已知的与这些分析技术有关的变化。例如，对于DSC图谱中边界清楚的峰，通常会具有多达±0.2℃的变化，对于宽峰甚至更大(例如多达±1℃)。
本申请中的核磁谱图优选在Bruker AVANCE-III(Bruker,GER)核磁共振仪上采集，除非另外说明，以DMSO-d6作为溶剂。
本申请中的偏光显微数据优选通过Motic BA310Met(Motic，CN)偏光显微镜进行采集。
如本文中所使用，术语“良溶剂”意指在其中化合物I能够溶解或具有相对更高的溶解度的溶剂。如本文中所使用，术语“反溶剂”意指在其中化合物I不或基本上不溶或者具有相对更低的溶解度的溶剂。在本文中，术语“良溶剂”和“反溶剂”也可以是相对而言的，不表示化合物I在其中的绝对溶解性。同一溶剂在某些情况下可以作为良溶剂，在其他情况下可以作为反溶剂。例如，水或甲苯在某些情况下，例如在单独用来溶解化合物I时，可以作为良溶剂，但在某些情况下，例如在与DMF配合使用时，可以作为反溶剂。
如本文中所使用的数值范围(如“1至10个”)及其子范围(如“2至10个”、“2至6个”、“3至10个”)等涵盖所述数值范围中的任意个(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个)。
如本文中所使用，术语“室温”是指20℃±5℃。
化合物I的盐的晶型
在第一方面，本发明提供化合物I的盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I和游离态的化合物I的晶型A。
盐酸盐的晶型I
本发明提供具有下式的化合物I的盐酸盐的晶型I：
Figure PCTCN2022130227-appb-000003
在一些实施方案中，所述化合物I的盐酸盐的晶型I的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的盐酸盐的晶型I的XRPD图谱包括在约7.6±0.2°、20.4±0.2°、22.5±0.2°和/或26.7±0.2°的衍射角(2θ)处的衍射峰。优选地，所述盐酸盐的晶型I的XRPD图谱还包括在约19.6±0.2°、22.1±0.2°、26.2±0.2°、30.8±0.2°和/或31.7±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述盐酸盐的晶型I的XRPD图谱还包括在约7.4±0.2°、12.8±0.2°、18.6±0.2°、19.2±0.2°、20.0±0.2°、21.0±0.2°、21.4±0.2°、22.9±0.2°、23.6±0.2°、24.4±0.2°、25.3±0.2°、27.1±0.2°、27.4±0.2°、28.2±0.2°、29.1±0.2°、33.5±0.2°和/或40.4±0.2°的衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述盐酸盐的晶型I的XRPD图谱基本上如图1所示，更优选如图1所示。
在一些实施方案中，所述盐酸盐的晶型I在加热至130±5℃(优选约130±2℃)过程中失重约4.0％，在继续加热至约200±5℃(优选约200±2℃)的过程中进一步失重约8.2％，在约210±5℃(优选约210±2℃)可能发生分解，如使用TGA所测得的。优选地，所述盐酸盐的晶型I的TGA图谱基本上如图2所示，更优选如图2所示。
在一些实施方案中，所述盐酸盐的晶型I在约91±5℃(优选约91±2℃)和约192±5℃(优选约192±2℃)有吸热峰。优选地，所述盐酸盐的晶型I的DSC图谱基本上如图2所示，更优选如图2所示。
在一些实施方案中，所述盐酸盐的晶型I的NMR图谱基本上如图3的(a)所示，优选如图3的(a)所示。所述NMR图谱(a)与化合物I的NMR图谱(b)的比较显示，所述盐酸盐的晶型I的氨基峰位有变化，表明所测试的盐酸盐样品的确为盐。
如图4所示，所述盐酸盐的晶型I在DVS测试后的XRPD图谱与测试前一致，没有晶型变化。
在一些实施方案中，所述盐酸盐的晶型I的PLM图像基本上如图5所示，优选如图5所示。所述盐酸盐的晶型I的粒径普遍小于约20μm，有团聚现象。
硫酸盐的晶型I
本发明还提供具有下式的化合物I的硫酸盐的晶型I：
Figure PCTCN2022130227-appb-000004
在一些实施方案中，所述化合物I的硫酸盐的晶型I的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的硫酸盐的晶型I的XRPD图谱包括在约14.9±0.2°、20.9±0.2°、23.2±0.2°、27.9±0.2°和/或30.8±0.2°的衍射角(2θ)处的衍射峰。优选地，所述硫酸盐晶型I的XRPD图谱还包括在约7.3±0.2°、21.8±0.2°、22.1±0.2°、22.5±0.2°和/或27.4±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述硫酸盐晶型I的XRPD图谱还包括在约5.9±0.2°、8.0±0.2°、10.2±0.2°、10.6±0.2°、11.4±0.2°、16.0±0.2°、17.3±0.2°、18.0±0.2°、18.4±0.2°、19.0±0.2°、19.4±0.2°、19.9±0.2°、20.1±0.2°、21.3±0.2°、23.7±0.2°、24.4±0.2°、24.7±0.2°、25.2±0.2°、26.2±0.2°、27.0±0.2°、28.4±0.2°、28.9±0.2°、29.5±0.2°、29.7±0.2°和/或35.1±0.2°的衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述硫酸盐的晶型I的XRPD图谱基本上如图6所示，更优选如图6所示。
在一些实施方案中，所述硫酸盐的晶型I在加热至约120℃±5℃(优选约120±2℃)的过程中失重约6.5％，在继续加热至约210±5℃(优选约210±2℃)的过程中进一步失重约7.6％，在超过约210±5℃(优选约210±2℃)时可能发生分解，如使用TGA所测得的。优选地，所述硫酸盐的晶型I的TGA图谱基本上如图7所示，更优选如图7所示。
在一些实施方案中，所述硫酸盐的晶型I具有两个吸热峰，具体而言，在约25-120℃和约120-210℃间各有一个非常宽的吸热峰，分别与TGA在相应温度区间的失重现象吻合。优选地，所述硫酸盐的晶型I的DSC图谱基本上如图7所示，更优选如图7所示。
在一些实施方案中，所述硫酸盐的晶型I的NMR图谱基本上如图8的(a)所示，优选如图8的(a)所示。所述NMR图谱(a)与化合物I的NMR图谱(b)的比较显示约6.79ppm处的峰有变化，表明所测试的硫酸盐样品的确为盐。
甲磺酸盐的晶型I
本发明还提供具有下式的化合物I的甲磺酸盐的晶型I：
Figure PCTCN2022130227-appb-000005
在一些实施方案中，所述化合物I的甲磺酸盐的晶型I的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的甲磺酸盐的晶型I的XRPD图谱包括在约4.2±0.2°、20.9±0.2°、21.9±0.2°、22.0±0.2°和/或27.8±0.2°的衍射角(2θ)处的衍射峰。优选地，所述甲磺酸盐的晶型I的XRPD图谱还包括在约14.8±0.2°、22.5±0.2°、23.2±0.2°、27.2±0.2°和/或30.7±0.2°的衍射角(2θ)处的衍射峰。优选地，所述甲磺酸盐的晶型I的XRPD图谱还包括在约7.3±0.2°、8.0±0.2°、10.2±0.2°、17.2±0.2°、18.3±0.2°、19.0±0.2°、19.5±0.2°、19.9±0.2°、20.2±0.2°、21.4±0.2°、23.6±0.2°、24.6±0.2°、25.1±0.2°、26.1±0.2°、26.8±0.2°、28.3±0.2°、28.9±0.2°、29.4±0.2°、29.5±0.2°、29.9±0.2°、34.0±0.2°和/或41.8±0.2°的衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述甲磺酸盐的晶型I的XRPD图谱基本上如图9所示，更优选地如图9所示。
在一些实施方案中，所述甲磺酸盐的晶型I在加热至约100±5℃(优选约100±2℃)的过程中失重约19.0％，在约150℃±5℃(优选约150±2℃)以上可能发生分解，如使用TGA所测得的。优选地，所述甲磺酸盐的晶型I的TGA图谱基本上如图10所示，更优选地如图10所示。
在一些实施方案中，所述甲磺酸盐的晶型I的DSC图谱基本上如图10所示，优选如10所示。所述甲磺酸盐的晶型I在约84±5℃(优选约84±2℃)有对应TGA失重信号的吸热峰；在约147±5℃(优选约147±2℃)有吸热峰，结合TGA开始持续失重，可能对应伴随着分解的熔融过程。
在一些实施方案中，所述甲磺酸盐的晶型I的NMR图谱基本上如图11的(a)所示，优选如图11的(a)所示。所述NMR图谱的(a)与甲磺酸的NMR图谱(b)和化合物I的NMR图谱(c)的比较显示，在约6.79ppm处的峰有变化，表明所测试的甲磺酸盐样品的确为盐，积分结果表明在该盐中化合物1与甲磺酸的摩尔比为1:2。
本发明还提供具有下式的化合物I的对甲苯磺酸盐的晶型I、晶型II和晶型III：
Figure PCTCN2022130227-appb-000006
对甲苯磺酸盐的晶型I
在一些实施方案中，所述化合物I的对甲苯磺酸盐的晶型I的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的对甲苯磺酸盐晶型I的XRPD图谱包括在约5.6±0.2°、15.1±0.2°、16.7±0.2°、17.0±0.2°和/或22.8±0.2°的衍射角(2θ)处的衍射峰。优选地，所述对甲苯磺酸盐的晶型I的XRPD图谱还包括在约19.9±0.2°、21.4±0.2°、25.8±0.2°和/或27.1±0.2°的衍射角(2θ)处的衍射峰。优选地，所述对甲苯磺酸盐的晶型I的XRPD图谱还包括在约7.9±0.2°、10.6±0.2°、11.3±0.2°、12.4±0.2°、14.0±0.2°、15.6±0.2°、16.0±0.2°、17.3±0.2°、17.9±0.2°、18.8±0.2°、19.3±0.2°、20.3±0.2°、20.4±0.2°、21.6±0.2°、21.9±0.2°、24.1±0.2°、24.5±0.2°、25.2±0.2°、28.8±0.2°、31.6±0.2°、34.7±0.2°和/或43.6±0.2°的衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述对甲苯磺酸盐的晶型I的XRPD图谱基本上如图12所示，更优选地如图12所示。
在一些实施方案中，所述对甲苯磺酸盐的晶型I在加热至约150±5℃(优选约150±2℃)的过程中失重约5.5％，在约200±5℃(优选约200±2℃)可能发生分解，如使用TGA所测得的。优选地，所述对甲苯磺酸盐的晶型I的TGA图谱基本上如图13所示，更优选地如图13所示。
在一些实施方案中，所述对甲苯磺酸盐的晶型I的DSC图谱基本上如图13所示，优选如13所示。所述对甲苯磺酸盐的晶型I在约25-100℃间有较宽的吸热信号，与TGA失重信号吻合，在约216±5℃(优选约216±2℃)有熔融吸热峰。
对甲苯磺酸盐的晶型II
在一些实施方案中，所述化合物I的对甲苯磺酸盐的晶型II的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的对甲苯磺酸盐的晶型II的XRPD图谱包括在约4.9±0.2°、5.7±0.2°、15.2±0.2°、17.1±0.2°和/或22.8±0.2°的衍射角(2θ)处的衍射峰。优选地，所述对甲苯磺酸盐的晶型II的XRPD图谱还包括在约11.4±0.2°、17.4±0.2°、20.3±0.2°、21.4±0.2°和/或28.7±0.2°的衍射角(2θ)处的衍射峰。优选地，所述对甲苯磺酸盐的晶型II的XRPD图谱还包括在约8.0±0.2°、12.5±0.2°、16.8±0.2°、19.9±0.2°、20.5±0.2°、21.7±0.2°、24.6±0.2°、29.9±0.2°、30.6±0.2°、31.7±0.2°和/或40.0±0.2°的衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述对甲苯磺酸盐的晶型II的XRPD图谱基本上如图14所示，更优选地如图14所示。
在一些实施方案中，所述对甲苯磺酸盐的晶型II在加热过程中持续失重，在加热至约128±5℃(优选约128±2℃)的过程中失重约3.4％，在约200±5℃(优选约200±2℃)以上可能发生分解，如使用TGA所测得的。优选地，所述对甲苯磺酸盐的晶型II的TGA图谱基本上如图15所示，更优选地如图15所示。
在一些实施方案中，所述对甲苯磺酸盐的晶型II的DSC图谱基本上如图15所示，优选如15所示。所述对甲苯磺酸盐的晶型II在约25-100℃间有较宽的吸热信号，与TGA失重信号吻合，在约224±5℃(优选约224±2℃)有熔融伴随分解的信号。
在一些实施方案中，所述对甲苯磺酸盐的晶型II的NMR图谱基本上如图16的(a) 所示，优选如图16的(a)所示。所述NMR图谱的(a)与对甲苯磺酸的NMR图谱(b)和化合物I的NMR图谱(c)的比较显示，对甲苯磺酸盐的晶型II的氨基峰位有变化，表明所测试的对甲苯磺酸盐样品的确为盐，积分结果表明该盐中化合物I与对甲苯磺酸的摩尔比为1:1.5。
如图17所示，所述对甲苯磺酸盐的晶型II在DVS测试后的XRPD图谱与测试前一致，没有晶型变化。
在一些实施方案中，所述对甲苯磺酸盐的晶型II的PLM图像基本上如图18所示，优选如图18所示。所述对甲苯磺酸盐的晶型II为棒状晶体，粒径普遍小于20μm。
对甲苯磺酸盐的晶型III
在一些实施方案中，所述化合物I的对甲苯磺酸盐的晶型III的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的对甲苯磺酸盐的晶型III的XRPD图谱包括在约3.6±0.2°、7.2±0.2°、20.4±0.2°和/或25.7±0.2°的衍射角(2θ)处的衍射峰。优选地，所述对甲苯磺酸盐的晶型III的XRPD图谱还包括在约9.6±0.2°、12.6±0.2°、15.9±0.2°、18.3±0.2°、19.4±0.2°和/或22.9±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述对甲苯磺酸盐晶型III的XRPD图谱还包括在约5.0±0.2°、13.1±0.2°、14.6±0.2°、16.7±0.2°、19.1±0.2°、20.8±0.2°、22.0±0.2°和/或28.8±0.2°衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述对甲苯磺酸盐的晶型III的XRPD图谱基本上如图19所示，更优选如图19所示。
本发明还提供具有下式的化合物I的钠盐的晶型I和晶型II：
Figure PCTCN2022130227-appb-000007
钠盐的晶型I
在一些实施方案中，所述化合物I的钠盐的晶型I的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的钠盐的晶型I的XRPD图谱包括在约8.8±0.2°、17.9±0.2°、27.1±0.2°和/或26.9±0.2°的衍射角(2θ)处的衍射峰。优选地，所述钠盐的晶型I的XRPD图谱还包括在约16.8±0.2°、20.9±0.2°、21.7±0.2°、28.0±0.2°和/或30.9±0.2°的衍射角(2θ)处的衍射峰。优选地，所述钠盐的晶型I的XRPD图谱还包括在约12.5±0.2°、19.1±0.2°、20.0±0.2°、24.7±0.2°、25.2±0.2°、27.6±0.2°、31.6±0.2°、32.2±0.2°和/或36.0±0.2°的衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述钠盐的晶型I的XRPD图谱基本上如图20所示，更优选地如图20所示。
在一些实施方案中，所述钠盐的晶型I在加热过程持续失重，在加热至约120±5℃(优选约120±2℃)的过程中失重约6.1％，在约200±5℃(优选约200±2℃)以上 可能发生分解，如使用TGA所测得的。优选地，所述钠盐的晶型I的TGA图谱基本上如图21所示，更优选地如图21所示。
在一些实施方案中，所述钠盐的晶型I的DSC图谱基本上如图21所示，优选如21所示。所述钠盐的晶型I在约25-127℃间有较宽的吸热信号，与TGA失重信号吻合，在约150±5℃(优选约150±2℃)有一个吸热峰。
钠盐的晶型II
在一些实施方案中，所述化合物I的钠盐的晶型II的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的钠盐的晶型II的XRPD图谱包括在约12.2±0.2°、14.2±0.2°、18.8±0.2°和/或23.3±0.2°的衍射角(2θ)处的衍射峰。优选地，所述钠盐的晶型II的XRPD图谱还包括在约7.0±0.2°、17.9±0.2°、33.2±0.2°、21.8±0.2°和/或22.6±0.2°的衍射角(2θ)处的衍射峰。优选地，所述钠盐的晶型II的XRPD图谱还包括在约16.2±0.2°、18.4±0.2°、19.8±0.2°、20.2±0.2°、21.3±0.2°、24.0±0.2°、24.5±0.2°、25.4±0.2°、25.7±0.2°、27.9±0.2°、28.4±0.2°、28.7±0.2°、29.3±0.2°、30.1±0.2°、30.7±0.2°、33.0±0.2°和/或40.3±0.2°的衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述钠盐的晶型II的XRPD图谱基本上如图22所示，更优选地如图22所示。
在一些实施方案中，所述钠盐的晶型II在加热过程持续失重，在加热至约100±5℃(优选约100±2℃)的过程中失重约4.2％，在继续加热至约200±5℃(优选约200±2℃)的过程中失重约3.4％，在220±5℃(优选约220±2℃)以上可能发生分解，如使用TGA所测得的。优选地，所述钠盐的晶型II的TGA图谱基本上如图23所示，更优选地如图23所示。
在一些实施方案中，所述钠盐的晶型II的DSC图谱基本上如图23所示，优选如23所示。所述钠盐的晶型II在约25-100℃和约100-200℃间分别有一个较宽的吸热峰，与TGA失重信号吻合。
在一些实施方案中，所述钠盐的晶型II的NMR图谱基本上如图24的(a)所示，优选如图24的(a)所示。所述NMR图谱(a)与化合物I的NMR图谱(b)的比较显示，在约4.4-4.5ppm处峰位有明显偏移，表明所测试的钠盐样品的确为盐。
乙醇胺盐的晶型I
本发明还提供具有下式的化合物I的乙醇胺盐的晶型I：
Figure PCTCN2022130227-appb-000008
在一些实施方案中，所述化合物I的乙醇胺盐的晶型I的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的乙醇胺盐的晶型I的XRPD图谱包括在约 10.2±0.2°、18.8±0.2°、23.6±0.2°和/或28.2±0.2°的衍射角(2θ)处的衍射峰。优选地，所述乙醇胺盐的晶型I的XRPD图谱还包括在约9.9±0.2°、20.0±0.2°、22.8±0.2°、24.5±0.2°和/或29.8±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述乙醇胺盐的晶型I的XRPD图谱还包括在约14.0±0.2°、14.7±0.2°、18.0±0.2°、19.1±0.2°、20.6±0.2°、20.8±0.2°、22.2±0.2°、24.9±0.2°、25.2±0.2°、26.6±0.2°、28.8±0.2°、34.8±0.2°和/或35.9±0.2°的衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述乙醇胺盐的晶型I的XRPD图谱基本上如图25所示，更优选地如图25所示；
在一些实施方案中，所述乙醇胺盐的晶型I在加热过程持续失重，在加热至约100±5℃(优选约100±2℃)过程中失重约3.9％，在160±5℃(优选约160±2℃)以上可能发生分解，如使用TGA所测得的。优选地，所述乙醇胺盐的晶型I的TGA图谱基本上如图26所示，更优选如图26所示。
在一些实施方案中，所述乙醇胺盐的晶型I在约25-100℃间有较宽的吸热信号，与TGA失重信号吻合，在约209±5℃(优选约209±2℃)有吸热熔融峰。优选地，所述乙醇胺盐的晶型I的DSC图谱基本上如图26所示，更优选如图26所示。
在一些实施方案中，所述乙醇胺盐的晶型I的NMR图谱基本上如图27的(a)所示，优选如图27的(a)所示。所述NMR图谱的(a)与乙醇胺的NMR图谱(b)和化合物I的NMR图谱(c)的比较显示，在约2.5-4.5ppm处峰位均有明显偏移，在约2.8ppm和约3.5ppm处可见乙醇胺的特征峰，表明所测定的乙醇胺盐样品的确为盐。
如图28所示，所述乙醇胺盐的晶型I在DVS测试后的XRPD图谱与测试前一致，没有晶型变化。
在一些实施方案中，所述乙醇胺盐的晶型I的PLM图像基本上如图29所示，优选如图29所示。所述乙醇胺盐的晶型I为棒状晶体，粒径普遍小于20μm。
游离态的化合物I的晶型A
在一些实施方案中，所述化合物I的晶型A的XRPD图谱以最大强度显示至少两个、至少三个、至少四个、至少五个或至少六个衍射角2θ(°)。
在一些实施方案中，所述化合物I的晶型A的XRPD图谱包括在约6.7±0.2°、18.2±0.2°、27.4±0.2°和/或28.2±0.2°的衍射角(2θ)处的衍射峰。优选地，所述晶型A的XRPD图谱还包括在约16.9±0.2°、20.2±0.2°、20.7±0.2°、21.0±0.2°和/或21.8±0.2°的衍射角(2θ)处的衍射峰。更优选地，所述晶型A的XRPD图谱还包括在约14.0±0.2°、15.1±0.2°、17.3±0.2°、19.1±0.2°、19.7±0.2°、20.5±0.2°、22.4±0.2°、23.1±0.2°、24.4±0.2°、24.8±0.2°、26.9±0.2°、28.5±0.2°、29.2±0.2°、30.6±0.2°、30.8±0.2°、32.8±0.2°、33.5±0.2°、34.2±0.2°、41.2±0.2°和/或43.5±0.2°的衍射角(2θ)处的衍射峰。
在一些优选的实施方案中，所述晶型A的XRPD图谱基本上如图30所示，更优选如图30所示。
在一些实施方案中，所述晶型A的吸热峰的起始温度为约185±5℃，优选为约185±2℃。优选地，所述晶型A的DSC图谱基本上如图31所示，更优选如图31所示。
在一些实施方案中，所述晶型A在加热至约100±5℃(优选约100±2℃)的过程中失重约2.24％，在约200±5℃(优选约200±2℃)可能开始分解，如使用TGA所测 得的。优选地，所述晶型A的TGA图谱基本上如图31所示，更优选如图31所示。
在一些实施方案中，所述晶型A的NMR图谱基本上如图32所示，优选如图32所示。所述NMR图谱显示未见明显的有机溶剂特征峰。
在一些实施方案中，所述晶型A不是溶剂合物，更优选地为无水物。
在一些实施方案中，所述晶型A的PLM图像基本上如图34所示，优选如图34所示。所述晶型A为片状颗粒，其粒径一般小于约20μm。
化合物I的盐的晶型的制备
在第二方面，本发明提供用于制备如上文所述的化合物I的盐的晶型的方法，所述方法包括：
(1)使化合物I和适合的酸性/碱性化合物在适量的适合溶剂中反应，使反应混合物混悬一段时间；
(2)对所得的混悬液进行固液分离(例如通过离心)，干燥所得的固体，得到所述晶型；或者
将所得的混悬液冷却以析晶，干燥通过固液分离(例如通过离心)得到的晶体，得到所述晶型；或者
向所得的混悬液加入反溶剂以析晶，干燥通过固液分离(例如通过离心)得到的晶体，得到所述晶型。
在一些实施方案中，所述化合物I是化合物I的晶型A。
所述酸性化合物包括但不限于盐酸、硫酸、甲磺酸和对苯甲磺酸。所述碱性化合物包括但不限于氢氧化钠、异辛酸钠或其他碱性的钠试剂(例如异己酸钠、异戊酸钠)、乙醇胺。
所述溶剂包括选自水、乙酸乙酯、四氢呋喃、甲醇以及它们中的两种或更多种的组合。
盐酸盐的晶型I的制备
在一些实施方案中，本发明提供用于制备如上文所述的盐酸盐的晶型I的方法，所述方法包括：
(1)提供化合物I在适当的溶剂(包括但不限于乙酸乙酯)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
(2)向所述混悬液中加入含有2倍当量或过量的氯化氢的溶液(其中溶剂包括但不限于水、乙酸乙酯)并搅拌，在化合物I完全转化成盐酸盐后进行固液分离，干燥所得的固体，得到所述盐酸盐的晶型I。
在一些实施方案中，所述化合物I是化合物I的晶型A。
在一些实施方案中，所述含有氯化氢的溶液是稀盐酸。
硫酸盐的晶型I的制备
在一些实施方案中，本发明提供用于制备上文所述的硫酸盐的晶型I的方法，所述方法包括：
(1)提供化合物I在适当的溶剂(包括但不限于乙酸乙酯)中的混悬液，优选地化合 物I在所述悬浮液中的含量为约1-200mg/ml；
(2)向所述混悬液中加入含有2倍当量或过量的硫酸的溶液(其中溶剂包括但不限于水)并搅拌，在化合物I完全转化成硫酸盐后进行固液分离，干燥所得的固体，得到所述硫酸盐的晶型I。
在一些实施方案中，所述化合物I是化合物I的晶型A。
在一些实施方案中，所述含有硫酸的溶液是稀硫酸水溶液。
对甲苯磺酸盐的晶型I的制备
在一些实施方案中，本发明提供用于制备上文所述的对甲苯磺酸盐的晶型I的方法，所述方法包括：
(1)提供化合物I在适当的溶剂(包括但不限于四氢呋喃)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
(2)向所述混悬液中加入2倍当量或过量的对甲苯磺酸并搅拌，在化合物I完全转化成对甲苯磺酸盐后进行固液分离，干燥所得的固体，得到所述对甲苯磺酸盐的晶型I。
在一些实施方案中，所述化合物I是化合物I的晶型A。
所述对甲苯磺酸可以其自身、或者以在适当的溶剂中的溶液的形式添加。
对甲苯磺酸盐的晶型II的制备
在一些实施方案中，本发明提供用于制备上文所述的对甲苯磺酸盐的晶型II的方法，所述方法包括：
(1)提供化合物I在适当的溶剂(包括但不限于四氢呋喃)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
(2)向所述混悬液中加入2倍当量或过量的对甲苯磺酸并搅拌，在化合物I完全转化成对甲苯磺酸盐后进行固液分离，干燥所得的固体，得到所述对甲苯磺酸盐的晶型II。
在一些实施方案中，所述化合物I是化合物I的晶型A。
所述对甲苯磺酸可以其自身、或者以在适当的溶剂中的溶液的形式添加。
甲磺酸盐的晶型I的制备
在一些实施方案中，本发明提供用于制备上文所述的甲磺酸盐的晶型I的方法，所述方法包括：
(1)提供化合物I在适当的溶剂(包括但不限于四氢呋喃)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
(2)向所述混悬液中加入2倍当量或过量的甲磺酸并搅拌，在化合物I完全转化成甲磺酸盐后进行固液分离，干燥所得的固体，得到所述甲磺酸盐的晶型I。
在一些实施方案中，所述化合物I是化合物I的晶型A。
所述甲磺酸可以其自身、或者以在适当的溶剂中的溶液的形式添加。
钠盐的晶型I的制备
在一些实施方案中，本发明提供用于制备上文所述的钠盐的晶型I的方法，所述方法包括：
(1)提供化合物I在适当的溶剂(包括但不限于乙酸乙酯)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
(2)向所述混悬液中加入2倍当量或过量的氢氧化钠并搅拌，在化合物I完全转化成钠盐后进行固液分离，干燥所得的固体，得到所述钠盐的晶型I。
在一些实施方案中，所示化合物I是化合物I的晶型A。
所述氢氧化钠可以其自身、或者以在适当的溶剂中的溶液的形式添加。
钠盐的晶型II的制备
在一些实施方案中，本发明提供用于制备上文所述的钠盐的晶型II的方法，所述方法包括：
(1)提供化合物I在适当的溶剂(包括但不限于四氢呋喃)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
(2)向所述混悬液中加入2倍当量或过量的异辛酸钠(或其他碱性的钠试剂)并搅拌，在化合物I完全转化成钠盐后进行固液分离，干燥所得的固体，得到所述钠盐的晶型II。
在一些实施方案中，所述化合物I是化合物I的晶型A。
所述异辛酸钠或其他碱性的钠试剂可以其自身、或者以在适当的溶剂中的溶液的形式添加。
在一些实施方案中，所述其他碱性的钠试剂包括但不限于异己酸钠和异戊酸钠。
乙醇胺盐的晶型I的制备
在一些实施方案中，本发明提供用于制备上文所述的乙醇胺盐的晶型I的方法，所述方法包括：
(1)提供化合物I在适当的溶剂(包括但不限于甲醇、四氢呋喃和乙酸乙酯)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
(2)向所述混悬液中加入2倍当量或过量的乙醇胺并搅拌，在化合物I完全转化成乙醇胺盐后进行固液分离，干燥所得的固体，得到所述乙醇胺盐的晶型I。
在一些实施方案中，所示化合物I是化合物I的晶型A。
所述乙醇胺可以其自身、或者以在适当的溶剂中的溶液的形式添加。
化合物I的晶型A的制备
在一些实施方案中，本发明提供用于制备上文所述的晶型A的方法，所述方法包括：
a1)提供化合物I在适当的溶剂中的悬浮液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
a2)在室温下搅拌所述悬浮液足够的时间，然后进行固液分离(例如通过离心)，干燥所得的固体，得到所述晶型A。
在一些优选的实施方案中，所述适当的溶剂选自DMF、DMSO、甲醇、乙醇、正丙醇、异丙醇、丙酮、4-甲基-2-戊酮、乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸丁酯、正庚烷、环己烷、二氧六环、乙醚、甲基叔丁基醚、乙二醇甲醚、乙二醇二甲醚、水、乙腈、甲苯、二氯甲烷、氯仿、四氢呋喃及其混合物。
在一些优选的实施方案中，在步骤a2)中，所述在室温下搅拌持续约3-7天。例如，在小试实验中，所述在室温下搅拌持续约7天；在放大生产中，所述在室温下搅拌持续约3天。
在另一些实施方案中，本发明提供用于制备所述游离态晶型A的方法，所述方法包括：
b1)将化合物I加入良溶剂中，然后加入适当的碱，在固体溶清后过滤；
b2)向步骤b1)中得到滤液中加入适当的酸，析出固体，得到所述晶型A；
在一些优选的实施方案中，所述良溶剂为水、异丙醚、正庚烷或甲苯，更优选水。
在一些优选的实施方案中，所述碱为乙醇胺。
在一些优选的实施方案中，所述酸为盐酸、硫酸或磷酸。
在第三方面，本发明提供药物组合物，其包含有效量的选自如上文所述的盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I和化合物I的晶型A中的任一种以及一种或多种药学上可接受的载体。
在第四方面，本发明提供如上文所述的盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I和化合物I的晶型A中任一种或所述药物组合物，其用于肾功能监测，其中所述肾功能监测是GFR监测，特别是实时GFR监测。
在第五方面，本发明提供如上文所述的盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I和化合物I的晶型A中的任一种或所述药物组合物在制备用于肾功能监测的药物(“示踪剂”)中的用途，其中所述肾功能监测是GFR监测，特别是实时GFR监测。
在第六方面，本发明提供用于个体的肾功能监测的方法，所述方法包括向所述个体施用有效量的如上文所述的盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I和化合物I的晶型A中的任一种或所述药物组合物，其中所述肾功能监测是GFR监测，特别是实时GFR监测。
所述盐酸盐的晶型I、硫酸盐的晶型I、对甲苯磺酸盐的晶型I、对甲苯磺酸盐的晶型II、甲磺酸盐的晶型I、钠盐的晶型I、钠盐的晶型II、乙醇胺盐的晶型I和化合物I的晶型A或者所述药物组合物或药物可以通过多种途径施用，包括但不限于口服、肠胃外、透皮、皮下、肠内或静脉内施用。
本发明的有益效果
化合物I会与盐酸、硫酸、对甲苯磺酸、甲磺酸、氢氧化钠、乙醇胺等形成稳定的盐。游离态的化合物I的晶型A、其盐酸盐的晶型I、对甲苯磺酸盐的晶型II、乙醇胺盐的晶型I在固态稳定性和动态溶解度等方面具有良好的性质。尤其是乙醇胺盐的晶型I具有较好的溶解度，能够满足口服等给药途径的要求。游离态化合物I的晶型A在光照、高温、高湿的条件下稳定性具有优势，能够满足生产运输储存的药用要求，生产工 艺稳定可重复可控，能够适应于工业化生产。
实施例
以下将参考附图，结合具体实施例对本发明做进一步阐述，其目的仅在于举例说明以便更好地理解本发明，但并意图限制本发明的范围。
方法和材料
通过X射线粉末衍射(XRPD)、差示扫描量热法(DSC)、热重量分析法(TGA)、核磁共振( 1H NMR)波谱和偏光显微镜分析(PLM)对实施例制备的各晶型进行表征。
1H NMR
将若干毫克固体样品溶解于二甲基亚砜-d6中，在Bruker AVANCE-III(Bruker,GER)上进行核磁分析。
XRPD
将样品用X射线粉末衍射仪Bruker D8 Advance(Bruker，GER)进行分析。扫描2θ范围为3°到45°(Cu-Kα(Kα1
Figure PCTCN2022130227-appb-000009
1.5406))，扫描步长为0.02°，曝光时间为0.2秒(对于各种盐的晶型)或0.12秒(对于游离态的化合物I的晶型A)。测试样品时光管电压和电流分别为40kV和40mA，样品盘为零背景样品盘。
TGA
采用热重分析仪TA Discovery 55(TA，US)。将2至5mg样品置于已平衡的开口铝制样品盘中，在TGA加热炉内自动称量。样品以10℃/min的速率加热至最终温度，样品处氮气吹扫速度为60ml/min，天平处氮气吹扫速度为40ml/min。
DSC
采用差示扫描量热分析仪TA Discovery 2500(TA，US)。将1-2mg样品经精确称重后置于扎孔的DSC Tzero样品盘中，以10℃/min的速率加热至最终温度，炉内氮气吹扫速度为50ml/min。
PLM
采用偏光显微镜Motic BA310Met(Motic，CN)。将少量样品放置在载玻片上，选择合适的镜头观察样品形貌。
动态水分吸附分析(DVS)
采用DVSIntrinsic(SMS，UK)进行动态水分吸附分析。测试采用梯度模式，湿度变化为50％—95％—0％—50％，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。测试完成后，对样品进行XRPD分析，以确认固体形态是否发生变化。
化合物I
化合物I参考WO 2019/084475 A1实施例12所述的方法获得，而且除非另有明确说明，在本文的上下文中提到的化合物I是以所获得的产物的形式。
实施例1：化合物I的盐的晶型制备筛选
方法1-溶液混悬法：
称取19mg(0.05mmol)化合物I和至少两当量的如表1中所列出的酸性/碱性化合 物并加入至适量的如表1中所选的溶剂中，室温混悬4天，将有固体存在的混悬液离心以分离固体并于室温真空干燥。
方法2-冷却结晶法：
将溶液混悬法中没有固体析出的溶液放置于5℃或-15℃的冰箱中冷却1天，将有固体析出的溶液离心以分离固体并于室温真空干燥。
方法3-溶析结晶法：
对于在冷却结晶方法中没有固体析出的溶液，在室温下向其中逐滴加入反溶剂甲基叔丁基醚直至少量浑浊产生并搅拌过夜，然后将有固体析出的溶液离心分离固体并于室温真空干燥。
对获得的固体进行XRPD检测以确定晶型。
表1：筛选实验总结
Figure PCTCN2022130227-appb-000010
注：
*由溶液混悬法获得；
**进行溶液混悬法、冷却结晶法后无固体析出，经溶析结晶法获得胶状物；
***由溶液混悬法获得，结晶性差，可能混有游离态的固体。
表2. 1H NMR数据
Figure PCTCN2022130227-appb-000011
经测定，盐酸盐的晶型I的XRPD图谱如图1所示；硫酸盐的晶型I的XRPD图谱如图6所示；甲磺酸盐的晶型I的XRPD图谱如图9所示；对甲苯磺酸盐的晶型I的XRPD图谱如图12所示；钠盐的晶型I的XRPD图谱如图20所示；钠盐的晶型II的XRPD图谱如图22所示；乙醇胺盐的晶型I的XRPD图谱如图25所示。
实施例2：化合物I的盐酸盐的晶型I的制备
将化合物I的晶型A(532.0mg)、1mol/L的盐酸(2.9mL)与乙酸乙酯(56mL)混合，于室温搅拌3天后离心，室温真空干燥所得到的固体，获得橙黄色的粉末固体(512mg)。XRPD图谱基本上如图1所示，表明该固体为盐酸盐的晶型I。
对放大制备所得的盐酸盐的晶型I进行XRPD、DSC、TGA、NMR、DVS、PLM表征。XRPD结果显示盐酸盐的晶型I为具有较高结晶度的晶体。TGA结果如图2所示，显示盐酸盐的晶型I在加热至约130℃的过程中有约4.0％的失重台阶，在130-200℃的过程中失重约8.2％；在200℃之后剧烈失重，表明可能分解。DSC结果如图2所示，显示盐酸盐的晶型I在约90℃和约195℃有吸热信号，与TGA的失重信号吻合；在约212℃有熔融伴随分解的信号。NMR结果如图3所示，显示盐酸盐的氨基峰位有变化，表明所测试的样品的确为盐；在4.0-5.0ppm有较宽的信号，表明该样品含水。离子色谱测试结果显示样品的氯离子含量为6.52％，表明该盐中化合物1与HCl的摩尔比为1:1。如图4所示，DVS测试后样品的XRPD图谱与测试前一致，没有晶型变化。显微镜图 像如图5所示，显示盐酸盐的晶型I颗粒较小，团聚现象明显。综上，盐酸盐的晶型I可能是含有吸附水的无水物或水合物。
实施例3：化合物I的乙醇胺盐的晶型I的制备
将化合物I的晶型A(532.1mg)、乙醇胺(200μL)与乙酸乙酯(56mL)混合，室温搅拌3天后离心，室温真空干燥所得到的固体，获得橙红色的粉末固体(588mg)。XRPD图谱基本上如图25所示，表明该固体为乙醇胺盐的晶型I。
对所得的乙醇胺盐的晶型I进行XRPD、DSC、TGA、NMR、DVS、PLM表征。TGA结果如图26所示，显示乙醇胺盐的晶型I在加热过程中持续失重，在加热至100℃的过程中失重约3.9％，在160℃以上可能发生分解。DSC结果如图26所示，显示乙醇胺盐的晶型I在25-100℃间有较宽的吸热信号，与TGA失重信号吻合；在约209℃有吸热熔融峰。NMR结果如图27所示，显示在2.5-4.5ppm处峰位有明显偏移，在2.8ppm和3.5ppm处可见乙醇胺的特征峰，表明所测定的样品的确为盐，积分结果得出该盐中化合物与乙醇胺的摩尔比为1:2；在约3.3ppm处有较宽信号，可能对应样品里的水。如图28所示，DVS测试后样品的XRPD图谱与测试前整体一致。显微镜图像如图29所示，显示乙醇胺盐的晶型I颗粒较小，团聚现象明显。综合以上信息，乙醇胺盐的晶型I有可能是含有吸附水的无水物。
实施例4：化合物I的对甲苯磺酸盐的晶型II的制备
将化合物I的晶型A(532.1mg)、对甲苯磺酸(568.2mg)与四氢呋喃(56mL)混合，于室温搅拌3天后离心，室温真空干燥所得到的固体，获得黄色的粉末固体(630mg)。XRPD图谱基本上如图14所示，表明该固体为对甲苯磺酸盐的晶型II。
1H NMR(400MHz,DMSO)δ8.46(d,J＝8.3Hz,2H),7.47(d,J＝8.1Hz,3H),7.11(d,J＝7.8Hz,2H),4.52–4.42(m,2H),3.89(dd,J＝11.0,3.8Hz,2H),3.74(dd,J＝11.0,3.4Hz,2H),2.29(s,4.5H).
对放大制备所得的对甲苯磺酸盐的晶型II进行XRPD、DSC、TGA、NMR、DVS、PLM表征。XRPD结果显示对甲苯磺酸盐的晶型II为结晶度较高的晶体。TGA结果如图15所示，显示对甲苯磺酸盐的晶型II在加热过程中持续失重，在加热至128℃的过程中失重约3.4％，在200℃以上可能发生分解。DSC结果如图15所示，显示对甲苯磺酸盐的晶型II在25-100℃间有较宽的吸热信号，与TGA失重信号吻合；在224℃有熔融伴随分解的信号。NMR结果如图16所示，显示对甲苯磺酸盐的晶型II的氨基峰位有变化，表明所测试的样品的确为盐，积分结果得出该盐中化合物1与对甲苯磺酸的摩尔比为1:1.5；在约5ppm处有较宽信号，可能对应样品里的水。如图17所示，DVS测试后样品的XRPD图谱与测试前整体一致。显微镜图像如图18所示，显示对甲苯磺酸盐的晶型II颗粒为棒状晶体，粒径较小，有团聚现象。综上，对甲苯磺酸盐的晶型II有可能是含有吸附水的无水物。
实施例5：稳定性研究
在高温(60℃)、高湿(25℃，92.5％RH)和光照(25℃，4500Lux)条件下，分 别对盐酸盐的晶型I、对甲苯磺酸盐的晶型II、乙醇胺盐的晶型I和化合物I的晶型A进行稳定性研究，其中在第7天和第16天取样测定XRPD图谱。结果如下表3所示。
表3
Figure PCTCN2022130227-appb-000012
实施例6：在生物媒介中的溶解度试验
FaSSIF是空腹状态下模拟肠液，其如下制备：(1)称量0.042g氢氧化钠、0.3438g磷酸二氢钠和0.6186g氯化钠，加入90mL纯净水并混合均匀，然后用1N盐酸或者1N氢氧化钠调节pH＝6.5，用纯净水定容至100mL；(2)取50mL在上述(1)中配制好的缓冲液，加入0.224g的FaSSIF/FeSSIF/FaSSGF市售粉末(Biorelevant.com)，搅拌直至溶解，然后用在(1)中配制好的缓冲液定容至100mL。将配制的缓冲液放置室温，静置两小时后观察缓冲液为轻微的乳白色，即可使用。
FeSSIF是进食状态下模拟肠液，其如下制备：(1)称量0.404g氢氧化钠、0.865g冰醋酸和1.1874g氯化钠，加入90mL纯净水并混合均匀，然后用1N盐酸或者1N氢氧化钠调节pH＝5.0，用纯净水定容至100mL；(2)取50mL在上述(1)中配制好的缓冲液，加入1.12g的FaSSIF/FeSSIF/FaSSGF市售粉末(Biorelevant.com)，搅拌直至溶解，然后用在(1)中配制好的缓冲液定容至100mL。将配制的缓冲液放置室温，静置两小时后观察缓冲液为透明液体，即可使用。
FaSSGF(SGF)是模拟胃液，其如下制备：(1)称量0.2g氯化钠，加入90mL纯净水并混合均匀，然后用1N盐酸调节pH＝1.8，用纯净水定容至100mL，静置至室温；(2)取50mL在上述(1)中配置好的缓冲液，加入0.006g的FaSSIF/FeSSIF/FaSSGF市售粉末(Biorelevant.com)，搅拌直至溶解，用在(1)中配制好的缓冲液定容至100mL。将配制的缓冲液放置室温，静置两小时后观察缓冲液为透明液体，即可使用。
测定盐酸盐的晶型I、对甲苯磺酸盐的晶型II、乙醇胺盐的晶型I和化合物I的晶型A在FaSSIF、FeSSIF和FaSSGF这三种生物媒介中的溶解度。三种盐的晶型和游离态的化合物I的晶型A在这些生物介质中的动态溶解度测试结果如下表4所示。
表4
Figure PCTCN2022130227-appb-000013
Figure PCTCN2022130227-appb-000014
注：溶解度数值以游离态的化合物I计，根据游离态化合物I的标准曲线计算而得。
结果显示，乙醇胺盐的晶型I在3种生物介质中的溶解度均远高于其他3种固体形态；同时由于溶解度过大，没有剩余固体可以进行XRPD表征。XRPD和NMR结果显示盐酸盐和对甲苯磺酸盐在溶解度测试过程中均发生了歧化现象，两种盐在溶解度测试后均转变为游离态。化合物I的晶型A在溶解度测试过程中没有发生晶型变化。此外，所有盐在FeSSIF中的溶解度均高于在FaSSIF和FaSSGF中的溶解度，这表明餐后给药可能是有利的。
通过溶解度实验发现，盐酸盐的晶型I、对甲苯磺酸盐的晶型II、乙醇胺盐的晶型I和游离态化合物I的晶型A在FaSSIF、FeSSIF和FaSSGF中均同样具有较好的溶解度，特别是乙醇胺盐的晶型I，因而可在制备的制剂中具备相当的溶出优势，有利于在施用过程中在不同的生物媒介条件下的溶出和生物利用。
除本文中描述的那些外，根据前述描述，本发明的多种修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (20)

  1. 具有下式的化合物I的盐酸盐的晶型I：
    Figure PCTCN2022130227-appb-100001
    其特征在于所述盐酸盐的晶型I的X射线粉末衍射(XRPD)图谱包括在约7.6±0.2°、20.4±0.2°、22.5±0.2°和/或26.7±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约19.6±0.2°、22.1±0.2°、26.2±0.2°、30.8±0.2°和/或31.7±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约7.4±0.2°、12.8±0.2°、18.6±0.2°、19.2±0.2°、20.0±0.2°、21.0±0.2°、21.4±0.2°、22.9±0.2°、23.6±0.2°、24.4±0.2°、25.3±0.2°、27.1±0.2°、27.4±0.2°、28.2±0.2°、29.1±0.2°、33.5±0.2°和/或40.4±0.2°的衍射角(2θ)处的衍射峰；
    进一步优选地，所述盐酸盐的晶型I的XRPD图谱基本上如图1所示，更进一步优选如图1所示。
  2. 具有下式的化合物I的硫酸盐的晶型I：
    Figure PCTCN2022130227-appb-100002
    其特征在于所述硫酸盐的晶型I的XRPD图谱包括在约14.9±0.2°、20.9±0.2°、23.2±0.2°、27.9±0.2°和/或30.8±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约7.3±0.2°、21.8±0.2°、22.1±0.2°、22.5±0.2°和/或27.4±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约5.9±0.2°、8.0±0.2°、10.2±0.2°、10.6±0.2°、11.4±0.2°、16.0±0.2°、17.3±0.2°、18.0±0.2°、18.4±0.2°、19.0±0.2°、19.4±0.2°、19.9±0.2°、20.1±0.2°、21.3±0.2°、23.7±0.2°、24.4±0.2°、24.7±0.2°、25.2±0.2°、26.2±0.2°、27.0±0.2°、28.4±0.2°、28.9±0.2°、29.5±0.2°、29.7±0.2°和/或35.1±0.2°的衍射角(2θ)处的衍射峰；
    进一步优选地，所述硫酸盐的晶型I的XRPD图谱基本上如图6所示，更进一步优选如图6所示。
  3. 具有下式的化合物I的甲磺酸盐的晶型I：
    Figure PCTCN2022130227-appb-100003
    其特征在于所述甲磺酸盐的晶型I的XRPD图谱包括在约4.2±0.2°、20.9±0.2°、21.9±0.2°、22.0±0.2°和/或27.8±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约14.8±0.2°、22.5±0.2°、23.2±0.2°、27.2±0.2°和/或30.7±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约7.3±0.2°、8.0±0.2°、10.2±0.2°、17.2±0.2°、18.3±0.2°、19.0±0.2°、19.5±0.2°、19.9±0.2°、20.2±0.2°、21.4±0.2°、23.6±0.2°、24.6±0.2°、25.1±0.2°、26.1±0.2°、26.8±0.2°、28.3±0.2°、28.9±0.2°、29.4±0.2°、29.5±0.2°、29.9±0.2°、34.0±0.2°和/或41.8±0.2°的衍射角(2θ)处的衍射峰；
    进一步优选地，所述甲磺酸盐的晶型I的XRPD图谱基本上如图9所示，更进一步优选如图9所示。
  4. 具有下式的化合物I的对甲苯磺酸盐的晶型I：
    Figure PCTCN2022130227-appb-100004
    其特征在于所述对甲苯磺酸盐的晶型I的XRPD图谱包括在约5.6±0.2°、15.1±0.2°、16.7±0.2°、17.0±0.2°和/或22.8±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约19.9±0.2°、21.4±0.2°、25.8±0.2°和/或27.1±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约7.9±0.2°、10.6±0.2°、11.3±0.2°、12.4±0.2°、14.0±0.2°、15.6±0.2°、16.0±0.2°、17.3±0.2°、17.9±0.2°、18.8±0.2°、19.3±0.2°、20.3±0.2°、20.4±0.2°、21.6±0.2°、21.9±0.2°、24.1±0.2°、24.5±0.2°、25.2±0.2°、28.8±0.2°、31.6±0.2°、34.7±0.2°和/或43.6±0.2°的衍射角(2θ)处的衍射峰；
    进一步优选地，所述对甲苯磺酸盐的晶型I的XRPD图谱基本上如图12所示，更进一步优选如图12所示。
  5. 具有下式的化合物I的对甲苯磺酸盐的晶型II：
    Figure PCTCN2022130227-appb-100005
    其特征在于所述对甲苯磺酸盐的晶型II的XRPD图谱包括在约4.9±0.2°、5.7±0.2°、 15.2±0.2°、17.1±0.2°和/或22.8±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约11.4±0.2°、17.4±0.2°、20.3±0.2°、21.4±0.2°和/或28.7±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约8.0±0.2°、12.5±0.2°、16.8±0.2°、19.9±0.2°、20.5±0.2°、21.7±0.2°、24.6±0.2°、29.9±0.2°、30.6±0.2°、31.7±0.2°和/或40.0±0.2°的衍射角(2θ)处的衍射峰；
    进一步优选地，所述对甲苯磺酸盐的晶型II的XRPD图谱基本上如图14所示，更进一步优选如图14所示。
  6. 具有下式的化合物I的钠盐的晶型I，
    Figure PCTCN2022130227-appb-100006
    其特征在于所述钠盐的晶型I的XRPD图谱包括在约8.8±0.2°、17.9±0.2°、27.1±0.2°和/或26.9±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约16.8±0.2°、20.9±0.2°、21.7±0.2°、28.0±0.2°和/或30.9±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约12.5±0.2°、19.1±0.2°、20.0±0.2°、24.7±0.2°、25.2±0.2°、27.6±0.2°、31.6±0.2°、32.2±0.2°和/或36.0±0.2°的衍射角(2θ)处的衍射峰；
    进一步优选地，所述钠盐的晶型I的XRPD图谱基本上如图20所示，更进一步优选如图20所示。
  7. 具有下式的化合物I的钠盐的晶型II：
    Figure PCTCN2022130227-appb-100007
    其特征在于所述钠盐的晶型II的XRPD图谱包括在约12.2±0.2°、14.2±0.2°、18.8±0.2°和/或23.3±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约7.0±0.2°、17.9±0.2°、33.2±0.2°、21.8±0.2°和/或22.6±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约16.2±0.2°、18.4±0.2°、19.8±0.2°、20.2±0.2°、21.3±0.2°、24.0±0.2°、24.5±0.2°、25.4±0.2°、25.7±0.2°、27.9±0.2°、28.4±0.2°、28.7±0.2°、29.3±0.2°、30.1±0.2°、30.7±0.2°、33.0±0.2°和/或40.3±0.2°的衍射角(2θ)处的衍射峰；
    进一步优选地，所述钠盐的晶型II的XRPD图谱基本上如图22所示，更进一步优选如图22所示。
  8. 具有下式的化合物I的乙醇胺盐的晶型I：
    Figure PCTCN2022130227-appb-100008
    其特征在于所述乙醇胺盐的晶型I的XRPD图谱包括在约10.2±0.2°、18.8±0.2°、23.6±0.2°和/或28.2±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约9.9±0.2°、20.0±0.2°、22.8±0.2°、24.5±0.2°和/或29.8±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约14.0±0.2°、14.7±0.2°、18.0±0.2°、19.1±0.2°、20.6±0.2°、20.8±0.2°、22.2±0.2°、24.9±0.2°、25.2±0.2°、26.6±0.2°、28.8±0.2°、34.8±0.2°和/或35.9±0.2°的衍射角(2θ)处的衍射峰；
    进一步优选地，所述乙醇胺盐的晶型I的XRPD图谱基本上如图25所示，更进一步优选如图25所示。
  9. 化合物I的晶型A：
    Figure PCTCN2022130227-appb-100009
    其特征在于所述晶型A的XRPD图谱包括在约6.7±0.2°、18.2±0.2°、27.4±0.2°和/或28.2±0.2°的衍射角(2θ)处的衍射峰，优选还包括在约16.9±0.2°、20.2±0.2°、20.7±0.2°、21.0±0.2°和/或21.8±0.2°的衍射角(2θ)处的衍射峰，更优选还包括在约14.0±0.2°、15.1±0.2°、17.3±0.2°、19.1±0.2°、19.7±0.2°、20.5±0.2°、22.4±0.2°、23.1±0.2°、24.4±0.2°、24.8±0.2°、26.9±0.2°、28.5±0.2°、29.2±0.2°、30.6±0.2°、30.8±0.2°、32.8±0.2°、33.5±0.2°、34.2±0.2°、41.2±0.2°和/或43.5±0.2°的衍射角(2θ)处的衍射峰；
    进一步优选地，所述晶型A的XRPD图谱基本上如图30所示，更进一步优选如图30所示；
    更进一步优选地，所述晶型A不是溶剂合物，更优选地为无水物。
  10. 制备如权利要求1所述的盐酸盐的晶型I的方法，其特征在于所述方法包括：
    (1)提供化合物I(包括化合物I的晶型A)在适当的溶剂(包括但不限于乙酸乙酯)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
    (2)向所述混悬液中加入含有2倍当量或过量的氯化氢的溶液(其中溶剂包括但不限于水、乙酸乙酯)并搅拌，在化合物I完全转化成盐酸盐后进行固液分离，干燥所得的固体，得到所述盐酸盐的晶型I。
  11. 制备如权利要求2所述的硫酸盐的晶型I的方法，其特征在于所述方法包括：
    (1)提供化合物I(包括化合物I的晶型A)在适当的溶剂(包括但不限于乙酸乙酯)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
    (2)向所述混悬液中加入含有2倍当量或过量的硫酸的溶液(其中溶剂包括但不限于水)并搅拌，在化合物I完全转化成硫酸盐后进行固液分离，干燥所得的固体，得到所述硫酸盐的晶型I。
  12. 制备如权利要求3所述的甲磺酸盐的晶型I的方法，其特征在于所述方法包括：
    (1)提供化合物I(包括化合物I的晶型A)在适当的溶剂(包括但不限于四氢呋喃)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
    (2)向所述混悬液中加入2倍当量或过量的甲磺酸并搅拌，在化合物I完全转化成甲磺酸盐后进行固液分离，干燥所得的固体，得到所述甲磺酸盐的晶型I。
  13. 制备如权利要求4所述的对甲苯磺酸盐的晶型I的方法，其特征在于所述方法包括：
    (1)提供化合物I(包括化合物I的晶型A)在适当的溶剂(包括但不限于四氢呋喃)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
    (2)向所述混悬液中加入2倍当量或过量的对甲苯磺酸并搅拌，在化合物I完全转化成对甲苯磺酸盐后进行固液分离，干燥所得的固体，得到所述对甲苯磺酸盐的晶型I。
  14. 制备如权利要求5所述的对甲苯磺酸盐的晶型II的方法，其特征在于所述方法包括：
    (1)提供化合物I(包括化合物I的晶型A)在适当的溶剂(包括但不限于四氢呋喃)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
    (2)向所述混悬液中加入2倍当量或过量的对甲苯磺酸并搅拌，在化合物I完全转化成对甲苯磺酸盐后进行固液分离，干燥所得的固体，得到所述对甲苯磺酸盐的晶型II。
  15. 制备如权利要求6所述的钠盐的晶型I的方法，其特征在于所述方法包括：
    (1)提供化合物I(包括化合物I的晶型A)在适当的溶剂(包括但不限于乙酸乙酯)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
    (2)向所述混悬液中加入2倍当量或过量的氢氧化钠并搅拌，在化合物I完全转化成钠盐后进行固液分离，干燥所得的固体，得到所述钠盐的晶型I。
  16. 制备如权利要求7所述的钠盐的晶型II的方法，其特征在于所述方法包括：
    (1)提供化合物I(包括化合物I的晶型A)在适当的溶剂(包括但不限于四氢呋喃)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
    (2)向所述混悬液中加入2倍当量或过量的异辛酸钠或其他碱性的钠试剂并搅拌，在化合物I完全转化成钠盐后进行固液分离，干燥所得的固体，得到所述钠盐的晶型II。
  17. 制备如权利要求8所述的乙醇胺盐的晶型I的方法，其特征在于所述方法包括：
    (1)提供化合物I(包括化合物I的晶型A)在适当的溶剂(包括但不限于甲醇、四氢呋喃和乙酸乙酯)中的混悬液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
    (2)向所述混悬液中加入2倍当量或过量的乙醇胺并搅拌，在化合物I完全转化成乙醇胺盐后进行固液分离，干燥所得的固体，得到所述乙醇胺盐的晶型I。
  18. 制备如权利要求9所述的化合物I的晶型A的方法，其特征在于，所述方法包括：
    a1)提供化合物I在适当的溶剂中的悬浮液，优选地化合物I在所述悬浮液中的含量为约1-200mg/ml；
    a2)在室温下搅拌所述悬浮液足够的时间，然后进行固液分离，干燥所得的固体，得到所述晶型A；
    优选地，其中所述适当的溶剂选自DMF、DMSO、甲醇、乙醇、正丙醇、异丙醇、丙酮、4-甲基-2-戊酮、乙酸乙酯、乙酸异丙酯、甲酸乙酯、甲酸丁酯、正庚烷、环己烷、二氧六环、乙醚、甲基叔丁基醚、乙二醇甲醚、乙二醇二甲醚、水、乙腈、甲苯、二氯甲烷、氯仿、四氢呋喃及其混合物；和/或
    优选地，其中在步骤a2)中，所述在室温下搅拌持续约3-7天；或者
    所述方法包括：
    b1)将化合物I加入良溶剂中，然后加入适当的碱，在固体溶清后过滤；
    b2)向步骤b1)中得到滤液中加入适当的酸，析出固体，得到所述晶型A；
    优选地，其中所述良溶剂为水、异丙醚、正庚烷或甲苯；和/或
    优选地，其中所述碱为乙醇胺；和/或
    优选地，其中所述酸为盐酸、硫酸或磷酸。
  19. 药物组合物，其包含有效量的选自如权利要求1所述的化合物I的盐酸盐的晶型I、如权利要求2所述的化合物I的硫酸盐的晶型I、如权利要求3所述的化合物I的甲磺酸盐的晶型I、如权利要求4所述的化合物I的对甲苯磺酸盐的晶型I、如权利要求5所述的化合物I的对甲苯磺酸盐的晶型II、如权利要求6所述的化合物I的钠盐的晶型I、如权利要求7所述的化合物I的钠盐的晶型II、如权利要求8所述的化合物I的乙醇胺盐的晶型I和如权利要求9所述的化合物I的晶型A中的任一种，以及
    一种或多种药学上可接受的载体。
  20. 如权利要求1所述的化合物I的盐酸盐的晶型I、如权利要求2所述的化合物I的硫酸盐的晶型I、如权利要求3所述的化合物I的甲磺酸盐的晶型I、如权利要求4所述的化合物I的对甲苯磺酸盐的晶型I、如权利要求5所述的化合物I的对甲苯磺酸盐的晶型II、如权利要求6所述的化合物I的钠盐的晶型I、如权利要求7所述的化合物I的钠盐的晶型II、如权利要求8所述的化合物I的乙醇胺盐的晶型I和如权利要求9所述的化合物I的晶型A、或如权利要求19所述的药物组合物在制备用于肾功能监测的药物中的用途，其中所述肾功能监测是GFR监测，特别是实时GFR监测。
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