Crystal forms of pyrazine derivative salts, their preparation methods, pharmaceutical compositions, and uses.

Abstract

This invention relates to the crystal forms and preparation methods of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminomethylpyrazine}pyrazine (compound I) and its salts, specifically to eight salt crystal forms: 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 methanesulfonate, crystal form I of sodium salt, crystal form II of sodium salt, and crystal form I of ethanolamine salt, and their preparation methods. Crystal form I of hydrochloride, crystal form II of p-toluenesulfonate, and crystal form I of ethanolamine salt exhibit good properties in terms of solid-state stability and dynamic solubility. Crystal form I of ethanolamine salt has good solubility, which meets the requirements for oral administration and other routes of administration.

Description

Crystal forms of pyrazine derivative salts and their preparation methods This invention relates to the crystal forms and preparation methods of compound 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminomethylpyrazine} and its salts. 3,6-Diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminomethylpyrazine}pyrazine is a fluorescent compound with excellent photophysical properties and other chemical and physical properties. As disclosed in 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, this compound is known for its use in renal function monitoring. 3,6-Diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminomethylpyrazine}pyrazine is being developed as a fluorescent agent for real-time glomerular filtration rate (GFR) measurement. When excited at 434 nm, it emits a strong fluorescent signal at 556 nm. Human clinical trials are currently underway. Notably, the clearance rate of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminomethylpyrazine}pyrazine in a patient's bloodstream can be measured transcutaneously and real-time, thereby translating the patient's glomerular filtration rate. The crystal structure of a pharmaceutical active ingredient often affects its chemical stability. Different crystallization and storage conditions can lead to changes in the crystal structure of a compound, sometimes even resulting in other crystal forms. Different crystal forms of the same drug may also have varying bioavailability; furthermore, their stability, flowability, and compressibility may differ. These physicochemical properties influence the application of the drug, thereby affecting its efficacy. No reports have been found regarding the crystal forms of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminomethylpyrazine} and its salts. To meet the requirements for raw material forms in the development of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminomethylpyrazine} formulations, while also ensuring the reproducibility and controllability of the crystallization process in industrial production, and satisfying pharmaceutical requirements for production, transportation, and storage, it is necessary to develop the crystal forms of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminomethylpyrazine} and its salts, as well as corresponding preparation methods suitable for industrial production. A first aspect of the present invention provides crystalline forms of 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2-hydroxyethyl]aminomethyl}pyrazine (hereinafter referred to as "Compound I") and its salts as described below: This includes 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 methanesulfonate, 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. These crystal forms simultaneously satisfy the requirements for reproducibility and controllability of the crystallization process in industrial production, and exhibit good properties in terms of solid-state stability and dynamic solubility. A second aspect of the present invention provides a method for preparing the crystal form I of the hydrochloride, the crystal form I of the sulfate, the crystal form I of the p-toluenesulfonate, the crystal form II of the p-toluenesulfonate, the crystal form I of the methanesulfonate, the crystal form I of the sodium salt, the crystal form II of the sodium salt, the crystal form I of the ethanolamine salt, or the crystal form A of compound I. A third aspect of the invention provides a pharmaceutical composition comprising an effective amount of any one selected from crystal form I of the hydrochloride, crystal form I of the sulfate, crystal form I of p-toluenesulfonate, crystal form II of p-toluenesulfonate, crystal form I of methanesulfonate, crystal form I of the sodium salt, crystal form II of the sodium salt, crystal form I of the ethanolamine salt, or crystal form A of compound I, and one or more pharmaceutically acceptable carriers. A fourth aspect of the invention provides any one of the following crystal forms: hydrochloride I, sulfate I, p-toluenesulfonate I, p-toluenesulfonate II, methanesulfonate I, sodium salt I, sodium salt II, ethanolamine salt I, or compound I crystal form A, or the pharmaceutical composition thereof, for use in renal function monitoring, wherein the renal function monitoring is GFR monitoring, particularly real-time GFR monitoring. The fifth aspect of the invention provides the use of any one of the crystal form I of the hydrochloride, crystal form I of the sulfate, crystal form I of the p-toluenesulfonate, crystal form II of the p-toluenesulfonate, crystal form I of the methanesulfonate, crystal form I of the sodium salt, crystal form II of the sodium salt, crystal form I of the ethanolamine salt, or crystal form A of compound I, or the pharmaceutical composition thereof, in the preparation of a medicament for monitoring renal function, wherein the renal function monitoring is GFR monitoring, particularly real-time GFR monitoring. A sixth aspect of the invention provides a method for monitoring renal function in an individual, the method comprising administering to the individual an effective amount of any one of the following crystal forms: hydrochloride (crystal form I), sulfate (crystal form I), p-toluenesulfonate (crystal form I), p-toluenesulfonate (crystal form II), mesylate (crystal form I), sodium salt (crystal form I), sodium salt (crystal form II), ethanolamine salt (crystal form I), or compound I (crystal form A), or the pharmaceutical composition thereof, wherein the renal function monitoring is GFR monitoring, particularly immediate GFR monitoring. A seventh aspect of the present invention provides a method for preparing a crystal form of a salt of the compound I described above, the method comprising reacting the compound I with a suitable acidic / basic compound in a suitable solvent to form the crystal form. The present invention will be further explained below. It should be understood that the terms used are for descriptive purposes and not for limiting the invention. definition Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions herein shall prevail. When a quantity, concentration, or other value or parameter is expressed as a range, preferred range, or a preferred upper and lower limit of a numerical value, it should be understood that this is equivalent to specifically disclosing any range by combining any pair of upper or preferred values ​​with any lower or preferred value. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within that range. When used with a numerical variable, the term "about" usually means that the value of the variable and all values ​​of the variable are within the experimental error (e.g., within the 95% confidence interval for the mean) or within ±20%, ±10%, ±5%, or ±2% of the specified value. As used herein, the term "about" in describing the XRPD diffraction angle means, as would be considered by one of ordinary skill in the art, to be within an acceptable standard error of the value, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3. The terms "comprising," or similar expressions such as "including," "containing," and "having," are open-ended and do not exclude additional unlisted elements, steps, or components. The expression "consisting of" excludes any unspecified elements, steps, or components. The term "substantially consisting of" limits the scope to the specified elements, steps, or components, plus optional elements, steps, or components that do not materially affect the essential and novel features of the claimed subject matter. It should be understood that the terms "comprising," "including," and similar terms encompass the terms "substantially consisting of" and "consisting of." As used herein, the terms "optional" or "optionally" mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation. Unless otherwise stated, all percentages, parts, etc. in this document are by weight. As used herein, the term "crystal form" or "crystal" refers to any solid material exhibiting a three-dimensional arrangement, as opposed to amorphous solid materials, which produce characteristic XRPD patterns with clearly defined peaks. As used herein, the terms "X-ray powder diffraction pattern" or "XRPD pattern" refer to an experimentally observed diffraction pattern or the parameters, data, or values ​​derived from it. XRPD patterns are typically characterized by peak position (x-axis) and / or peak intensity (y-axis). As used herein, the terms "diffraction angle" or "2θ" refer to the peak position in degrees (°) based on the setup of an X-ray diffraction experiment, and are typically the horizontal axis unit in a diffraction pattern. If the reflected beam is diffracted when the incident beam forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. It should be understood that specific 2θ values ​​for a particular crystal form mentioned herein are intended to represent 2θ values ​​(in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, monochromatic Cu-Kα (Kα1 (Å): 1.5406) ​​radiation is used. The XRPD patterns in this paper were preferably acquired on a Bruker D8 Advance (Bruker, GER) X-ray powder diffractometer, and the transmission mode was preferably acquired on a Bruker D8 Advance (Bruker, GER) X-ray powder diffractometer. As used herein, the terms "substantially identical" or "substantially as shown in Figure ×" for X-ray diffraction peaks mean that representative peak positions and intensity variations are taken into account. For example, those skilled in the art will understand that peak positions (2θ) will show some variation, typically up to 0.1 to 0.2 degrees, and that the instrument used to measure diffraction will also cause some variation. Furthermore, those skilled in the art will understand that relative peak intensities will vary due to differences between instruments, as well as the degree of crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art. Similarly, as used herein, the phrase "basically as shown in Figure ×" for DSC and TGA spectra is intended to cover variations associated with these analytical techniques known to those skilled in the art. For example, for well-defined peaks in DSC spectra, there can typically be variations of up to ±0.2ºC, and even greater variations (e.g., up to ±1ºC) for broad peaks. The NMR spectra in this application are preferably acquired on a Bruker AVANCE-III (Bruker, GER) NMR spectrometer, with DMSO-d6 as the solvent unless otherwise specified. The polarized light microscopy data in this application were preferably acquired using a Motic BA310Met (Motic, CN) polarizing microscope. As used herein, the term "good solvent" means a solvent in which compound I is soluble or has a relatively higher solubility. As used herein, the term "antisolvent" means a solvent in which compound I is not or substantially insoluble or has a relatively lower solubility. In this document, the terms "good solvent" and "antisolvent" may also be relative and do not indicate the absolute solubility of compound I. The same solvent may act as a good solvent in some cases and as an antisolvent in others. For example, water or toluene may act as a good solvent in some cases, such as when used alone to dissolve compound I, but may act as an antisolvent in others, such as when used in combination with DMF. The numerical ranges used in this document (such as "1 to 10") and their subranges (such as "2 to 10", "2 to 6", "3 to 10") cover any number of the numerical ranges (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10). As used in this article, the term "room temperature" refers to 20ºC ± 5ºC. compound I Crystal form of salt In a first aspect, the present invention provides crystal form I of the hydrochloride salt of compound I, crystal form I of the sulfate salt, crystal form I of the p-toluenesulfonate salt, crystal form II of the p-toluenesulfonate salt, crystal form I of the methanesulfonate salt, crystal form I of the sodium salt, crystal form II of the sodium salt, crystal form I of the ethanolamine salt, and crystal form A of the free state of compound I. Crystal forms of hydrochloride I This invention provides crystal form I of the hydrochloride salt of compound I having the following formula: . In some embodiments, the XRPD pattern of crystal form I of the hydrochloride salt of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ ( ). o ). In some embodiments, the XRPD pattern of crystal form I of the hydrochloride salt of compound I includes diffraction peaks at diffraction angles (2θ) of about 7.6 ± 0.2°, 20.4 ± 0.2°, 22.5 ± 0.2°, and / or 26.7 ± 0.2°. Preferably, the XRPD pattern of crystal form I of the hydrochloride salt also includes diffraction peaks at diffraction angles (2θ) of about 19.6 ± 0.2°, 22.1 ± 0.2°, 26.2 ± 0.2°, 30.8 ± 0.2°, and / or 31.7 ± 0.2°. More preferably, the XRPD pattern of crystal form I of the hydrochloride also includes diffraction peaks at diffraction angles (2θ) of approximately 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° and / or 40.4±0.2°. In some preferred embodiments, the XRPD pattern of crystal form I of the hydrochloride is substantially as shown in Figure 1, and more preferably as shown in Figure 1. In some embodiments, the hydrochloride crystal form I loses about 4.0% of its weight when heated to 130 ± 5ºC (preferably about 130 ± 2ºC), and further loses about 8.2% of its weight when heated to about 200 ± 5ºC (preferably about 200 ± 2ºC). Decomposition may occur at about 210 ± 5ºC (preferably about 210 ± 2ºC), as measured using a TGA. Preferably, the TGA spectrum of the hydrochloride crystal form I is substantially as shown in Figure 2, more preferably as shown in Figure 2. In some embodiments, the crystal form I of the hydrochloride has endothermic peaks at about 91 ± 5ºC (preferably about 91 ± 2ºC) and about 192 ± 5ºC (preferably about 192 ± 2ºC). Preferably, the DSC spectrum of the crystal form I of the hydrochloride is substantially as shown in Figure 2, more preferably as shown in Figure 2. In some embodiments, the NMR spectrum of crystal form I of the hydrochloride is substantially as shown in Figure 3(a), preferably as shown in Figure 3(a). A comparison of the NMR spectrum (a) with the NMR spectrum (b) of compound I shows a change in the position of the amino group peaks in crystal form I of the hydrochloride, indicating that the tested hydrochloride sample is indeed a salt. As shown in Figure 4, the XRPD pattern of the hydrochloride crystal form I after DVS testing is consistent with that before testing, and there is no change in crystal form. In some embodiments, the PLM image of crystal form I of the hydrochloride is essentially as shown in Figure 5, preferably as shown in Figure 5. The particle size of crystal form I of the hydrochloride is generally less than about 20 μm, and agglomeration occurs. Crystal forms of sulfates I This invention also provides crystal form I of the sulfate of compound I having the following formula: . In some embodiments, the XRPD pattern of crystal form I of the sulfate of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (…). o ). In some embodiments, the XRPD pattern of the sulfate form I of compound I includes diffraction peaks at diffraction angles (2θ) of approximately 14.9 ± 0.2°, 20.9 ± 0.2°, 23.2 ± 0.2°, 27.9 ± 0.2°, and / or 30.8 ± 0.2°. Preferably, the XRPD pattern of the sulfate form I also includes diffraction peaks at diffraction angles (2θ) of approximately 7.3 ± 0.2°, 21.8 ± 0.2°, 22.1 ± 0.2°, 22.5 ± 0.2°, and / or 27.4 ± 0.2°. More preferably, the XRPD pattern of the sulfate crystal form I further includes values ​​at approximately 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°, and 2... Diffraction peaks at diffraction angles (2θ) of 0.1±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° and / or 35.1±0.2°. In some preferred embodiments, the XRPD pattern of the sulfate crystal form I is substantially as shown in Figure 6, and more preferably as shown in Figure 6. In some embodiments, the sulfate crystal form I loses about 6.5% of its weight upon heating to about 120 ºC ± 5ºC (preferably about 120 ± 2ºC), and further loses about 7.6% of its weight upon continued heating to about 210 ± 5ºC (preferably about 210 ± 2ºC). Decomposition may occur above about 210 ± 5ºC (preferably about 210 ± 2ºC), as measured using a TGA. Preferably, the TGA spectrum of the sulfate crystal form I is substantially as shown in Figure 7, more preferably as shown in Figure 7. In some embodiments, the sulfate crystal form I has two endothermic peaks, specifically, one very broad endothermic peak between approximately 25-120 ºC and another between approximately 120-210 ºC, which correspond to the weight loss phenomenon of TGA in the corresponding temperature ranges. Preferably, the DSC spectrum of the sulfate crystal form I is substantially as shown in Figure 7, more preferably as shown in Figure 7. In some embodiments, the NMR spectrum of crystal form I of the sulfate is substantially as shown in Figure 8(a), preferably as shown in Figure 8(a). A comparison of the NMR spectrum (a) with the NMR spectrum (b) of compound I shows a change in the peak at approximately 6.79 ppm, indicating that the tested sulfate sample is indeed a salt. Crystal forms of methanesulfonates I This invention also provides crystal form I of methanesulfonate of compound I having the following formula: . In some embodiments, the XRPD pattern of crystal form I of the methanesulfonate of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ ( ). o ). In some embodiments, the XRPD pattern of crystal form I of the methanesulfonate of compound I includes diffraction peaks at diffraction angles (2θ) of approximately 4.2 ± 0.2°, 20.9 ± 0.2°, 21.9 ± 0.2°, 22.0 ± 0.2°, and / or 27.8 ± 0.2°. Preferably, the XRPD pattern of crystal form I of the methanesulfonate also includes diffraction peaks at diffraction angles (2θ) of approximately 14.8 ± 0.2°, 22.5 ± 0.2°, 23.2 ± 0.2°, 27.2 ± 0.2°, and / or 30.7 ± 0.2°. Preferably, the XRPD pattern of crystal form I of the methanesulfonate further includes values ​​at approximately 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°, and 23.6± Diffraction peaks at diffraction angles (2θ) of 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° and / or 41.8±0.2°. In some preferred embodiments, the XRPD pattern of crystal form I of the methanesulfonate is substantially as shown in Figure 9, more preferably as shown in Figure 9. In some embodiments, the methanesulfonate crystal form I loses about 19.0% of its weight when heated to about 100 ± 5ºC (preferably about 100 ± 2ºC), and may decompose above about 150 ºC ± 5ºC (preferably about 150 ± 2ºC), as measured using TGA. Preferably, the TGA spectrum of the methanesulfonate crystal form I is substantially as shown in Figure 10, more preferably as shown in Figure 10. In some embodiments, the DSC spectrum of crystal form I of the methanesulfonate is substantially as shown in Figure 10, preferably as shown in Figure 10. Crystal form I of the methanesulfonate has an endothermic peak corresponding to the TGA weight loss signal at about 84 ± 5ºC (preferably about 84 ± 2ºC); and an endothermic peak at about 147 ± 5ºC (preferably about 147 ± 2ºC). Combined with the continuous weight loss of TGA, this may correspond to a melting process accompanied by decomposition. In some embodiments, the NMR spectrum of crystal form I of the methanesulfonate is substantially as shown in Figure 11(a), preferably as shown in Figure 11(a). A comparison of the NMR spectrum (a) with the NMR spectrum of methanesulfonic acid (b) and the NMR spectrum of compound I (c) shows a change in the peak at approximately 6.79 ppm, indicating that the tested methanesulfonate sample is indeed a salt, and the integration results show that the molar ratio of compound I to methanesulfonic acid in this salt is 1:2. The present invention also provides polymorphs I, II and III of p-toluenesulfonate of compound I having the following formula: Crystal form of p-toluenesulfonate I In some embodiments, the XRPD pattern of crystal form I of the p-toluenesulfonate of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (…). o ). In some embodiments, the XRPD pattern of p-toluenesulfonate crystal form I of compound I includes diffraction peaks at diffraction angles (2θ) of approximately 5.6 ± 0.2°, 15.1 ± 0.2°, 16.7 ± 0.2°, 17.0 ± 0.2°, and / or 22.8 ± 0.2°. Preferably, the XRPD pattern of p-toluenesulfonate crystal form I also includes diffraction peaks at diffraction angles (2θ) of approximately 19.9 ± 0.2°, 21.4 ± 0.2°, 25.8 ± 0.2°, and / or 27.1 ± 0.2°. Preferably, the XRPD pattern of crystal form I of the p-toluenesulfonate further includes values ​​at approximately 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°, and 19.3°. Diffraction peaks at diffraction angles (2θ) of ±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°. In some preferred embodiments, the XRPD pattern of crystal form I of the p-toluenesulfonate is substantially as shown in Figure 12, more preferably as shown in Figure 12. In some embodiments, the p-toluenesulfonate crystal form I loses about 5.5% of its weight upon heating to about 150 ± 5ºC (preferably about 150 ± 2ºC) and may decompose at about 200 ± 5ºC (preferably about 200 ± 2ºC), as measured using TGA. Preferably, the TGA spectrum of the p-toluenesulfonate crystal form I is substantially as shown in Figure 13, more preferably as shown in Figure 13. In some embodiments, the DSC spectrum of crystal form I of the p-toluenesulfonate is substantially as shown in Figure 13, preferably as shown in Figure 13. Crystal form I of the p-toluenesulfonate has a broad endothermic signal in the range of about 25-100 ºC, which matches the TGA weight loss signal, and has a melting endothermic peak at about 216 ± 5ºC (preferably about 216 ± 2ºC). Crystal form of p-toluenesulfonate II In some embodiments, the XRPD pattern of crystal form II of the p-toluenesulfonate of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (…). o ). In some embodiments, the XRPD pattern of crystal form II of the p-toluenesulfonate of compound I includes diffraction peaks at diffraction angles (2θ) of about 4.9 ± 0.2°, 5.7 ± 0.2°, 15.2 ± 0.2°, 17.1 ± 0.2°, and / or 22.8 ± 0.2°. Preferably, the XRPD pattern of crystal form II of the p-toluenesulfonate also includes diffraction peaks at diffraction angles (2θ) of about 11.4 ± 0.2°, 17.4 ± 0.2°, 20.3 ± 0.2°, 21.4 ± 0.2°, and / or 28.7 ± 0.2°. Preferably, the XRPD pattern of the p-toluenesulfonate crystal form II further includes diffraction peaks at diffraction angles (2θ) of approximately 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° and / or 40.0±0.2°. In some preferred embodiments, the XRPD pattern of crystal form II of the p-toluenesulfonate is substantially as shown in Figure 14, more preferably as shown in Figure 14. In some embodiments, the p-toluenesulfonate crystal form II continues to lose weight during heating, losing approximately 3.4% of its weight at approximately 128 ± 5ºC (preferably approximately 128 ± 2ºC), and may decompose above approximately 200 ± 5ºC (preferably approximately 200 ± 2ºC), as measured using TGA. Preferably, the TGA spectrum of the p-toluenesulfonate crystal form II is substantially as shown in Figure 15, more preferably as shown in Figure 15. In some embodiments, the DSC spectrum of crystal form II of the p-toluenesulfonate is substantially as shown in Figure 15, preferably as shown in Figure 15. Crystal form II of the p-toluenesulfonate exhibits a broad endothermic signal in the range of about 25-100 ºC, which matches the TGA weight loss signal, and shows a melting-decomposition signal at about 224 ± 5ºC (preferably about 224 ± 2ºC). In some embodiments, the NMR spectrum of crystal form II of the p-toluenesulfonate is substantially as shown in Figure 16(a), preferably as shown in Figure 16(a). A comparison of the NMR spectrum (a) with the NMR spectrum of p-toluenesulfonic acid (b) and the NMR spectrum of compound I (c) shows a change in the amino group peak position of crystal form II of the p-toluenesulfonate, indicating that the tested p-toluenesulfonate sample is indeed a salt. The integration results show that the molar ratio of compound I to p-toluenesulfonic acid in this salt is 1:1.5. As shown in Figure 17, the XRPD pattern of the p-toluenesulfonate crystal form II after DVS testing is consistent with that before testing, and there is no change in crystal form. In some embodiments, the PLM image of crystal form II of the p-toluenesulfonate is substantially as shown in Figure 18, preferably as shown in Figure 18. Crystal form II of the p-toluenesulfonate is rod-shaped crystal with a particle size generally less than 20 μm. Crystal form of p-toluenesulfonate III In some embodiments, the XRPD pattern of crystal form III of the p-toluenesulfonate of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ ( ). o ). In some embodiments, the XRPD pattern of crystal form III of the p-toluenesulfonate of compound I includes diffraction peaks at diffraction angles (2θ) of about 3.6 ± 0.2°, 7.2 ± 0.2°, 20.4 ± 0.2°, and / or 25.7 ± 0.2°. Preferably, the XRPD pattern of crystal form III of the p-toluenesulfonate also includes diffraction peaks at diffraction angles (2θ) of about 9.6 ± 0.2°, 12.6 ± 0.2°, 15.9 ± 0.2°, 18.3 ± 0.2°, 19.4 ± 0.2°, and / or 22.9 ± 0.2°. More preferably, the XRPD pattern of the p-toluenesulfonate crystal form III also includes diffraction peaks at diffraction angles (2θ) of approximately 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°. In some preferred embodiments, the XRPD pattern of the p-toluenesulfonate crystal form III is substantially as shown in Figure 19, and more preferably as shown in Figure 19. The present invention also provides crystal forms I and II of sodium salts of compound I having the following formula: . Crystal forms of sodium salts I In some embodiments, the XRPD pattern of crystal form I of the sodium salt of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ (…). o ). In some embodiments, the XRPD pattern of crystal form I of the sodium salt of compound I includes diffraction peaks at diffraction angles (2θ) of approximately 8.8 ± 0.2°, 17.9 ± 0.2°, 27.1 ± 0.2°, and / or 26.9 ± 0.2°. Preferably, the XRPD pattern of crystal form I of the sodium salt also includes diffraction peaks at diffraction angles (2θ) of approximately 16.8 ± 0.2°, 20.9 ± 0.2°, 21.7 ± 0.2°, 28.0 ± 0.2°, and / or 30.9 ± 0.2°. Preferably, the XRPD pattern of crystal form I of the sodium salt also includes diffraction peaks at diffraction angles (2θ) of 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±0.2°, 32.2±0.2° and / or 36.0±0.2°. In some preferred embodiments, the XRPD pattern of crystal form I of the sodium salt is substantially as shown in Figure 20, more preferably as shown in Figure 20. In some embodiments, the sodium salt in crystal form I undergoes continuous weight loss during heating, losing approximately 6.1% of its weight at approximately 120 ± 5ºC (preferably approximately 120 ± 2ºC), and may decompose above approximately 200 ± 5ºC (preferably approximately 200 ± 2ºC), as measured using TGA. Preferably, the TGA spectrum of the sodium salt in crystal form I is substantially as shown in Figure 21, more preferably as shown in Figure 21. In some embodiments, the DSC spectrum of the sodium salt in crystal form I is substantially as shown in Figure 21, preferably as shown in Figure 21. The sodium salt in crystal form I has a broad endothermic signal in the range of about 25-127 ºC, which matches the TGA weight loss signal, and has an endothermic peak at about 150 ± 5ºC (preferably about 150 ± 2ºC). Crystal forms of sodium salts II In some embodiments, the XRPD pattern of crystal form II of the sodium salt of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ ( ). o ). In some embodiments, the XRPD pattern of crystal form II of the sodium salt of compound I includes diffraction peaks at diffraction angles (2θ) of approximately 12.2 ± 0.2°, 14.2 ± 0.2°, 18.8 ± 0.2°, and / or 23.3 ± 0.2°. Preferably, the XRPD pattern of crystal form II of the sodium salt also includes diffraction peaks at diffraction angles (2θ) of approximately 7.0 ± 0.2°, 17.9 ± 0.2°, 33.2 ± 0.2°, 21.8 ± 0.2°, and / or 22.6 ± 0.2°. Preferably, the XRPD pattern of crystal form II of the sodium salt also includes diffraction peaks at diffraction angles (2θ) of approximately 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 40.3±0.2°. In some preferred embodiments, the XRPD pattern of crystal form II of the sodium salt is substantially as shown in Figure 22, more preferably as shown in Figure 22. In some embodiments, the sodium salt in crystal form II continues to lose weight during heating, losing approximately 4.2% of its weight when heated to approximately 100 ± 5ºC (preferably approximately 100 ± 2ºC), and approximately 3.4% of its weight when heated further to approximately 200 ± 5ºC (preferably approximately 200 ± 2ºC). Decomposition may occur above 220 ± 5ºC (preferably approximately 220 ± 2ºC), as measured using TGA. Preferably, the TGA spectrum of the sodium salt in crystal form II is substantially as shown in Figure 23, more preferably as shown in Figure 23. In some embodiments, the DSC spectrum of crystal form II of the sodium salt is substantially as shown in Figure 23, preferably as shown in Figure 23. Crystal form II of the sodium salt has a broad endothermic peak between about 25-100 ºC and about 100-200 ºC, which is consistent with the TGA weight loss signal. In some embodiments, the NMR spectrum of crystal form II of the sodium salt is substantially as shown in Figure 24(a), preferably as shown in Figure 24(a). A comparison of the NMR spectrum (a) with the NMR spectrum (b) of compound I shows a significant shift in the peak position at approximately 4.4-4.5 ppm, indicating that the tested sodium salt sample is indeed a salt. Crystal forms of ethanolamine salts I This invention also provides crystal form I of the ethanolamine salt of compound I having the following formula: . In some embodiments, the XRPD pattern of crystal form I of the ethanolamine salt of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ ( ). o ). In some embodiments, the XRPD pattern of crystal form I of the ethanolamine salt of compound I includes diffraction peaks at diffraction angles (2θ) of approximately 10.2 ± 0.2°, 18.8 ± 0.2°, 23.6 ± 0.2°, and / or 28.2 ± 0.2°. Preferably, the XRPD pattern of crystal form I of the ethanolamine salt also includes diffraction peaks at diffraction angles (2θ) of approximately 9.9 ± 0.2°, 20.0 ± 0.2°, 22.8 ± 0.2°, 24.5 ± 0.2°, and / or 29.8 ± 0.2°. More preferably, the XRPD pattern of crystal form I of the ethanolamine salt also includes diffraction peaks at diffraction angles (2θ) of approximately 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° and / or 35.9±0.2°. In some preferred embodiments, the XRPD pattern of crystal form I of the ethanolamine salt is substantially as shown in Figure 25, more preferably as shown in Figure 25. In some embodiments, the crystalline form I of the ethanolamine salt undergoes continuous weight loss during heating, with a weight loss of approximately 3.9% at approximately 100 ± 5ºC (preferably approximately 100 ± 2ºC), and decomposition may occur above 160 ± 5ºC (preferably approximately 160 ± 2ºC), as measured using TGA. Preferably, the TGA spectrum of the crystalline form I of the ethanolamine salt is substantially as shown in Figure 26, more preferably as shown in Figure 26. In some embodiments, crystal form I of the ethanolamine salt exhibits a broad endothermic signal between approximately 25-100 °C, consistent with the TGA weight loss signal, and has an endothermic melting peak at approximately 209 ± 5 °C (preferably approximately 209 ± 2 °C). Preferably, the DSC spectrum of crystal form I of the ethanolamine salt is substantially as shown in Figure 26, more preferably as shown in Figure 26. In some embodiments, the NMR spectrum of crystal form I of the ethanolamine salt is substantially as shown in Figure 27(a), preferably as shown in Figure 27(a). A comparison of the NMR spectrum (a) with the NMR spectrum of ethanolamine (b) and the NMR spectrum of compound I (c) shows a significant shift in peak positions at approximately 2.5-4.5 ppm, and characteristic peaks of ethanolamine are visible at approximately 2.8 ppm and approximately 3.5 ppm, indicating that the measured ethanolamine salt sample is indeed a salt. As shown in Figure 28, the XRPD pattern of the ethanolamine salt in crystal form I after DVS testing is consistent with that before testing, and there is no change in crystal form. In some embodiments, the PLM image of crystal form I of the ethanolamine salt is essentially as shown in Figure 29, and preferably as shown in Figure 29. Crystal form I of the ethanolamine salt is rod-shaped crystal with a particle size generally less than 20 μm. free state compounds I Crystal form A In some embodiments, the XRPD pattern of crystal form A of compound I shows at maximum intensity at at least two, at least three, at least four, at least five, or at least six diffraction angles 2θ ( ). o ). In some embodiments, the XRPD pattern of crystal form A of compound I includes diffraction peaks at diffraction angles (2θ) of approximately 6.7 ± 0.2°, 18.2 ± 0.2°, 27.4 ± 0.2°, and / or 28.2 ± 0.2°. Preferably, the XRPD pattern of crystal form A also includes diffraction peaks at diffraction angles (2θ) of approximately 16.9 ± 0.2°, 20.2 ± 0.2°, 20.7 ± 0.2°, 21.0 ± 0.2°, and / or 21.8 ± 0.2°. More preferably, the XRPD pattern of crystal form A also includes diffraction peaks at diffraction angles (2θ) of approximately 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°. In some preferred embodiments, the XRPD pattern of crystal form A is substantially as shown in Figure 30, and more preferably as shown in Figure 30. In some embodiments, the onset temperature of the endothermic peak of crystal form A is about 185 ± 5ºC, more preferably about 185 ± 2ºC. Preferably, the DSC spectrum of crystal form A is substantially as shown in Figure 31, more preferably as shown in Figure 31. In some embodiments, crystal form A loses approximately 2.24% of its weight upon heating to approximately 100 ± 5ºC (preferably approximately 100 ± 2ºC) and may begin to decompose at approximately 200 ± 5ºC (preferably approximately 200 ± 2ºC), as measured using a TGA. Preferably, the TGA spectrum of crystal form A is substantially as shown in Figure 31, more preferably as shown in Figure 31. In some embodiments, the NMR spectrum of crystal form A is essentially as shown in Figure 32, preferably as shown in Figure 32. The NMR spectrum shows no obvious characteristic peaks of organic solvents. In some embodiments, the crystal form A is not a solvate, but more preferably an anhydrous form. In some embodiments, the PLM image of crystal form A is essentially as shown in Figure 34, preferably as shown in Figure 34. Crystal form A is a plate-like particle with a particle size generally less than about 20 μm. compound I Preparation of the crystal form of the salt In a second aspect, the present invention provides a method for preparing a crystal form of a salt of compound I as described above, the method comprising: (1) reacting compound I with a suitable acidic / basic compound in an appropriate amount of a suitable solvent, and suspending the reaction mixture for a period of time; (2) subjecting the resulting suspension to solid-liquid separation (e.g., by centrifugation), drying the resulting solid to obtain the crystal form; or cooling the resulting suspension to crystallize, drying the crystal obtained by solid-liquid separation (e.g., by centrifugation) to obtain the crystal form; or adding an antisolvent to the resulting suspension to crystallize, drying the crystal obtained by solid-liquid separation (e.g., by centrifugation) to obtain the crystal form. In some embodiments, compound I is crystal form A of compound I. The acidic compounds include, but are not limited to, hydrochloric acid, sulfuric acid, methanesulfonic acid, and p-benzenesulfonic acid. The basic compounds include, but are not limited to, sodium hydroxide, sodium isooctanoate or other basic sodium reagents (e.g., sodium isohexanoate, sodium isovalerate), and ethanolamine. The solvent includes a selection from water, ethyl acetate, tetrahydrofuran, methanol, and combinations of two or more of these. Crystal forms of hydrochloride I Preparation In some embodiments, the present invention provides a method for preparing crystal form I of the hydrochloride as described above, the method comprising: (1) providing a suspension of compound I in a suitable solvent (including but not limited to ethyl acetate), preferably in a concentration of compound I of about 1-200 mg / ml; (2) adding to the suspension a solution containing 2 equivalents or excess of hydrogen chloride (wherein the solvent includes but is not limited to water and ethyl acetate) and stirring, performing solid-liquid separation after the compound I is completely converted into hydrochloride, and drying the resulting solid to obtain crystal form I of the hydrochloride. In some embodiments, compound I is crystal form A of compound I. In some embodiments, the solution containing hydrogen chloride is dilute hydrochloric acid. Crystal forms of sulfates I Preparation In some embodiments, the present invention provides a method for preparing crystal form I of the sulfate described above, the method comprising: (1) providing a suspension of compound I in a suitable solvent (including but not limited to ethyl acetate), preferably in a concentration of compound I of about 1-200 mg / ml; (2) adding a solution containing 2 equivalents or excess of sulfuric acid (wherein the solvent includes but is not limited to water) to the suspension and stirring, performing solid-liquid separation after compound I has been completely converted into sulfate, and drying the resulting solid to obtain crystal form I of the sulfate. In some embodiments, compound I is crystal form A of compound I. In some embodiments, the sulfuric acid-containing solution is a dilute aqueous solution of sulfuric acid. Crystal form of p-toluenesulfonate I Preparation In some embodiments, the present invention provides a method for preparing crystal form I of the p-toluenesulfonate described above, the method comprising: (1) providing a suspension of compound I in a suitable solvent (including but not limited to tetrahydrofuran), preferably in which the content of compound I in the suspension is about 1-200 mg / ml; (2) adding two equivalents or excess of p-toluenesulfonic acid to the suspension and stirring, performing solid-liquid separation after the compound I is completely converted into p-toluenesulfonate, and drying the resulting solid to obtain crystal form I of the p-toluenesulfonate. In some embodiments, compound I is crystal form A of compound I. The p-toluenesulfonic acid may be added either on its own or as a solution in a suitable solvent. Crystal form of p-toluenesulfonate II Preparation In some embodiments, the present invention provides a method for preparing crystal form II of the p-toluenesulfonate described above, the method comprising: (1) providing a suspension of compound I in a suitable solvent (including but not limited to tetrahydrofuran), preferably in a concentration of compound I of about 1-200 mg / ml in the suspension; (2) adding two equivalents or excess of p-toluenesulfonic acid to the suspension and stirring, performing solid-liquid separation after compound I has been completely converted to p-toluenesulfonate, and drying the resulting solid to obtain crystal form II of the p-toluenesulfonate. In some embodiments, compound I is crystal form A of compound I. The p-toluenesulfonic acid may be added either on its own or as a solution in a suitable solvent. Crystal forms of methanesulfonates I Preparation In some embodiments, the present invention provides a method for preparing crystal form I of the methanesulfonate described above, the method comprising: (1) providing a suspension of compound I in a suitable solvent (including but not limited to tetrahydrofuran), preferably in which the content of compound I in the suspension is about 1-200 mg / ml; (2) adding 2 equivalents or excess of methanesulfonic acid to the suspension and stirring, performing solid-liquid separation after the compound I is completely converted into methanesulfonate, and drying the resulting solid to obtain crystal form I of the methanesulfonate. In some embodiments, compound I is crystal form A of compound I. The methanesulfonic acid may be added either on its own or as a solution in a suitable solvent. Crystal forms of sodium salts I Preparation In some embodiments, the present invention provides a method for preparing crystal form I of the sodium salt described above, the method comprising: (1) providing a suspension of compound I in a suitable solvent (including but not limited to ethyl acetate), preferably having a content of compound I in the suspension of about 1-200 mg / ml; (2) adding two equivalents or excess of sodium hydroxide to the suspension and stirring, performing solid-liquid separation after compound I has been completely converted into sodium salt, and drying the resulting solid to obtain crystal form I of the sodium salt. In some embodiments, compound I shown is crystal form A of compound I. The sodium hydroxide may be added either on its own or in the form of a solution in a suitable solvent. Crystal forms of sodium salts II Preparation In some embodiments, the present invention provides a method for preparing crystal form II of the sodium salt described above, the method comprising: (1) providing a suspension of compound I in a suitable solvent (including but not limited to tetrahydrofuran), preferably in a concentration of compound I of about 1-200 mg / ml; (2) adding two equivalents or an excess of sodium isooctanoate (or other basic sodium reagent) to the suspension and stirring, performing solid-liquid separation after compound I has been completely converted into sodium salt, and drying the resulting solid to obtain crystal form II of the sodium salt. In some embodiments, compound I is crystal form A of compound I. The sodium isooctanoate or other basic sodium reagent may be added either on its own or in the form of a solution in a suitable solvent. In some embodiments, the other alkaline sodium reagents include, but are not limited to, sodium isohexanoate and sodium isovalerate. Crystal forms of ethanolamine salts I Preparation In some embodiments, the present invention provides a method for preparing crystal form I of the ethanolamine salt described above, the method comprising: (1) providing a suspension of compound I in a suitable solvent (including but not limited to methanol, tetrahydrofuran and ethyl acetate), preferably wherein the content of compound I in the suspension is about 1-200 mg / ml; (2) adding 2 equivalents or excess of ethanolamine to the suspension and stirring, performing solid-liquid separation after compound I is completely converted into ethanolamine salt, and drying the resulting solid to obtain crystal form I of the ethanolamine salt. In some embodiments, compound I shown is crystal form A of compound I. The ethanolamine may be added either on its own or in the form of a solution in a suitable solvent. compound I Crystal form A Preparation In some embodiments, the present invention provides a method for preparing the crystal form A described above, the method comprising: a1) providing a suspension of compound I in a suitable solvent, preferably in which the content of compound I in the suspension is about 1-200 mg / ml; a2) stirring the suspension at room temperature for a sufficient time, then performing solid-liquid separation (e.g., by centrifugation), and drying the resulting solid to obtain the crystal form A. In some preferred embodiments, the suitable solvent is selected from DMF, DMSO, methanol, ethanol, n-propanol, isopropanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, 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. In some preferred embodiments, in step a2), the stirring at room temperature continues for approximately 3-7 days. For example, in small-scale experiments, the stirring at room temperature continues for approximately 7 days; in scale-up production, the stirring at room temperature continues for approximately 3 days. In other embodiments, the present invention provides a method for preparing the free crystalline form A, the method comprising: b1) adding compound I to a good solvent, then adding an appropriate base, and filtering after the solid has dissolved; b2) adding an appropriate acid to the filtrate obtained in step b1), precipitating a solid to obtain the crystalline form A; in some preferred embodiments, the good solvent is water, isopropyl ether, n-heptane, or toluene, more preferably water. In some preferred embodiments, the base is ethanolamine. In some preferred embodiments, the acid is hydrochloric acid, sulfuric acid, or phosphoric acid. In a third aspect, the present invention provides a pharmaceutical composition comprising an effective amount of any one selected from the 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 methanesulfonate, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt, and crystal form A of compound I, as well as one or more pharmaceutically acceptable carriers. In a fourth aspect, the present invention provides any one of the 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 methanesulfonate, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt, and crystal form A of compound I, or the pharmaceutical composition thereof, for use in renal function monitoring, wherein the renal function monitoring is GFR monitoring, particularly real-time GFR monitoring. In a fifth aspect, the present invention provides the use of any one of the 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 methanesulfonate, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt, and crystal form A of compound I, or the pharmaceutical composition thereof, in the preparation of a medicament for monitoring renal function ("tracer"), wherein the renal function monitoring is GFR monitoring, particularly real-time GFR monitoring. In a sixth aspect, the present invention provides a method for monitoring renal function in an individual, the method comprising administering to the individual an effective amount of any one of the 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 methanesulfonate, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt, and crystal form A of compound I, or the pharmaceutical composition thereof, wherein the renal function monitoring is GFR monitoring, particularly immediate GFR monitoring. The crystal form I of the hydrochloride, crystal form I of the sulfate, crystal form I of p-toluenesulfonate, crystal form II of p-toluenesulfonate, crystal form I of methanesulfonate, crystal form I of sodium salt, crystal form II of sodium salt, crystal form I of ethanolamine salt, and crystal form A of compound I, or the pharmaceutical composition or drug, can be administered via various routes, including but not limited to oral, parenteral, transdermal, subcutaneous, enteric, or intravenous administration. Beneficial effects of the present invention Compound I forms stable salts with hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, sodium hydroxide, and ethanolamine. The free form (crystal form A), its hydrochloride salt (crystal form I), its p-toluenesulfonic acid salt (crystal form II), and the ethanolamine salt (crystal form I) of compound I exhibit good properties in terms of solid-state stability and dynamic solubility. In particular, the ethanolamine salt (crystal form I) has good solubility, meeting the requirements for oral administration. The free form (crystal form A) of compound I demonstrates superior stability under light, high temperature, and high humidity conditions, meeting the pharmaceutical requirements for production, transportation, and storage. Its production process is stable, repeatable, and controllable, making it suitable for industrial production. Example The present invention will be further described below with reference to the accompanying drawings and specific embodiments. The purpose of this description is merely to illustrate the invention in order to better understand it, but it is not intended to limit the scope of the invention. Methods and Materials X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and nuclear magnetic resonance (NMR) were used to analyze the data. 1 The crystal forms prepared in the examples were characterized by 1H NMR spectroscopy and polarized light microscopy (PLM). 1 H NMR Dissolve a certain amount of solid sample in dimethyl sulfoxide. In d6, NMR analysis was performed on a Bruker AVANCE-III (Bruker, GER). XRPD The samples were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, GER). The 2θ scan range was 3º to 45º (Cu-Kα (Kα1 (Å): 1.5406)), with a scan step of 0.02º and an exposure time of 0.2 s (for various salt crystal forms) or 0.12 s (for free compound I in crystal form A). The phototube voltage and current were 40 kV and 40 mA, respectively, and the sample disk was a zero-background sample disk. TGA A TA Discovery 55 thermogravimetric analyzer (TA, US) was used. 2 to 5 mg of sample were placed in a pre-equilibrated open aluminum sample pan and automatically weighed within the TGA furnace. The sample was heated to the final temperature at a rate of 10 ºC / min, with nitrogen purging at 60 ml / min at the sample location and 40 ml / min at the balance location. DSC 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. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at a rate of 50 ml / min. PLM A polarizing microscope, Motic BA310Met (Motic, CN), was used. A small number of samples were placed on a glass slide, and the morphology of the samples was observed using a suitable lens. Dynamic moisture adsorption analysis ( DVS ) Dynamic moisture adsorption analysis was performed using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations of 50%–95%–0%–50%. Within the 0%–90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint. After the test, XRPD analysis was performed on the samples to confirm whether the solid form had changed. compound I Compound I was obtained by the method described in Example 12 of WO 2019 / 084475 A1, and unless otherwise expressly stated, Compound I is referred to in the context of this document as the product obtained. Example 1 Compound I Method 1 for preparing and screening the crystal form of salts - Solution suspension method: Weigh 19 mg (0.05 mmol) of compound I and at least two equivalents of the acidic / basic compound listed in Table 1 and add them to an appropriate amount of the solvent selected in Table 1. Suspend at room temperature for 4 days. Centrifuge the suspension containing solids to separate the solids and dry under vacuum at room temperature. Method 2 - Cooling Crystallization: For solutions without solid precipitation in the suspension method, place them in a refrigerator at 5°C or -15°C for one day to cool. For solutions with solid precipitation, centrifuge to separate the solids and then vacuum dry at room temperature. Method 3 - Dissolution-crystallization method: For solutions that do not precipitate solids during the cooling crystallization method, add the antisolvent methyl tert-butyl ether dropwise at room temperature until a small amount of turbidity is produced and stir overnight. Then, centrifuge the solution with solid precipitates to separate the solids and dry it under vacuum at room temperature. The obtained solids were subjected to XRPD analysis to determine their crystal form. Table 1: Summary of Screening Experiments Note: * Obtained by solution suspension method; ** No solid precipitated after solution suspension and cooling crystallization, a gel-like substance was obtained by dissolution crystallization method; *** Obtained by solution suspension method, poor crystallinity, may contain free solids. Table 2. 1 H NMR data The XRPD patterns of crystal form I of hydrochloride are shown in Figure 1; those of crystal form I of sulfate are shown in Figure 6; those of crystal form I of methanesulfonate are shown in Figure 9; those of crystal form I of p-toluenesulfonate are shown in Figure 12; those of crystal form I of sodium salt are shown in Figure 20; those of crystal form II of sodium salt are shown in Figure 22; and those of crystal form I of ethanolamine salt are shown in Figure 25. Example 2 Compound I Crystal form of hydrochloride I Preparation The crystal form A of compound I (532.0 mg), 1 mol / L hydrochloric acid (2.9 mL), and ethyl acetate (56 mL) were mixed, stirred at room temperature for 3 days, centrifuged, and dried under vacuum at room temperature to obtain an orange-yellow powder solid (512 mg). The XRPD pattern is basically as shown in Figure 1, indicating that the solid is the crystal form I of the hydrochloride. The hydrochloride crystal form I obtained from the scale-up preparation was characterized by XRPD, DSC, TGA, NMR, DVS, and PLM. XRPD results showed that crystal form I of hydrochloride is a highly crystalline crystal. TGA results, as shown in Figure 2, showed that crystal form I of hydrochloride exhibited a weight loss step of approximately 4.0% during heating to approximately 130ºC, and a weight loss of approximately 8.2% during the 130-200ºC range; drastic weight loss occurred after 200ºC, indicating possible decomposition. DSC results, also shown in Figure 2, showed endothermic signals at approximately 90ºC and 195ºC, consistent with the weight loss signals observed in TGA; a melting signal accompanied by decomposition was observed at approximately 212ºC. NMR results, as shown in Figure 3, showed a change in the amino group peak position of the hydrochloride, confirming that the tested sample was indeed a salt; a broad signal in the 4.0-5.0 ppm range indicated the presence of water in the sample. Ion chromatography results showed that the chloride ion content of the sample was 6.52%, indicating that the molar ratio of compound 1 to HCl in the salt was 1:1. As shown in Figure 4, the XRPD spectrum of the sample after DVS testing was consistent with that before testing, showing no change in crystal form. The microscopic image, shown in Figure 5, shows that crystal form I of hydrochloride has small particles and obvious aggregation. In summary, crystal form I of hydrochloride may be an anhydrous form or a hydrate containing adsorbed water. Example 3 Compound I Crystal form of ethanolamine salt I Preparation The crystal form A of compound I (532.1 mg), ethanolamine (200 μL), and ethyl acetate (56 mL) were mixed, stirred at room temperature for 3 days, centrifuged, and dried under vacuum at room temperature to obtain an orange-red powder solid (588 mg). The XRPD pattern is basically as shown in Figure 25, indicating that the solid is crystal form I of ethanolamine salt. The obtained ethanolamine salt, crystal form I, was characterized by XRPD, DSC, TGA, NMR, DVS, and PLM. The TGA results, shown in Figure 26, indicate that ethanolamine salt crystal form I continuously loses weight during heating, with a weight loss of approximately 3.9% at 100ºC, and decomposition may occur above 160ºC. The DSC results, also shown in Figure 26, show a broad endothermic signal in the ethanolamine salt crystal form I between 25-100ºC, consistent with the weight loss signal from TGA; an endothermic melting peak is present at approximately 209ºC. The NMR results, shown in Figure 27, show a significant peak shift in the 2.5-4.5 ppm range, with characteristic peaks of ethanolamine visible at 2.8 ppm and 3.5 ppm, confirming that the sample is indeed a salt. The integration results indicate a molar ratio of ethanolamine to the compound in the salt of 1:2; a broad signal is present at approximately 3.3 ppm, possibly corresponding to water in the sample. As shown in Figure 28, the XRPD pattern of the sample after DVS testing was generally consistent with that before testing. The microscopic image, shown in Figure 29, reveals that the ethanolamine salt crystal form I particles are small and exhibit significant aggregation. Based on the above information, ethanolamine salt crystal form I may be an anhydrous form containing adsorbed water. Example 4 Compound I Crystal form of p-toluenesulfonate II Preparation The crystal form A of compound I (532.1 mg), p-toluenesulfonic acid (568.2 mg), and tetrahydrofuran (56 mL) were mixed, stirred at room temperature for 3 days, centrifuged, and dried under vacuum at room temperature to obtain a yellow powder solid (630 mg). The XRPD pattern is basically as shown in Figure 14, indicating that the solid is crystal form II of p-toluenesulfonate. 1 H NMR (400 MHz, DMSO) δ 8.46 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.1 Hz, 3H), 7.11 (d, J= 7.8 Hz, 2H), 4.52 – 4.42 (m, 2H), 3.89 (dd, J= 11.0, 3.8 Hz, 2H), 3.74 (dd, J= 11.0, 3.4 Hz, 2H), 2.29 (s, 4.5H). The p-toluenesulfonate crystal form II obtained from the scale-up preparation was characterized by XRPD, DSC, TGA, NMR, DVS, and PLM. XRPD results showed that p-toluenesulfonate crystal form II was a highly crystalline crystal. TGA results, shown in Figure 15, indicated that p-toluenesulfonate crystal form II continuously lost weight during heating, with a weight loss of approximately 3.4% at 128ºC, and decomposition was possible above 200ºC. DSC results, also shown in Figure 15, showed a broad endothermic signal in the 25-100ºC range for p-toluenesulfonate crystal form II, consistent with the TGA weight loss signal; a melting and decomposition signal was observed at 224ºC. NMR results, shown in Figure 16, showed a change in the amino group peak position in p-toluenesulfonate crystal form II, indicating that the tested sample was indeed a salt. The integration results showed a molar ratio of compound 1 to p-toluenesulfonic acid of 1:1.5 in this salt; a broad signal was observed at approximately 5 ppm, possibly corresponding to water in the sample. As shown in Figure 17, the XRPD pattern of the sample after DVS testing was consistent with that before testing. The microscopic image, shown in Figure 18, reveals that the p-toluenesulfonate crystal form II particles are rod-shaped crystals with small particle size and exhibit agglomeration. In conclusion, p-toluenesulfonate crystal form II may be an anhydrous form containing adsorbed water. Example 5 : Stability Study Stability studies were conducted on crystal form I of hydrochloride, crystal form II of p-toluenesulfonate, crystal form I of ethanolamine salt, and crystal form A of compound I under high temperature (60ºC), high humidity (25ºC, 92.5 %RH), and light irradiation (25ºC, 4500 Lux) conditions. XRPD spectra were measured on days 7 and 16. The results are shown in Table 3 below. Table 3 Example 6 : Solubility test in biological media FaSSIF is a simulated intestinal fluid in a fasting state, and it is prepared as follows: (1) Weigh 0.042 g sodium hydroxide, 0.3438 g sodium dihydrogen phosphate and 0.6186 g sodium chloride, add 90 mL of purified water and mix well, then adjust the pH to 6.5 with 1N hydrochloric acid or 1N sodium hydroxide, and make up to 100 mL with purified water; (2) Take 50 mL of the buffer solution prepared in (1) above, add 0.224 g of commercially available FaSSIF / FeSSIF / FaSSGF powder (Biorelevant.com), stir until dissolved, and then make up to 100 mL with the buffer solution 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, then it is ready for use. FeSSIF is a simulated intestinal fluid under feeding conditions, and it is prepared as follows: (1) Weigh 0.404 g sodium hydroxide, 0.865 g glacial acetic acid, and 1.1874 g sodium chloride, add 90 mL of purified water and mix well. Then adjust the pH to 5.0 with 1N hydrochloric acid or 1N sodium hydroxide, and bring the volume to 100 mL with purified water. (2) Take 50 mL of the buffer solution prepared in (1) above, add 1.12 g of commercially available FaSSIF / FeSSIF / FaSSGF powder (Biorelevant.com), stir until dissolved, and then bring the volume to 100 mL 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. It is then ready for use. FaSSGF (SGF) is a gastric juice simulator, prepared as follows: (1) Weigh 0.2 g of sodium chloride, add 90 mL of purified water and mix well. Then adjust the pH to 1.8 with 1N hydrochloric acid, and bring the volume to 100 mL with purified water. Let it stand at room temperature. (2) Take 50 mL of the buffer solution prepared in (1) above, add 0.006 g of commercially available FaSSIF / FeSSIF / FaSSGF powder (Biorelevant.com), stir until dissolved, and bring the volume to 100 mL with the buffer solution prepared in (1). After the prepared buffer solution is placed at room temperature and allowed to stand for two hours, observe that the buffer solution is a clear liquid, and it is ready for use. The solubility of hydrochloride (crystal form I), p-toluenesulfonate (crystal form II), ethanolamine salt (crystal form I), and compound I (crystal form A) in three biological media—FaSSIF, FeSSIF, and FaSSGF—was determined. The results of the dynamic solubility tests of the three salt crystal forms and free compound I (crystal form A) in these biological media are shown in Table 4. Table 4 Note: Solubility values ​​are based on free compound I and are calculated from the standard curve of free compound I. The results showed that the solubility of ethanolamine salt crystal form I in all three biological media was significantly higher than that of the other three solid forms; furthermore, due to its high solubility, no solid remained for XRPD characterization. XRPD and NMR results indicated that both hydrochloride and p-toluenesulfonate salts underwent disproportionation during the solubility test, transforming into a free state after the test. Crystal form A of compound I did not undergo any crystal form change during the solubility test. Furthermore, all salts showed higher solubility in FeSSIF than in FaSSIF and FaSSGF, suggesting that postprandial administration may be advantageous. Solubility experiments revealed that crystal form I of hydrochloride, crystal form II of p-toluenesulfonate, crystal form I of ethanolamine salt, and crystal form A of free compound I all exhibited good solubility in FaSSIF, FeSSIF, and FaSSGF. In particular, crystal form I of ethanolamine salt demonstrated a significant dissolution advantage in the prepared formulation, which is beneficial for dissolution and bioavailability under different biological media conditions during application. In addition to those described herein, various modifications of the invention are also intended to fall within the scope of the appended claims, based on the foregoing description. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety. Figure 1: XRPD spectrum of crystal form I of compound I hydrochloride. Figure 2: Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) spectra of crystal form I of compound I hydrochloride. Figure 3: Comparison of crystal form I and crystal form A of compound I hydrochloride. 1 Figure 4: XRPD spectra of crystal form I of compound I hydrochloride before and after dynamic water adsorption (DVS) testing. Figure 5: PLM image of crystal form I of compound I hydrochloride. Figure 6: XRPD spectrum of crystal form I of compound I sulfate. Figure 7: TGA and DSC spectra of crystal form I of compound I sulfate. Figure 8: Comparison of crystal form I of compound I sulfate with crystal form A of compound I. 1 Figure 9: XRPD spectrum of crystal form I of methanesulfonate of compound I. Figure 10: TGA and DSC spectra of crystal form I of methanesulfonate of compound I. Figure 11: Crystal form I of methanesulfonate of compound I compared with crystal form A of compound I. 1Figure 12: XRPD spectrum of crystal form I of p-toluenesulfonate of compound I. Figure 13: TGA and DSC spectra of crystal form I of p-toluenesulfonate of compound I. Figure 14: XRPD spectrum of crystal form II of p-toluenesulfonate of compound I. Figure 15: TGA and DSC spectra of crystal form II of p-toluenesulfonate of compound I. Figure 16: Crystal form II of p-toluenesulfonate of compound I compared with crystal form A of compound I. 1 Figure 17: XRPD spectra of crystal form II of p-toluenesulfonate of compound I before and after DVS testing. Figure 18: PLM image of crystal form II of p-toluenesulfonate of compound I. Figure 19: XRPD spectra of crystal form III of p-toluenesulfonate of compound I. Figure 20: XRPD spectra of crystal form I of sodium salt of compound I. Figure 21: TGA and DSC spectra of crystal form I of sodium salt of compound I. Figure 22: XRPD spectra of crystal form II of sodium salt of compound I. Figure 23: TGA and DSC spectra of crystal form II of sodium salt of compound I. Figure 24: Crystal form II of sodium salt of compound I compared with crystal form A of compound I. 1 Figure 25: XRPD spectrum of crystal form I of the ethanolamine salt of compound I. Figure 26: TGA and DSC spectra of crystal form I of the ethanolamine salt of compound I. Figure 27: Crystal form I and crystal form A of compound I. 1 Figure 28: XRPD spectra of crystal form I of the ethanolamine salt of compound I before and after DVS testing. Figure 29: PLM image of crystal form I of the ethanolamine salt of compound I. Figure 30: XRPD spectrum of crystal form A of compound I. Figure 31: TGA and DSC spectra of crystal form A of compound I. Figure 32: XRPD spectrum of crystal form A of compound I. 1 1H NMR spectrum. Figure 33: PLM image of crystal form A of compound I.

Claims

1. A crystal form I of an ethanolamine salt having the following formula, characterized in that the XRPD pattern of the crystal form I of the ethanolamine salt includes diffraction peaks at diffraction angles (2θ) of 10.2±0.2°, 18.8±0.2°, 23.6±0.2° and 28.2±0.2°.

2. Crystal form I of the ethanolamine salt of compound I as claimed in claim 1, characterized in that the XRPD pattern of crystal form I of the ethanolamine salt further includes diffraction peaks at diffraction angles (2θ) of 9.9±0.2°, 20.0±0.2°, 22.8±0.2°, 24.5±0.2° or 29.8±0.2°.

3. Crystal form I of the ethanolamine salt of compound I as claimed in claim 2, characterized in that the XRPD pattern of crystal form I of the ethanolamine salt further includes diffraction peaks at diffraction angles (2θ) of 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° or 35.9±0.2°.

4. The ethanolamine salt of compound I of claim 3, in crystal form I, characterized in that the XRPD pattern of crystal form I of the ethanolamine salt is substantially as shown in Figure 25.

5. The ethanolamine salt of compound I of claim 4, in crystal form I, characterized in that the XRPD pattern of crystal form I of the ethanolamine salt is shown in Figure 25.

6. A method for preparing crystal form I of the ethanolamine salt of compound I as described in any one of claims 1 to 5, characterized in that the method comprises: (1) Provide a suspension of compound I in a suitable solvent; (2) Add 2 times the equivalent or excess of ethanolamine to the suspension and stir. After compound I is completely converted into ethanolamine salt, perform solid-liquid separation and dry the obtained solid to obtain crystal form I of ethanolamine salt of compound I.

7. The method of claim 6, characterized in that, in step (1), the content of compound I in the suspension is 1-200 mg / mL.

8. The method of claim 6, characterized in that, in step (1), the suitable solvent is selected from methanol, tetrahydrofuran and ethyl acetate.

9. A pharmaceutical composition comprising crystal form I of an ethanolamine salt of compound I as described in any one of claims 1 to 5, and one or more pharmaceutically acceptable carriers.

10. Use of a crystal form I of an ethanolamine salt of compound I as claimed in any one of claims 1 to 5, or a pharmaceutical composition as claimed in claim 9, in the preparation of a medicament for monitoring renal function, wherein the renal function monitoring is GFR monitoring.

11. As used in claim 10, wherein the renal function monitoring is real-time GFR monitoring.

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