Solid forms of d-glucose-6, 6 '-d2

Abstract

The invention provides a solid form of D-glucose-6, 6 '-d2 and a preparation method of the D-glucose-6, 6'-d2. D-glucose-6, 6 '-d2 (compound I).

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a solid form of D-glucose-6,6'-d2. Background Art

[0002] D-glucose-6,6'-d2 (Compound I) is a molecular probe used for deuterium metabolism imaging. It can obtain information on cellular metabolism through magnetic resonance imaging (MRI) scanning technology. It can accurately diagnose diseases involving metabolism and provide a new, non-invasive, radiation-free and simple imaging technology.

[0003] Due to the varying physical and chemical properties of different crystalline forms, solid-state drug molecules may exhibit varying solubility, bioavailability, and stability in the body, which in turn may affect the drug's clinical efficacy and safety to a certain extent. Therefore, drug crystalline form is a crucial component of solid-state drug research and development, and a key indicator of drug quality control. When a drug exists in different crystalline forms, it is ideal to select the most useful crystalline form for manufacturing.

[0004] There are currently no patent reports on the crystal form of D-glucose-6,6'-d2 (Compound I), and no relevant crystal form information is available for reference. This field needs to develop a crystal form with good solubility and stability to meet the bioavailability of the drug, be suitable for industrial development, and have comprehensive performance in all aspects that meet the requirements of pharmaceutical development. Summary of the Invention

[0005] In one aspect, the present invention provides a solid form of Compound I or a salt thereof, or a solvate thereof, or a solvate of a salt thereof, or a mixture thereof:

[0006]

[0007] Compound I,

[0008] Pharmaceutical compositions comprising the solid form, and uses of the solid form and pharmaceutical compositions comprising the solid form.

[0009] In one specific aspect, the present invention provides a crystalline Form I of the free base of Compound I. In one embodiment, the crystalline Form I is characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 17.0°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 28.5°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.6°±0.2°. In one embodiment, the crystalline Form I is characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.8°±0.2°, 19.3°±0.2°, 20.6°±0.2°, 23.5°±0.2°, 25.5°±0.2°, 28.5°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.6°±0.2°. In one embodiment, the crystalline Form I is characterized in that it has substantially Figure 1 The XRPD spectrum shown.

[0010] In one specific aspect, the present invention provides Form II of Compound I monohydrate. In one embodiment, the Form II is characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 19.7°±0.2°, 20.1°±0.2°, and 22.7°±0.2°. In one embodiment, the crystalline Form II is characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 9.1°±0.2°, 12.7°±0.2°, 14.5°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 22.7°±0.2°, 25.4°±0.2°, 27.5°±0.2°, 28.2°±0.2°, 31.1°±0.2°, 33.3°±0.2°, 35.3°±0.2°, 35.6°±0.2°, and 36.9°±0.2°. In one embodiment, the crystalline Form II is characterized in that it has substantially Figure 5 The XRPD spectrum shown.

[0011] In one specific aspect, the present invention provides Form III of the free base of Compound I. In one embodiment, the Form III is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 28.4°±0.2°, and 36.2°±0.2°. In one embodiment, the Form III is characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 25.5°±0.2°, 28.4°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.5°±0.2°. In one embodiment, the crystalline Form III is characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 10.4°±0.2°, 11.9°±0.2°, 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 25.5°±0.2°, 28.4°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.5°±0.2°. In one embodiment, the crystalline Form III is characterized in that it has substantially Figure 9 The XRPD spectrum shown.

[0012] In one aspect, the present invention relates to the use of a solid form of Compound I in the preparation of molecular probes and tumor contrast agents. In one embodiment, the tumor comprises one of breast cancer, hepatocellular carcinoma, prostate cancer, brain tumor, lung cancer, gastric cancer, thyroid cancer, or colorectal cancer.

[0013] The present invention also relates to a specific crystalline form of D-glucose-6,6'-d2 (Compound I). The crystalline form of Compound I has at least one advantage in terms of stability, solubility, and hygroscopicity, and is suitable for pharmaceutical research and production.

[0014] Compound Ⅰ BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the XRPD pattern of Form I.

[0016] Figure 2 This is the TGA curve of Form I.

[0017] Figure 3 This is the DSC curve of Form I.

[0018] Figure 4For the crystal form I 1 H NMR spectrum.

[0019] Figure 5 This is the XRPD pattern of Form II.

[0020] Figure 6 This is the TGA curve of Form II.

[0021] Figure 7 This is the DSC curve of Form II.

[0022] Figure 8 For the crystal form II 1 H NMR spectrum.

[0023] Figure 9 This is the XRPD pattern of Form III.

[0024] Figure 10 This is the TGA curve of Form III.

[0025] Figure 11 This is the DSC curve of Form III.

[0026] Figure 12 For the crystal form III 1 H NMR spectrum.

[0027] Figure 13 This is the XRPD comparison chart of the suspension competition between Form I and Form III (25°C).

[0028] Figure 14 This is the XRPD comparison chart of the suspension competition between Form I and Form III (50°C).

[0029] Figure 15 XRPD comparison chart of water activity. DETAILED DESCRIPTION

[0030] To make the purpose, technical solutions, and advantages of the embodiments of the present disclosure more clear, the technical solutions of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, not all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present disclosure.

[0031] The present disclosure may be implemented in other specific forms without departing from the essential attributes of the present disclosure. It should be understood that, without conflict, any and all embodiments of the present disclosure may be combined with the technical features of any other embodiment or multiple other embodiments to obtain additional embodiments. The present disclosure includes additional embodiments obtained by such combinations.

[0032] All publications and patents mentioned in this disclosure are hereby incorporated into the present disclosure in their entirety by reference. If the purposes or terms used in any publications and patents incorporated by reference conflict with the purposes or terms used in this disclosure, then the purposes and terms of this disclosure shall prevail.

[0033] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0034] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly used in the art to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0035] The following terms and symbols used in this disclosure have the meanings described below, unless the context indicates otherwise.

[0036] Except in the working examples or otherwise indicated, all numbers stating quantitative properties such as dosages in the specification and claims should be understood as being modified in all cases by the term "about". It should also be understood that any numerical range recited in the present disclosure is intended to include all subranges within that range and any combination of the respective endpoints of that range or subrange. In the present disclosure, the term "about" shall have the meaning of within ±10%, preferably within ±5%, of the specified value or range. For example, the indicated value or range of values ​​may vary within ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1.5%, ±1%, ±0.5%, or ±0.25% of the recited value or range of values. For XRPD, if a value is not expressed as a specific value, it is given as ±0.2 degrees 2θ.

[0037] As used in this disclosure, words such as "include," "comprising," or "including" mean that the elements preceding the word include the elements listed after the word and their equivalents, without excluding unlisted elements. The terms "comprising" or "including" as used herein may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0038] As used herein, the term "mixing" refers to the mixing of one or more chemical entities with another or more chemical entities. Mixing includes the step of adding one or more compounds to a solid, liquid, or gaseous mixture, or a liquid solution or multiphase liquid mixture of one or more compounds (of the same or other chemical entities) to a process (e.g., bond formation or cleavage; salt formation, solvate formation, chelation, or other modification of non-bonded associations). The effect of mixing can include altering one or more compounds, such as by isomerization (e.g., interconversion, resolution of one isomer from another, or racemization).

[0039] As used herein, the term "pharmaceutically acceptable" means non-toxic, biologically tolerable, and suitable for administration to a subject.

[0040] The term "pharmaceutically acceptable salt" as used herein refers to a non-toxic, biologically tolerable salt suitable for administration to a subject. The pharmaceutically acceptable salt of the compound refers to a non-toxic, biologically tolerable acid addition salt suitable for administration to a subject, including but not limited to: acid addition salts formed by the compound with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acid addition salts formed by the compound with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts formed with alkanedicarboxylic acids of the formula HOOC-(CH2)n-COOH (wherein n is 0-4). In addition, if the compound of the present invention is obtained from an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. On the contrary, if the product is a free base, then a pharmaceutically acceptable salt can be prepared by conventional methods for preparing acid addition salts from free base compounds, by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable salts.

[0041] As used herein, the term "solvate" refers to a compound that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. For example, when the solvent is water, the solvate is a "hydrate." The solvate may be a channel solvate. It should be understood that the term "solvate" as used herein includes compounds and solvates of compounds, as well as mixtures thereof.

[0042] As used herein, unless otherwise indicated, the terms "solvent," "organic solvent," and "inert solvent" each refer to an organic solvent that is inert under the reaction conditions described in conjunction therewith, including, but not limited to, benzene, toluene, xylene, acetonitrile (MeCN), ethyl acetate (EtOAc), isopropyl acetate (IPAc), hexane, heptane, n-hexane, n-heptane, dioxane, dimethyl sulfoxide, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane (DCM), diethyl ether, methanol (MeOH), ethanol, trifluoroethanol, n-propanol, isopropanol, butanol, n-butanol, methyl tert-butyl ether (MTBE or TBME), dioxane, methyl ethyl ketone, acetone, 2-butanone (MEK), N-methylpyrrolidone (NMP), pyridine, cyclopentyl methyl ether, N,N-dimethylformamide, isopropyl ether, methyl isobutyl ketone, anisole, methylcyclohexane, N-methylpyrrolidone, and the like. In some embodiments, including but not limited to ethyl acetate (EtOAc), tetrahydrofuran (THF), 2-methyltetrahydrofuran, methanol (MeOH), 75% ethanol, 1,4-dioxane, methyl tert-butyl ether, acetone, etc. Unless otherwise specified, the solvents used in the reactions described herein are inert organic solvents.

[0043] The solid form of Compound 1 can be administered orally or intravenously by infusion or injection.

[0044] Exemplary pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient, which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In any case, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.

[0045] Sterile injectable solutions can be prepared by incorporating the required amount of the solid form in an appropriate solvent with the various other ingredients listed above, as required, followed by filtered sterilization. For sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods may be vacuum drying and freeze drying techniques, which can produce a powder of the active ingredient plus any other desired ingredients that have been previously sterile-filtered.

[0046] The desired dose may conveniently be presented in a single dose or in divided doses administered at appropriately intervals.

[0047] As used herein, the term "solid form" and related terms refer to a physical form that is not predominantly liquid or gaseous. The solid form may be crystalline, amorphous, or a mixture thereof.

[0048] As used herein, the term "crystal form" refers to a crystalline form. It includes single-component crystalline forms and multi-component crystalline forms, and includes but is not limited to polymorphs, solvates, and other molecular complexes, and salts thereof, solvates of salts, other molecular complexes of salts, and polymorphs. In some embodiments, the crystalline form of a substance may be substantially free of amorphous and / or other crystalline forms. In some embodiments, the crystalline form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight of one or more amorphous and / or other crystalline forms. In some embodiments, the crystalline form of a substance may be physically and / or chemically pure. In some embodiments, the crystalline form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and / or chemically pure. In some embodiments, the crystalline forms described herein are substantially pure, i.e., substantially free of other crystalline forms and / or other compounds, containing less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% by weight of one or more other crystalline forms and / or other compounds.

[0049] A crystal form may exhibit various physical characteristic data that are unique to a particular crystal form, such as the crystal forms described herein. These characteristic data can be obtained using various techniques known to those skilled in the art, including, for example, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and nuclear magnetic resonance spectroscopy (HNMR). The data provided by these techniques can be used to identify a specific crystal form. One skilled in the art can determine whether a crystal form "complies" with the reference data provided herein that are identified as being unique to a specific crystal form. Characteristic data that "complies" with the data for a reference crystal form are understood by one skilled in the art to be equivalent to the same crystal form as the reference crystal form. In analyzing whether data "comply," one skilled in the art will understand that, due to, for example, experimental error and routine sample-to-sample analysis, specific characteristic data points may vary to a reasonable degree and still describe a given crystal form.

[0050] As used herein, "amorphous" or "amorphous form" and related terms refer to a substance, component, or product that is substantially non-crystalline as determined by X-ray powder diffraction. In particular, the term "amorphous" describes a disordered solid form, i.e., a solid form that lacks established crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous and / or crystalline forms. In some embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of one or more other amorphous and / or crystalline forms. In some embodiments, an amorphous form of a substance may be physically and / or chemically pure. In some embodiments, an amorphous form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure. Specific implementation plan

[0051] In some embodiments, a solid form of Compound 1 or a salt thereof, or a solvate thereof, or a solvate of a salt thereof, or a mixture thereof is provided:

[0052]

[0053] Compound Ⅰ

[0054] Optionally, the salt is a pharmaceutically acceptable salt.

[0055] Optionally, the solid form is a crystalline form.

[0056] In some embodiments, the solid form is the free base of Compound 1.

[0057] In some embodiments, the solid form is Form I of Compound 1 free base.

[0058] Optionally, the crystalline Form I has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 17.0°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 28.5°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.6°±0.2°.

[0059] Optionally, the Form I has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.8°±0.2°, 19.3°±0.2°, 20.6°±0.2°, 23.5°±0.2°, 25.5°±0.2°, 28.5°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.6°±0.2°.

[0060] Optionally, the Form I has an X-ray powder diffraction (XRPD) pattern comprising peaks at one or more 2θ values ​​according to the following table:

[0061]

[0062]

[0063] Optionally, the crystalline form I has substantially Figure 1 The XRPD spectrum shown.

[0064] Optionally, the differential scanning calorimetry thermogram of the crystalline form I has two endothermic peaks, respectively having an onset temperature of about 55.96°C and / or a peak temperature of about 61.88°C and an onset temperature of about 146.19°C and / or a peak temperature of about 150.49°C.

[0065] Optionally, the differential scanning calorimetry thermogram of the crystalline form I is substantially the same as Figure 3 consistent.

[0066] Optionally, thermogravimetric analysis (TGA) of the Form I shows that it loses approximately 1.06% of its weight at approximately 120°C.

[0067] Optionally, the thermogravimetric analysis curve of the crystal form I is substantially the same as Figure 2 consistent.

[0068] Optionally, the crystalline Form I has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 17.0°, 18.8°, 20.6°, 28.5°, 36.0°, 36.2°, and 36.6°.

[0069] Optionally, the Form I has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°, 17.0°, 18.8°, 19.3°, 20.6°, 23.5°, 25.5°, 28.5°, 36.0°, 36.2°, and 36.6°.

[0070] Optionally, the Form I has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table:

[0071]

[0072]

[0073] Optionally, the crystalline form I has Figure 1 The XRPD spectrum shown.

[0074] Optionally, the differential scanning calorimetry thermogram of the crystalline form I has two endothermic peaks, respectively having an onset temperature of 55.96°C and / or a peak temperature of 61.88°C and an onset temperature of 146.19°C and / or a peak temperature of 150.49°C.

[0075] Optionally, the differential scanning calorimetry thermogram of the crystalline form I is Figure 3 consistent.

[0076] Optionally, thermogravimetric analysis (TGA) of the crystalline form I shows that it loses 1.06% weight at 120°C.

[0077] Optionally, the thermogravimetric analysis curve of the crystal form I is Figure 2 consistent.

[0078] Optionally, the crystalline form I is prepared from the raw material compound I. The raw material compound I can be obtained commercially or prepared by referring to the method in Chinese patent application No. 202011030806.7.

[0079] Alternatively, the crystalline form I can be prepared from the raw material compound I by different crystallization methods, which include one or more steps of steps a), b) or c):

[0080] a) adding a raw material compound I to a first solvent, suspending and stirring at 5-50° C., and then centrifuging to obtain the crystalline form; preferably, the first solvent is selected from the group consisting of acetone, ethyl acetate, ethyl ether, dichloromethane, toluene, ethanol, tetrahydrofuran, n-propanol, n-heptane, isopropyl acetate, methyl isobutyl ketone, dimethyl sulfoxide, isopropyl alcohol, methyl ethyl ketone, chloroform, xylene, methanol, methyltetrahydrofuran, cyclopentyl methyl ether, N,N-dimethylformamide, isopropyl ether, trifluoroethanol, n-butanol, anisole, 1,4-dioxane, methylcyclohexane, n-hexane, N-methylpyrrolidone, or a combination thereof; wherein, when the solvent is a mixed solvent, the mixed solvent is a combination of two solvents selected from the above group, and the volume ratio of the two solvents is 9:1-1:1, for example, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1;

[0081] b) adding a second solvent to the raw material compound I, magnetically stirring the suspension under temperature cycling conditions, and then centrifuging to obtain a solid; preferably, the second solvent is selected from the group consisting of ethanol, sec-butanol, xylene, methyltetrahydrofuran, acetonitrile, 1,4-dioxane, methyl tert-butyl ether, acetone, methanol, ethyl acetate, methylcyclohexane, or a combination thereof; wherein, when the solvent is a mixed solvent, the mixed solvent is a combination of two solvents selected from the above group, and the volume ratio of the two solvents is 4:1-1:1, for example, 4:1, 3:1, 2:1 or 1:1; optionally, the temperature cycling conditions are maintained at 50 ° C for 120 min; cooling from 50 ° C to 5 ° C at a rate of 0.1 ° C / min, maintaining for 120 min; heating from 5 ° C to 50 ° C at a rate of 0.1 ° C / min, maintaining for 120 min; cooling from 50 ° C to 5 ° C at a rate of 0.1 ° C / min, maintaining for 120 min.

[0082] c) adding the raw material compound I to a third solvent, dissolving under ultrasonication at 50° C., filtering, and cooling to 5° C. to precipitate the crystalline form; preferably, the third solvent is selected from the following group: methanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, or a combination thereof; wherein, when the solvent is a mixed solvent, the mixed solvent is a combination of two solvents selected from the above group, and the volume ratio of the two solvents is 4:1-1:4, for example, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3 or 1:4.

[0083] In some embodiments, the solid form is a monohydrate of Compound 1.

[0084] In some embodiments, the solid form is Form II of Compound 1 monohydrate.

[0085] Optionally, the crystalline Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 19.7°±0.2°, 20.1°±0.2°, and 22.7°±0.2°.

[0086] Optionally, the crystalline Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 9.1°±0.2°, 12.7°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 22.7°±0.2°, 28.2°±0.2°, and 35.6°±0.2°.

[0087] Optionally, the Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 9.1°±0.2°, 12.7°±0.2°, 14.5°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 22.7°±0.2°, 25.4°±0.2°, 27.5°±0.2°, 28.2°±0.2°, 31.1°±0.2°, 33.3°±0.2°, 35.3°±0.2°, 35.6°±0.2°, and 36.9°±0.2°.

[0088] Optionally, the Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table:

[0089]

[0090]

[0091] Optionally, the crystalline form II has substantially Figure 5 The XRPD spectrum shown.

[0092] Optionally, the differential scanning calorimetry thermogram of the crystalline form II has two endothermic peaks, respectively having an onset temperature of about 79.82°C and / or a peak temperature of about 83.95°C and an onset temperature of about 150.57°C and / or a peak temperature of about 153.16°C.

[0093] Optionally, the differential scanning calorimetry thermogram of the crystalline form II is substantially the same as Figure 7 consistent.

[0094] Optionally, thermogravimetric analysis (TGA) of the Form II shows that it loses approximately 9.76% of its weight at approximately 120°C.

[0095] Optionally, the thermogravimetric analysis curve of the Form II is substantially the same as Figure 6 consistent.

[0096] Optionally, the crystalline Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 19.7°, 20.1°, and 22.7°.

[0097] Optionally, the Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 9.1°, 12.7°, 18.3°, 19.7°, 20.1°, 22.7°, 28.2°, and 35.6°.

[0098] Optionally, the Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 9.1°, 12.7°, 14.5°, 18.3°, 19.7°, 20.1°, 22.7°, 25.4°, 27.5°, 28.2°, 31.1°, 33.3°, 35.3°, 35.6°, and 36.9°.

[0099] Optionally, the Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table:

[0100]

[0101]

[0102] Optionally, the crystalline form II has Figure 5 The XRPD spectrum shown.

[0103] Optionally, the differential scanning calorimetry thermogram of the crystalline form II has two endothermic peaks, respectively having an onset temperature of 79.82°C and / or a peak temperature of 83.95°C and an onset temperature of 150.57°C and / or a peak temperature of 153.16.

[0104] Optionally, the differential scanning calorimetry thermogram of the crystal form II is Figure 7 consistent.

[0105] Optionally, thermogravimetric analysis (TGA) of the Form II shows that it loses 9.76% of its weight at 120°C.

[0106] Optionally, the thermogravimetric analysis curve of the Form II is Figure 6 consistent.

[0107] Optionally, the crystalline form II is prepared from the raw material compound I. The raw material compound I can be obtained commercially or prepared by referring to the method in Chinese patent application No. 202011030806.7.

[0108] Alternatively, the crystalline form II can be prepared from the raw material compound I by different crystallization methods, which include one or more steps of steps a), b) or c):

[0109] a) adding the raw material compound I to a first solvent, suspending and stirring at 5-50° C., and then centrifuging to obtain the crystalline form; preferably, the first solvent is selected from a combination of 1,4-dioxane and water, and the volume ratio of the two solvents is 9:1.

[0110] b) adding the raw material compound I to a second solvent, dissolving the mixture under ultrasonication at 50° C., filtering the mixture, and cooling the mixture to 5° C. to precipitate the crystalline form; preferably, the second solvent is selected from a combination of acetone and water, and the volume ratio of the two solvents is 9:1.

[0111] c) placing the raw material compound I in an open environment with high humidity; preferably, the high humidity environment is selected from a combination of room temperature and 85% relative humidity.

[0112] In some embodiments, the solid form is Form III of Compound 1 free base.

[0113] Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 28.4°±0.2°, and 36.2°±0.2°.

[0114] Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 25.5°±0.2°, 28.4°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.5°±0.2°.

[0115] Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 10.4°±0.2°, 11.9°±0.2°, 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 25.5°±0.2°, 28.4°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.5°±0.2°.

[0116] Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table:

[0117]

[0118]

[0119] Optionally, the crystalline form III has substantially Figure 9 The XRPD spectrum shown.

[0120] Optionally, the differential scanning calorimetry thermogram of the Form III has a single endothermic peak with an onset temperature of about 149.08°C and / or a peak temperature of about 153.69°C.

[0121] Optionally, the differential scanning calorimetry thermogram of the crystalline form III is substantially the same as Figure 11 consistent.

[0122] Optionally, thermogravimetric analysis (TGA) of the Form III shows that it loses about 1.00% weight at about 120°C.

[0123] Optionally, the thermogravimetric analysis curve of the Form III is substantially the same as Figure 10 consistent.

[0124] Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°, 17.0°, 18.7°, 20.6°, 28.4°, and 36.2°.

[0125] Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°, 17.0°, 18.7°, 20.6°, 20.8°, 25.5°, 28.4°, 36.0°, 36.2°, and 36.5°.

[0126] Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 10.4°, 11.9°, 14.6°, 17.0°, 18.7°, 20.6°, 20.8°, 25.5°, 28.4°, 36.0°, 36.2°, and 36.5°.

[0127] Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table:

[0128]

[0129]

[0130] Optionally, the crystalline form III has Figure 9 The XRPD spectrum shown.

[0131] Optionally, the differential scanning calorimetry thermogram of the Form III has a single endothermic peak with an onset temperature of 149.08°C and / or a peak temperature of 153.69°C.

[0132] Optionally, the differential scanning calorimetry thermogram of the crystalline form III is Figure 11 consistent.

[0133] Optionally, thermogravimetric analysis (TGA) of the Form III shows that it loses 1.00% weight at 120°C.

[0134] Optionally, the thermogravimetric analysis curve of the Form III is Figure 10 consistent.

[0135] Optionally, the crystalline form III is prepared from the raw material compound I. The raw material compound I can be obtained commercially or prepared by referring to the method in Chinese patent application No. 202011030806.7.

[0136] Optionally, the crystalline form III can be prepared from the raw material compound I by different crystallization methods, for example, the raw material compound I is added to a first solvent, suspended and stirred at 5-50°C, and then centrifuged to obtain the crystalline form; preferably, the first solvent is selected from methanol, ethanol, water, or a combination thereof; wherein, when the solvent is a mixed solvent, the mixed solvent is a combination of two solvents selected from the above group, and the volume ratio of the two solvents is 9:1.

[0137] In some embodiments, the present invention provides methods for preparing solid forms of Compound 1.

[0138] In some embodiments, the present invention provides a method for preparing Form I of the free base of Compound I, comprising one or more of steps a), b), or c):

[0139] a) adding a raw material compound I to a first solvent, suspending and stirring at 5-50° C., and then centrifuging to obtain the crystalline form; preferably, the first solvent is selected from the group consisting of acetone, ethyl acetate, ethyl ether, dichloromethane, toluene, ethanol, tetrahydrofuran, n-propanol, n-heptane, isopropyl acetate, methyl isobutyl ketone, dimethyl sulfoxide, isopropyl alcohol, methyl ethyl ketone, chloroform, xylene, methanol, methyltetrahydrofuran, cyclopentyl methyl ether, N,N-dimethylformamide, isopropyl ether, trifluoroethanol, n-butanol, anisole, 1,4-dioxane, methylcyclohexane, n-hexane, N-methylpyrrolidone, or a combination thereof; wherein, when the solvent is a mixed solvent, the mixed solvent is a combination of two solvents selected from the above group, and the volume ratio of the two solvents is 9:1-1:1, for example, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1;

[0140] b) adding a second solvent to the raw material compound I, magnetically stirring the suspension under temperature cycling conditions, and then centrifuging to obtain a solid; preferably, the second solvent is selected from the group consisting of ethanol, sec-butanol, xylene, methyltetrahydrofuran, acetonitrile, 1,4-dioxane, methyl tert-butyl ether, acetone, methanol, ethyl acetate, methylcyclohexane, or a combination thereof; wherein, when the solvent is a mixed solvent, the mixed solvent is a combination of two solvents selected from the above group, and the volume ratio of the two solvents is 4:1-1:1, for example, 4:1, 3:1, 2:1 or 1:1; optionally, the temperature cycling conditions are maintained at 50 ° C for 120 min; cooling from 50 ° C to 5 ° C at a rate of 0.1 ° C / min, maintaining for 120 min; heating from 5 ° C to 50 ° C at a rate of 0.1 ° C / min, maintaining for 120 min; cooling from 50 ° C to 5 ° C at a rate of 0.1 ° C / min, maintaining for 120 min.

[0141] c) adding the raw material compound I to a third solvent, dissolving under ultrasonication at 50° C., filtering, and cooling to 5° C. to precipitate the crystalline form; preferably, the third solvent is selected from the following group: methanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, or a combination thereof; wherein, when the solvent is a mixed solvent, the mixed solvent is a combination of two solvents selected from the above group, and the volume ratio of the two solvents is 4:1-1:4, for example, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3 or 1:4.

[0142] In some embodiments, the present invention provides a method for preparing Form II of Compound I monohydrate, comprising one or more of steps a), b), or c):

[0143] a) adding the raw material compound I to a first solvent, suspending and stirring at 5-50° C., and then centrifuging to obtain the crystalline form; preferably, the first solvent is selected from a combination of 1,4-dioxane and water, and the volume ratio of the two solvents is 9:1.

[0144] b) adding the raw material compound I to a second solvent, dissolving the mixture under ultrasonication at 50° C., filtering the mixture, and cooling the mixture to 5° C. to precipitate the crystalline form; preferably, the second solvent is selected from a combination of acetone and water, and the volume ratio of the two solvents is 9:1.

[0145] c) placing the raw material compound I in an open environment with high humidity; preferably, the high humidity environment is selected from a combination of room temperature and 85% relative humidity.

[0146] In some embodiments, the present invention provides a method for preparing the crystalline form III of the free base of compound I, which comprises adding the raw material compound I to a first solvent, suspending and stirring at 5-50°C, and then centrifuging to obtain the crystalline form; preferably, the first solvent is selected from methanol, ethanol, water, or a combination thereof; wherein, when the solvent is a mixed solvent, the mixed solvent is a combination of two solvents selected from the above group, and the volume ratio of the two solvents is 9:1.

[0147] In some embodiments, the present invention provides a pharmaceutical composition comprising a solid form of Compound 1 described herein and a pharmaceutically acceptable excipient. In particular, an effective amount of the solid form of Compound 1.

[0148] In some embodiments, the present invention provides solid forms and pharmaceutical compositions of Compound 1 for use as molecular probes.

[0149] In some embodiments, the present invention provides uses of solid forms and pharmaceutical compositions of Compound 1 in the preparation of molecular probes.

[0150] In some embodiments, the present invention provides solid forms and pharmaceutical compositions of Compound 1 for use as tumor imaging agents. In some specific embodiments, the tumor comprises one of breast cancer, lung cancer, hepatocellular carcinoma, prostate cancer, brain tumor, gastric cancer, thyroid cancer, or colorectal cancer.

[0151] In some embodiments, the present invention provides a solid form of Compound I and a pharmaceutical composition for use in preparing a tumor contrast agent. In some specific embodiments, the tumor comprises one of breast cancer, lung cancer, hepatocellular carcinoma, prostate cancer, brain tumor, gastric cancer, thyroid cancer, or colorectal cancer.

[0152] The crystalline forms I, II and III of the compound I described in the present invention can all be used as active pharmaceutical ingredients (APIs), among which the crystalline form III is preferred.

[0153] Crystal forms I, II and III show at least one advantage in terms of stability, solubility and hygroscopicity, and are suitable for use in pharmaceutical research and production.

[0154] Form I showed no significant change in HPLC purity after being exposed to air for 7 days at 25°C / 60% RH, 40°C / 75% RH, and 60°C / RH <30%. No significant change in form was observed after being exposed to air for 7 days at 60°C / RH <30%. Form I exhibited hygroscopic properties with a water absorption rate of 13.74% at 25°C / 80% RH, transforming to Form II upon absorption.

[0155] Form II was exposed to air for 7 days at 25°C / 60% RH, 40°C / 75% RH, and 60°C / RH <30% without significant change in HPLC purity. Form II was exposed to air for 7 days at 25°C / 60% RH and 40°C / 75% RH without significant change in crystal form. Form II had a water absorption rate of 0.3% at 25°C / 80% RH, indicating slight hygroscopicity, but the crystal form remained unchanged.

[0156] Form III showed no significant change in HPLC purity after 7 days of exposure at 25°C / 60% RH, 40°C / 75% RH, and 60°C / RH <30%. There was no significant change in the crystal form after 7 days of exposure at 25°C / 60% RH and 60°C / RH <30%. Form III had a water absorption rate of 0.97% at 25°C / 80% RH, indicating slight hygroscopicity. Upon hygroscopic absorption, it transformed into Form III+II.

[0157] The solubility of Form I, Form II and Form III in room temperature water is greater than 10 mg / mL.

[0158] At 25°C~50°C, Form III is a more stable form in methanol and ethanol systems, and Form I is a more stable form in acetone system.

[0159] The present invention also relates to the following embodiments:

[0160] 1. Solid forms, including solid forms of Compound 1 or its salt, or its solvate, or its salt solvate, or its mixture:

[0161]

[0162] Compound Ⅰ.

[0163] 2. The solid form of embodiment 1, wherein the solid form is a crystalline form.

[0164] 3. The solid form according to embodiment 1 or 2, characterized in that it is the free base of compound I.

[0165] 4. The solid form according to embodiment 3, wherein the solid form is crystalline Form I of the free base of Compound I.

[0166] 5. The solid form of embodiment 4, characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 17.0°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 28.5°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.6°±0.2°.

[0167] 6. The solid form of embodiment 4, wherein the solid form has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.8°±0.2°, 19.3°±0.2°, 20.6°±0.2°, 23.5°±0.2°, 25.5°±0.2°, 28.5°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.6°±0.2°.

[0168] 7. The solid form of embodiment 4, characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table:

[0169]

[0170]

[0171] 8. The solid form of embodiment 5, wherein the solid form has substantially Figure 1 The XRPD spectrum shown.

[0172] 9. The solid form of embodiment 5, wherein its differential scanning calorimetry thermogram has two endothermic peaks, respectively having an onset temperature of about 55.96°C and / or a peak temperature of about 61.88°C and an onset temperature of about 146.19°C and / or a peak temperature of about 150.49°C.

[0173] 10. The solid form of embodiment 5, wherein the differential scanning calorimetry thermogram is substantially the same as Figure 3 consistent.

[0174] 11. The solid form of embodiment 5, wherein thermogravimetric analysis (TGA) shows a weight loss of about 1.06% at about 120°C.

[0175] 12. The solid form of embodiment 5, wherein the thermogravimetric analysis curve is substantially the same as Figure 2 consistent.

[0176] 13. The solid form according to embodiment 1 or 2, characterized in that it is a monohydrate of Compound I.

[0177] 14. The solid form according to embodiment 13, characterized in that it is Form II of the monohydrate of Compound I.

[0178] 15. The solid form of embodiment 14, characterized in that it has an X-ray powder diffraction (XRPD) comprising peaks at 2θ values ​​at 19.7°±0.2°, 20.1°±0.2°, and 22.7°±0.2°.

[0179] 16. The solid form of embodiment 14, characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​at 9.1°±0.2°, 12.7°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 22.7°±0.2°, 28.2°±0.2°, and 35.6°±0.2°.

[0180] 17. The solid form of embodiment 14, characterized in that it has an X-ray powder diffraction (XRPD) comprising peaks at 2θ values ​​at 9.1°±0.2°, 12.7°±0.2°, 14.5°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 22.7°±0.2°, 25.4°±0.2°, 27.5°±0.2°, 28.2°±0.2°, 31.1°±0.2°, 33.3°±0.2°, 35.3°±0.2°, 35.6°±0.2°, and 36.9°±0.2°.

[0181] 18. The solid form of embodiment 14, characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table:

[0182]

[0183]

[0184] 19. The solid form of embodiment 14, wherein the solid form has substantially Figure 5 The XRPD spectrum shown.

[0185] 20. The solid form of embodiment 14, wherein its differential scanning calorimetry thermogram has two endothermic peaks, respectively having an onset temperature of about 79.82°C and / or a peak temperature of about 83.95°C and an onset temperature of about 150.57°C and / or a peak temperature of about 153.16°C.

[0186] 21. The solid form of embodiment 14, wherein the differential scanning calorimetry thermogram is substantially the same as Figure 7 consistent.

[0187] 22. The solid form of embodiment 14, wherein thermogravimetric analysis (TGA) shows a weight loss of about 9.76% at about 120°C.

[0188] 23. A solid form according to embodiment 14, characterized in that its thermogravimetric analysis curve is substantially the same as Figure 6 consistent.

[0189] 24. The solid form of embodiment 3, wherein the solid form is Form III of the free base of Compound I.

[0190] 25. The solid form of embodiment 24, characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 28.4°±0.2°, and 36.2°±0.2°.

[0191] 26. The solid form of embodiment 24, characterized in that it has an X-ray powder diffraction (XRPD) comprising peaks at 2θ values ​​at 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 25.5°±0.2°, 28.4°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.5°±0.2°.

[0192] 27. The solid form of embodiment 24, characterized in that it has an X-ray powder diffraction (XRPD) comprising peaks at 2θ values ​​at 10.4°±0.2°, 11.9°±0.2°, 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 25.5°±0.2°, 28.4°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.5°±0.2°.

[0193] 28. The solid form of embodiment 24, characterized in that it has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table:

[0194]

[0195]

[0196] 29. The solid form of embodiment 24, wherein the solid form has substantially Figure 9 The XRPD spectrum shown.

[0197] 30. The solid form of embodiment 24, wherein its differential scanning calorimetry thermogram has a single endothermic peak with an onset temperature of about 149.08°C and / or a peak temperature of about 153.69°C.

[0198] 31. The solid form of embodiment 24, wherein the differential scanning calorimetry thermogram is substantially the same as Figure 11 consistent.

[0199] 32. The solid form of embodiment 24, wherein thermogravimetric analysis (TGA) shows a weight loss of about 1.00% at about 120°C.

[0200] 33. A solid form according to embodiment 24, characterized in that its thermogravimetric analysis curve is substantially the same as Figure 10 consistent.

[0201] 34. A pharmaceutical composition comprising the solid form of any one of embodiments 1-33.

[0202] 35. The solid form of any one of embodiments 1-33 or the pharmaceutical composition of embodiment 34 for use as a molecular probe.

[0203] 36. Use of the solid form according to any one of embodiments 1 to 33 or the pharmaceutical composition according to embodiment 34 for the preparation of a molecular probe.

[0204] 37. The solid form of any one of embodiments 1 to 33 or the pharmaceutical composition of embodiment 34 for use as a tumor contrast agent.

[0205] 38. A solid form or pharmaceutical composition for use as a tumor contrast agent as described in embodiment 37, characterized in that the tumor is one of breast cancer, lung cancer, hepatocellular carcinoma, prostate cancer, brain tumor, gastric cancer, thyroid cancer or colorectal cancer.

[0206] 39. Use of the solid form according to any one of embodiments 1 to 33 or the pharmaceutical composition according to embodiment 34 for the preparation of a tumor contrast agent.

[0207] 38. The use as described in embodiment 39 is characterized in that the tumor is one of breast cancer, lung cancer, hepatocellular carcinoma, prostate cancer, brain tumor, gastric cancer, thyroid cancer or colorectal cancer.

[0208] Example

[0209] The following examples further illustrate the present invention. These examples are intended only to illustrate the present invention and should not be considered as limiting.

[0210] XRPD testing was performed using a Bruker D8 Advance diffractometer. The parameters of the X-ray powder diffraction of the present invention are as follows:

[0211] The instrument used Kα radiation with a copper target wavelength of 1.54 Å, operating at 40 kV and 40 mA, a θ-2θ goniometer, a nickel filter, and an SSD160-2 detector. The instrument was calibrated before use using the included standard (corundum). Samples were tested at room temperature, placed on a non-reflective plate. Detailed testing conditions are as follows: angular range: 3–40° 2θ, step size: 0.02° 2θ, and speed: 0.1 s / step.

[0212] The TGA data of the present invention were obtained from a METTLER TOLEDO TGA2, and the instrument control and analysis software was STAResoftware. The parameters of the TGA method of the present invention are as follows:

[0213] Usually, 1-10 mg of sample is placed in an alumina crucible (with the lid open), and the sample is heated from 30°C to 350°C at a heating rate of 10°C / min under the protection of 50 mL / min dry nitrogen.

[0214] The DSC data of the present invention were collected from a METTLER TOLEDO DSC3, and the instrument control and analysis software was STAResoftware. The parameters of the DSC method of the present invention are as follows:

[0215] Usually, 0.5~5 mg of sample is placed in an aluminum crucible (covered and perforated), and the temperature of the sample is raised from 30℃ to 300℃ at a heating rate of 10℃ / min under the protection of 50mL / min dry nitrogen.

[0216] The nuclear magnetic hydrogen spectrum of the present invention ( 1 H NMR) data were obtained using a Bruker AVANCE III 400 MHz / Bruker AVANCE NEO 400 MHz. 1 The parameters of the H NMR method are as follows:

[0217] Full-spectrum excitation, spectral width 20 ppm single pulse, 30° excitation angle scan 8 times, digital orthogonal detection, temperature control 298 K. Solvent: DMSO-d6.

[0218] Example 1. Preparation and characterization of Form I

[0219] Preparation of Form I

[0220] Method 1: Weigh approximately 20 mg of raw material compound I, add 0.5 mL of acetone, suspend and stir at 5°C for 3 days, and centrifuge to obtain form I.

[0221] The solvents and reaction temperatures in Method 1 can be replaced by those in Table 1.

[0222] Table 1

[0223]

[0224]

[0225] Method 2: About 20 mg of raw material compound I was weighed, 0.5 mL of ethanol was added, and the suspension was magnetically stirred under temperature cycling conditions (program: 50°C for 120 min; cooling from 50°C to 5°C at a rate of 0.1°C / min, and holding for 120 min; heating from 5°C to 50°C at a rate of 0.1°C / min, and holding for 120 min; cooling from 50°C to 5°C at a rate of 0.1°C / min, and holding for 120 min), and then centrifuged to obtain Form I.

[0226] The solvents in Method 2 can be replaced by those listed in Table 2.

[0227] Table 2

[0228]

[0229] Method 3: Weigh approximately 20 mg of the raw material compound I, suspend it in 1.0 mL of methanol, equilibrate at 50°C for 2 hours, filter, stir the filtrate at 5°C overnight, and centrifuge to obtain Form I.

[0230] The solvents in Method 3 can be replaced by those listed in Table 3.

[0231] Table 3

[0232]

[0233] Characterization of Form I

[0234] XRPD of Form I Figure 1 As shown, it shows the strongest peak at a 2θ value of 20.6°±0.2°.

[0235] In addition, the XRPD of Form I further shows one or more characteristic peaks at 2θ values ​​of 17.0°±0.2°, 18.8°±0.2°, 28.5°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.6°±0.2°.

[0236] The XRPD data of Form I are shown in Table 4.

[0237] Table 4

[0238]

[0239]

[0240] Thermogravimetric analysis (TGA) of Form I showed that the sample lost about 1.06% of its weight when heated to 120°C. Figure 2 .

[0241] Differential scanning calorimetry (DSC) showed that the sample had two endothermic peaks, located at 55.96℃ / 61.88℃ and 146.19℃ / 150.49℃ (onset temperature / peak temperature), and its DSC curve is shown in Figure 3 .

[0242] Form I 1 H NMR spectrum Figure 4 shown.

[0243] Example 2. Preparation and characterization of Form II

[0244] Preparation of Form II

[0245] About 20 mg of raw material compound I was weighed, 0.5 mL of 1,4-dioxane / water (9:1) was added, and the mixture was suspended and stirred at room temperature for 3 days. The resulting mixture was centrifuged to obtain form II.

[0246] About 20 mg of raw compound I was weighed and suspended in 0.5 mL of acetone / water (9:1), equilibrated at 50°C for 2 hours, filtered, and the filtrate was stirred at 5°C overnight and centrifuged to obtain Form II.

[0247] About 20 mg of the raw material compound I was weighed and added to a 3 mL vial (without the cap), and the vial was placed in a target humidity chamber (RT-85% RH) for 7 days to obtain Form II.

[0248] About 200 mg of raw material compound I was weighed and added to a 20 mL vial. The vial was opened and placed under 85% RH for 2 days to obtain Form II.

[0249] Characterization of Form II

[0250] XRPD of Form II Figure 5 As shown, it shows the strongest peaks at 2θ values ​​of 19.7°±0.2°, 20.1°±0.2°, and 22.7°±0.2°.

[0251] In addition, the XRPD of Form II further shows one or more characteristic peaks at 2θ values ​​of 9.1°±0.2°, 28.2°±0.2°, 12.7°±0.2°, 18.3°±0.2°, and 35.6°±0.2°.

[0252] In addition, the XRPD of Form II further shows one or more characteristic peaks at 2θ values ​​of 36.9°±0.2°, 31.1°±0.2°, 25.4°±0.2°, 35.3°±0.2°, 27.5°±0.2°, 33.3°±0.2°, and 14.5°±0.2°.

[0253] The XRPD data of Form II are shown in Table 5.

[0254] Table 5

[0255]

[0256]

[0257] Thermogravimetric analysis (TGA) of Form II shows that the sample loses about 9.76% of its weight when heated to 120°C. Figure 6 According to TGA data, Form II of Compound I is a monohydrate of Compound I.

[0258] Differential scanning calorimetry (DSC) of Form II shows that the sample has two endothermic peaks, located at 79.82°C / 83.95°C and 150.57°C / 153.16°C (onset temperature / peak temperature), respectively. The DSC curve is shown in Figure 7 .

[0259] Form II 1 H NMR spectrum Figure 8 shown.

[0260] Example 3. Preparation and characterization of Form III

[0261] Preparation of Form III

[0262] About 300.43 mg of raw material compound I was weighed, 4 mL of methanol was added, and the mixture was stirred at 5°C for 1 day. The mixture was filtered and the filter cake was dried at 50°C with forced air overnight.

[0263] About 20 mg of raw material compound I was weighed, 0.5 mL of methanol was added, and the mixture was suspended and stirred at 5°C for 3 days. The crystalline form III was obtained by centrifugation.

[0264] About 20 mg of raw material compound I was weighed, 0.5 mL of ethanol / water (9:1) was added, and the mixture was suspended and stirred at 50°C for 3 days, and then centrifuged to obtain form III.

[0265] Form III is not easy to prepare. By screening various solvents and preparation conditions in Examples 1-3, Form III was prepared only under the above solvent conditions, while Form I, which is easier to prepare, was obtained under other solvent conditions.

[0266] Characterization of Form III

[0267] XRPD of Form III Figure 9 As shown, it shows the strongest peak at a 2θ value of 20.6°±0.2°.

[0268] In addition, the XRPD of Form III further shows one or more characteristic peaks at 2θ values ​​of 18.7°±0.2°, 28.4°±0.2°, 14.6°±0.2°, 36.2°±0.2°, and 17.0°±0.2°.

[0269] The XRPD data of Form III are shown in Table 6.

[0270] Table 6

[0271]

[0272]

[0273] Thermogravimetric analysis (TGA) of Form III shows that the sample loses about 1.00% of its weight when heated to 120°C. Figure 10 .

[0274] Differential scanning calorimetry (DSC) of Form III shows that the sample has a single endothermic peak located at 149.08°C / 153.69°C (onset temperature / peak temperature). The DSC curve is shown in Figure 11 .

[0275] Form III 1 H NMR spectrum Figure 12 shown.

[0276] Example 4. Stability Evaluation of Form I

[0277] An appropriate amount of Form I solid was added to a 3 mL vial. The vial was sealed with parafilm and small holes were punctured in the film. The vial was exposed under long-term (25°C / 60% RH), accelerated (40°C / 75% RH), and high-temperature (60°C, RH <30%) conditions for 7 days, and then the HPLC purity and crystal form changes were tested.

[0278] The results showed that Form I showed no significant change in HPLC purity after 7 days of storage under the test conditions. After 7 days of storage under high temperature conditions, no significant change in the crystal form occurred. However, after 7 days of storage under long-term and accelerated conditions, Form I transformed into Form I+II. The results of the solid-state stability assessment of Form I are detailed in Table 7.

[0279] Table 7

[0280]

[0281] Example 5. Hygroscopicity Evaluation of Form I

[0282] A DVS test was performed on Form I to evaluate the stability risk of the sample with changes in humidity at 25°C, and the solid after the test was collected for XRPD testing to observe whether the crystal form changed.

[0283] The results showed that Form I was hygroscopic, and after testing, the sample absorbed moisture and transformed into Form II. The results of the hygroscopic evaluation of Form I are detailed in Table 8.

[0284] Table 8

[0285]

[0286] Example 6. Stability Evaluation of Form II

[0287] An appropriate amount of Form II solid was added to a 3 mL vial. The vial was sealed with sealing film and small holes were punctured in the film. The vial was exposed under long-term (25°C / 60% RH), accelerated (40°C / 75% RH), and high-temperature (60°C, RH <30%) conditions for 7 days, and then the HPLC purity and crystal form changes were tested.

[0288] The results showed that Form II showed no significant change in HPLC purity after 7 days of storage under the test conditions. There was no significant change in the crystal form after 7 days of storage under long-term and accelerated conditions. However, Form II transformed into Form III after 7 days of storage under high temperature conditions. The results of the solid-state stability assessment of Form II are detailed in Table 9.

[0289] Table 9

[0290]

[0291] Example 7. Hygroscopicity Evaluation of Form II

[0292] A DVS test was performed on Form II to evaluate the stability risk of the sample with changes in humidity at 25°C, and the solid after the test was collected for XRPD testing to observe whether the crystal form changed.

[0293] The results showed that Form II was slightly hygroscopic, and the sample's crystal form remained unchanged after testing. The results of the hygroscopic evaluation of Form II are detailed in Table 10.

[0294] Table 10

[0295]

[0296] Example 8. Stability Evaluation of Form III

[0297] An appropriate amount of Form III solid was added to a 3 mL vial. The vial was sealed with sealing film and small holes were punctured in the film. The vial was exposed under long-term (25°C / 60% RH), accelerated (40°C / 75% RH), and high-temperature (60°C, RH <30%) conditions for 7 days, and then the HPLC purity and crystal form changes were tested.

[0298] The results showed that Form III showed no significant change in HPLC purity after 7 days of storage under the test conditions. There was no significant change in the crystal form after 7 days of storage under long-term and high-temperature conditions. However, Form III transformed into Form III+II after 7 days of storage under accelerated conditions. The results of the solid-state stability assessment of Form III are detailed in Table 11.

[0299] Table 11

[0300]

[0301] Example 9. Hygroscopicity Evaluation of Form III

[0302] A DVS test was performed on Form III to evaluate the stability risk of the sample with changes in humidity at 25°C, and the solid after the test was collected for XRPD testing to observe whether the crystal form changed.

[0303] The results showed that Form III was slightly hygroscopic. After testing, the sample absorbed moisture and transformed into Form III+II. The hygroscopicity evaluation results of Form III are detailed in Table 12.

[0304] Table 12

[0305]

[0306] Example 10. Solubility of Form I, Form II, and Form III in water at room temperature

[0307] The equilibrium solubility of Form I, Form II, and Form III in pure water over a 24-hour period at room temperature was determined as follows: 10 mg of each sample was weighed into 1 mL of water, magnetically stirred at room temperature, and samples were taken after 24 hours for solubility testing.

[0308] The results showed that after stirring for 24 hours, the samples were all in clear state, and the solubility of Form I, Form II and Form III in room temperature water was greater than 10 mg / mL.

[0309] Example 11. Summary of characterization of Form I, Form II, and Form III

[0310] Table 13 shows the characterization summary of Forms I-III

[0311] Table 13

[0312]

[0313] Example 12. Interconversion between Form I, Form II and Form III

[0314] 1. Crystal-free suspension competition experiment

[0315] To confirm the interconversion relationship between anhydrous Form I and Form III, suspension competition experiments were conducted in methanol, ethanol, and acetone at 25°C and 50°C, respectively. First, a suspension of Compound I, fully equilibrated at the corresponding temperature and solvent, was filtered to obtain saturated solutions of Compound I under different conditions. Equal amounts of Form I and Form III samples were then added, vortexed, and stirred at the corresponding temperature.

[0316] The results are shown in Table 14 and Figure 13 and Figure 14 As shown in the figure, under the conditions of 25°C to 50°C, Form III is the more stable form in methanol and ethanol systems, while Form I is the more stable form in acetone system. This indicates that the choice of solvent has a decisive influence on the formation of the crystal form.

[0317] Table 14 Summary of suspension competition experiment

[0318]

[0319] 2. Water activity experiment

[0320] Water activity (aw) experiments were conducted on Forms I, II, and III. First, suspensions of the starting compound I in ethanol / water mixed solvents with varying water contents, equilibrated at room temperature for one hour, were filtered to obtain saturated solutions of the starting compound I at room temperature. The solid mixture of Forms I, II, and III was then added and stirred at room temperature.

[0321] like Figure 15 As shown in Table 15, the results show that at room temperature and a water activity of 0 to 0.305, Form III is a more stable form, and at a water activity of 0.49 to 0.616, Form II is a more stable form.

[0322] Table 15 Summary of water activity experiment

[0323]

[0324] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications and co-pending patent applications) are hereby expressly incorporated by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0325] All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature having the same, equivalent, or similar purpose. Therefore, unless expressly stated otherwise, each feature disclosed is merely an example of a series of equivalent or similar features.

[0326] From the above description, those skilled in the art can easily determine the essential features of the present invention, and without departing from the spirit and scope of the present invention, various changes and modifications can be made to the present invention to adapt it to various uses and conditions. Therefore, other embodiments are also within the scope of the appended claims.

Claims

1. Solid forms, including solid forms of Compound 1 or its salt, or its solvate, or its salt solvate, or its mixture: Compound I, Optionally, it is characterized in that The solid form is a crystalline form.

2. The solid form of claim 1, wherein It is the free base of compound I, preferably, it is the crystalline form I of the free base of compound I, Optionally, the Form I has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 17.0°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 28.5°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.6°±0.2°; Optionally, the Form I has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.8°±0.2°, 19.3°±0.2°, 20.6°±0.2°, 23.5°±0.2°, 25.5°±0.2°, 28.5°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.6°±0.2°; Optionally, the Form I has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table: ； Preferably, the crystalline Form I has an XRPD pattern substantially as shown in Figure 1.

3. The solid form of claim 1, wherein It is a monohydrate of compound I, preferably, it is a crystalline form II of the monohydrate of compound I, Optionally, the Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 19.7°±0.2°, 20.1°±0.2°, and 22.7°±0.2°; Optionally, the Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 9.1°±0.2°, 12.7°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 22.7°±0.2°, 28.2°±0.2°, and 35.6°±0.2°; Optionally, the Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 9.1°±0.2°, 12.7°±0.2°, 14.5°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 22.7°±0.2°, 25.4°±0.2°, 27.5°±0.2°, 28.2°±0.2°, 31.1°±0.2°, 33.3°±0.2°, 35.3°±0.2°, 35.6°±0.2°, and 36.9°±0.2°; Optionally, the Form II has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table: ； Preferably, the crystalline Form II has an XRPD pattern substantially as shown in FIG5 .

4. The solid form of claim 1, wherein It is the free base of compound I, preferably, it is the crystalline form III of the free base of compound I; Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 28.4°±0.2°, and 36.2°±0.2°; Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 25.5°±0.2°, 28.4°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.5°±0.2°; Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 10.4°±0.2°, 11.9°±0.2°, 14.6°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 25.5°±0.2°, 28.4°±0.2°, 36.0°±0.2°, 36.2°±0.2°, and 36.5°±0.2°; Optionally, the Form III has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​according to the following table: ； Preferably, the Form III has an XRPD pattern substantially as shown in FIG9 .

5. A pharmaceutical composition comprising the solid form of any one of claims 1 to 4.

6. Use of the solid form according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of a molecular probe.

7. Use of the solid form according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of a tumor contrast agent.

8. The use according to claim 7, characterized in that The tumor includes one of breast cancer, hepatocellular carcinoma, prostate cancer, brain tumor, lung cancer, gastric cancer, thyroid cancer or colorectal cancer.

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