Solid form of metalloenzyme inhibitor compound

Abstract

The present invention provides a solid form of a metalloenzyme inhibitor compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazine-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, and in particular to a crystal form and an amorphous solid form, and a preparation method for the compound, a pharmaceutical composition comprising the compound, and a use of the compound.

Description

Solid form of metalloenzyme inhibitor compounds Technical Field

[0001] This disclosure relates to the solid form of the metalloenzyme inhibitor compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzimidazole, and more particularly to crystalline and amorphous solid forms, as well as methods of preparation therefrom, pharmaceutical compositions thereon, and uses therein. Background Technology

[0002] A compound having the following formula (I), 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, is a metalloenzyme inhibitor, specifically a selective inhibitor of aldosterone synthase CYP11B2, and shows promising application potential in the treatment of aldosterone-related diseases. In this paper, it is also referred to simply as "Compound A".

[0003] The chemical formula of compound A is C 15 N4H 10 F4, molecular weight 322.3. Compound A is a metalloenzyme inhibitor, specifically a selective inhibitor of aldosterone synthase CYP11B2. The synthetic method and biological activity of compound A can be found, for example, in WO2018 / 125800, the entire contents of which are incorporated herein by reference.

[0004] In order to promote the development of the above-mentioned compounds as solid pharmaceutical substances and to ensure the quality and efficacy of the compounds during production, packaging, storage or use, at least one solid form of the compound is required, such as a crystal form with superior physicochemical properties, or an amorphous solid form that can exist stably, so as to facilitate its use in pharmaceutical processing and pharmaceutical compositions. Summary of the Invention

[0005] This invention provides various crystal forms and amorphous solids of metalloenzyme inhibitor compound A, as well as its preparation methods, pharmaceutical compositions and uses.

[0006] One aspect of this invention relates to crystal form I of compound A, which has characteristic peaks at diffraction angles of approximately 8.9°, 12.4°, 17.6°, 25.0°, and 25.8° in X-ray powder diffraction (XRPD) patterns.

[0007] The present invention also relates to crystal form I of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, 28.0°, and 28.8°.

[0008] The present invention also relates to crystal form I of compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.

[0009] In some specific embodiments, the crystal form I of compound A is the amorphous form.

[0010] In some specific embodiments, when the crystal form I of compound A is thermally analyzed using differential scanning calorimetry (DSC), it exhibits an endothermic peak at approximately 211.6 °C ± 2.0 °C.

[0011] In some specific embodiments, when the crystal form I of compound A is thermally analyzed using differential scanning calorimetry (DSC), it has a DSC spectrum that is essentially as shown in Figure 2.

[0012] In some specific embodiments, when the crystal form I of compound A is thermally analyzed using thermogravimetric analysis (TGA), it has a TGA spectrum that is essentially as shown in Figure 3.

[0013] In some specific embodiments, when the crystal form I of compound A is analyzed using dynamic water adsorption (DVS), it has a DVS pattern that is essentially as shown in Figure 6.

[0014] This invention also relates to a method for preparing crystal form I of compound A, comprising the following steps:

[0015] (1) The solid of compound A is dissolved in an organic solvent or suspended in an organic solvent, wherein the organic solvent is one or more selected from organic acids, amides, sulfones, alcohols, ethers, and nitriles, preferably selected from organic acids and amides;

[0016] (2) Add water to the above solution or suspension to precipitate crystals, wherein the amount of water used is 0.1 to 100 times the volume of the organic solvent;

[0017] (3) Filter and collect the crystals and dry them to obtain crystal form I of compound A.

[0018] In some specific embodiments, in the method for preparing crystal form I of compound A, the organic solvent is selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohols or polyols, tetrahydrofuran, anisole, or acetonitrile.

[0019] Another aspect of the present invention relates to crystal form III of compound A, which has characteristic peaks at diffraction angles of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, and 25.7° in X-ray powder diffraction (XRPD) patterns.

[0020] The present invention also relates to crystal form III of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.4°, 10.2°, 12.4°, 14.0°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2°.

[0021] The present invention also relates to crystal form III of compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7.

[0022] In some specific embodiments, the crystal form III of compound A is an acetic acid-containing crystal form, preferably an acetic acid solvate crystal form.

[0023] In some specific embodiments, when the crystal form III of compound A is thermally analyzed using differential scanning calorimetry (DSC), it exhibits endothermic peaks at approximately 78.3 °C ± 2 °C, 121.4 °C ± 2 °C, and / or 212.2 °C ± 2 °C.

[0024] In some specific embodiments, when the crystal form III of compound A is thermally analyzed using differential scanning calorimetry (DSC), it has a DSC spectrum that is essentially as shown in Figure 8.

[0025] In some specific embodiments, when the crystal form III of compound A is thermally analyzed using thermogravimetric analysis (TGA), it has a TGA spectrum that is essentially as shown in Figure 9.

[0026] This invention also relates to a method for preparing crystal form III of compound A, comprising the following steps:

[0027] (1) The solid of compound A was added to anhydrous acetic acid and suspended under heating conditions;

[0028] (2) Filtration, and the filtrate is allowed to settle under cooling conditions;

[0029] (3) Filter and collect the crystals and dry them to obtain crystal form III of compound A.

[0030] In some specific embodiments, in the method for preparing crystal form III of compound A, the heating suspension temperature is <60°C, preferably ≤55°C, more preferably ≤50°C; and the cooling and settling temperature is ≤10°C, preferably ≤5°C.

[0031] Another aspect of the present invention relates to crystal form IV of compound A, which has characteristic peaks at diffraction angles of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, and 24.5° in X-ray powder diffraction (XRPD) patterns.

[0032] The present invention also relates to crystal form IV of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 9.7°, 13.0°, 15.6°, 17.2°, 17.9°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3°.

[0033] The present invention also relates to crystal form IV of compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 10.

[0034] In some specific embodiments, the crystal form IV of compound A is a hydrochloric acid-containing crystal form, preferably the crystal form of the hydrochloride salt of the compound, and more preferably an amorphous crystal form.

[0035] In some specific embodiments, when the crystal form IV of compound A is thermally analyzed using differential scanning calorimetry (DSC), it exhibits endothermic peaks at approximately 180.5 °C ± 2 °C and 209.0 °C ± 2 °C.

[0036] In some specific embodiments, when the crystal form IV of compound A is thermally analyzed using differential scanning calorimetry (DSC), it has a DSC spectrum that is essentially as shown in Figure 11.

[0037] In some specific embodiments, when the crystal form IV of compound A is thermally analyzed using thermogravimetric analysis (TGA), it has a TGA spectrum that is essentially as shown in Figure 12.

[0038] This invention also relates to a method for preparing crystal form IV of compound A, comprising the following steps:

[0039] (1) Dissolve the solid of compound A in a heated organic solvent containing HCl, wherein the organic solvent preferably contains isopropyl acetate and isopropanol;

[0040] (2) Cool the solution to room temperature and stir under an inert atmosphere to allow crystals to precipitate;

[0041] (3) Filter, wash the wet filter cake with isopropyl acetate and dry to obtain crystal form IV of compound A.

[0042] In some specific embodiments, in the method for preparing crystal form IV of compound A, the number of moles of HCl is 2 to 5 times the number of moles of compound A, preferably 3 to 4 times.

[0043] Another aspect of the present invention relates to a composition comprising:

[0044] Crystal form I of compound A, and

[0045] At least one of crystal form III and crystal form IV of compound A.

[0046] In some specific embodiments, the above composition is a mixture of two or more crystal forms of compound A, which is a mixed crystal form prepared directly from a solution or suspension of compound A.

[0047] In some embodiments, the composition comprises any proportion of crystal form I, crystal form III, and / or crystal form IV of compound A. In some preferred embodiments, the composition comprises any proportion of crystal form I and crystal form III of compound A.

[0048] Another aspect of the present invention relates to a pharmaceutical composition comprising:

[0049] (i) Crystal form I of compound A, and / or

[0050] Crystal form III of compound A, and / or

[0051] Crystal form IV of compound A, and

[0052] (ii) Pharmaceutically acceptable carriers, diluents or excipients.

[0053] In some embodiments, the pharmaceutical composition also includes additional therapeutic agents.

[0054] In some specific embodiments, the pharmaceutical composition may include additional therapeutic agents selected from anticancer agents, antifungal agents, cardiovascular therapeutic agents, anti-inflammatory agents, chemotherapeutic agents, anti-angiogenic agents, cytotoxic agents, antiproliferative agents, metabolic disease therapeutic agents, ophthalmic disease therapeutic agents, central nervous system (CNS) disease therapeutic agents, urinary disease therapeutic agents, and gastrointestinal disease therapeutic agents.

[0055] Another aspect of the present invention relates to an amorphous solid of compound A, which does not exhibit obvious crystal diffraction characteristic peaks in X-ray powder diffraction (XRPD) patterns.

[0056] In some specific embodiments, the amorphous solid of compound A has an X-ray powder diffraction (XRPD) pattern that is substantially as shown in Figure 15.

[0057] In some specific embodiments, the amorphous solid of compound A further comprises a pharmaceutically acceptable polymer.

[0058] In some specific embodiments, the amorphous solid of compound A is a solid dispersion of the compound and the polymer.

[0059] In some specific embodiments, in the amorphous solid of compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymers (Eudragit).

[0060] In some specific embodiments, the hydroxypropyl methylcellulose in the amorphous solid of compound A is selected from HPMC E3, HPMC E5, or HPMC E50LV;

[0061] The hydroxypropyl methylcellulose acetate succinate is selected from HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP or HPMCAS MF;

[0062] The hydroxypropyl methylcellulose phthalate is selected from HPMCP HP50;

[0063] The acrylic resin copolymer is selected from methacrylic acid / methyl methacrylate copolymer (Eudragit L100) or butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer (Euragit EPO).

[0064] In some specific embodiments, in the amorphous solid of compound A, the polymer is selected from one or more of HPMC E3, HPMC E5, HPMC E50LV, HPMC LG, HPMC MG, HPMC HG, HPMC MMP, HPMC MF, HPMC HP50, Eudragit L100, and Euragit EPO, preferably one or more of HPMC MG, HPMC MMP, and HPMC MF.

[0065] In some specific embodiments, the compound A comprises about 5% to 25% of the weight of the amorphous solid, preferably about 5% to 20%, more preferably about 10% to 20%, and particularly preferably about 10% to 15%.

[0066] In some specific embodiments, in the amorphous solid of compound A, the mass ratio of the compound to the polymer is about 1:3 to 1:20, preferably about 1:4 to 1:20, more preferably about 1:4 to 1:9, and particularly preferably about 1:5.6 to 1:9.

[0067] In some specific embodiments, the amorphous solid of compound A is prepared by spray drying or hot melt extrusion.

[0068] Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:

[0069] The compound is dissolved in a solvent with a pharmaceutically acceptable polymer to form a solution;

[0070] The solution is spray-dried to form a solid dispersion, namely the amorphous solid.

[0071] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymer (Eudragit).

[0072] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the solvent is one or more selected from alcohols, haloalkanes, ketones, ethers, esters, amides, sulfones, and nitriles. In some specific embodiments, the solvent is one or more selected from C1-C6 alcohols or polyols, dichloromethane, trichloromethane, acetone, methyl ethyl ketone, tetrahydrofuran, anisole, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, and acetonitrile.

[0073] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the solvent is a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane and methanol in a volume ratio of 2:1.

[0074] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the concentration of the compound in the solution is about 3-15 mg / mL, preferably about 4-12 mg / mL, and more preferably about 5-10 mg / mL.

[0075] Therefore, the present invention also relates to an amorphous solid of compound A obtained by the above-described spray drying method.

[0076] Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:

[0077] The compound is mixed uniformly with a pharmaceutically acceptable polymer and then extruded through a hot melt extruder to obtain the amorphous solid.

[0078] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymer (Eudragit).

[0079] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the heating temperature of the hot melt extruder is 150-200°C, preferably 160-180°C.

[0080] In some specific embodiments, the method for preparing the amorphous solid of compound A further includes the steps of crushing and sieving the hot melt extruded material.

[0081] The present invention also relates to an amorphous solid of compound A obtained by the above-described hot melt extrusion method.

[0082] Another aspect of the present invention relates to a pharmaceutical composition comprising:

[0083] (i) the amorphous solid of compound A, and

[0084] (ii) Pharmaceutically acceptable carriers, diluents or excipients.

[0085] In some embodiments, the pharmaceutical composition also includes additional therapeutic agents.

[0086] In some specific embodiments, the pharmaceutical composition may include additional therapeutic agents selected from anticancer agents, antifungal agents, cardiovascular therapeutic agents, anti-inflammatory agents, chemotherapeutic agents, anti-angiogenic agents, cytotoxic agents, antiproliferative agents, metabolic disease therapeutic agents, ophthalmic disease therapeutic agents, central nervous system (CNS) disease therapeutic agents, urinary disease therapeutic agents, and gastrointestinal disease therapeutic agents.

[0087] Another aspect of the present invention relates to the use of crystal form I, crystal form III, crystal form IV or amorphous solid of compound A in pharmaceutical preparation.

[0088] In some specific embodiments, the drug is used to regulate the activity of metalloenzymes.

[0089] In some specific embodiments, the drug is used to regulate the activity of aldosterone synthase CYP11B2.

[0090] In some specific embodiments, the drug is used to treat metalloenzyme-related conditions or diseases, wherein the conditions or diseases are cancer, cardiovascular disease, endocrine disorders, fibrosis, kidney disease, inflammatory diseases, infectious diseases, gynecological diseases, metabolic diseases, ophthalmic diseases, central nervous system (CNS) diseases, urinary diseases, or gastrointestinal diseases.

[0091] In some specific embodiments, the condition or disease is adrenal carcinoma, adrenal adenoma, leukemia, breast cancer, hypertension, refractory hypertension, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, post-myocardial infarction syndrome, coronary artery disease, myocardial necrosis, atrial fibrillation, atherosclerosis, restenosis, endothelial dysfunction, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, vascular disease, and diseases associated with primary or secondary aldosteronism and adrenal hyperplasia. Diseases including diabetes, metabolic syndrome, insulin resistance, neuropathy, insulinopathy, diabetic nephropathy, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, diseases characterized by fibrosis and matrix remodeling after endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, renal failure, chronic renal failure, nephropathy, renal dysfunction, kidney disease, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, hypokalemia, retinopathy, sleep apnea, obstructive sleep apnea, muscular dystrophy, stroke, liver disease, non-alcoholic steatohepatitis, cirrhosis or non-alcoholic fatty liver disease.

[0092] In a preferred embodiment, the condition or disease is hypertension, refractory hypertension, pulmonary hypertension, atherosclerosis, or hypokalemia.

[0093] Another aspect of the present invention relates to a treatment for a symptom or disease, comprising administering to a subject in need an effective amount of crystal form I, crystal form III, or crystal form IV of compound A, or a mixture of at least any two or more crystal forms in any proportion. The symptom or disease is as described above. Attached Figure Description

[0094] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystal form I of compound A.

[0095] Figure 2 shows the differential scanning calorimetry (DSC) spectrum of crystal form I of compound A.

[0096] Figure 3 shows the thermogravimetric analysis (TGA) spectrum of crystal form I of compound A.

[0097] Figure 4 shows the crystal form I of compound A. 1 H NMR spectrum.

[0098] Figure 5 shows the crystal form I of compound A. 13 C NMR spectrum.

[0099] Figure 6 shows the dynamic water adsorption (DVS) spectrum of crystal form I of compound A.

[0100] Figure 7 shows the X-ray powder diffraction (XRPD) pattern of crystal form III of compound A.

[0101] Figure 8 shows the differential scanning calorimetry (DSC) spectrum of crystal form III of compound A.

[0102] Figure 9 shows the thermogravimetric analysis (TGA) spectrum of crystal form III of compound A.

[0103] Figure 10 shows the X-ray powder diffraction (XRPD) pattern of crystal form IV of compound A.

[0104] Figure 11 shows the differential scanning calorimetry (DSC) spectrum of crystal form IV of compound A.

[0105] Figure 12 shows the thermogravimetric analysis (TGA) spectrum of crystal form IV of compound A.

[0106] Figure 13 shows crystal form IV of compound A. 1 H NMR spectrum.

[0107] Figure 14 shows the XRPD spectra of some of the solid dispersions prepared in Example 22.

[0108] Figure 15 shows the X-ray powder diffraction (XRPD) pattern of the amorphous solid of compound A prepared in Example 24.

[0109] Figure 16 shows the modulation differential scanning calorimetry (mDSC) spectrum of the amorphous solid of compound A prepared in Example 24. The three curves from top to bottom in the figure are the reversible sample heat flow, the irreversible sample heat flow, and the total heat flow, respectively.

[0110] Figure 17 shows the thermogravimetric analysis (TGA) spectrum of the amorphous solid of compound A prepared in Example 24.

[0111] Figure 18 shows the X-ray powder diffraction (XRPD) pattern of the amorphous solid of compound A prepared in Example 27.

[0112] Figure 19 shows the modulation differential scanning calorimetry (mDSC) spectrum of the amorphous solid of compound A prepared in Example 27. The three curves from top to bottom in the figure are the irreversible sample heat flow, the total heat flow, and the reversible sample heat flow, respectively.

[0113] Figure 20 shows the thermogravimetric analysis (TGA) spectrum of the amorphous solid of compound A prepared in Example 27. Detailed Implementation

[0114] definition

[0115] To facilitate a better understanding of this invention, certain terms are defined herein.

[0116] As used herein, the term "treatment" of a disease includes the prevention, improvement, reduction, and / or management of the disease and / or symptoms that may lead to the disease. The terms "treatment" and "management" refer to methods of reducing or alleviating a disease and / or its accompanying symptoms. According to this disclosure, "treatment" includes preventing, blocking, inhibiting, weakening, protecting, modulating, reversing, and reducing the effects of a disease, such as its harmful effects.

[0117] As used herein, “inhibition” includes prevention, reduction, and cessation of progression. The term “regulation” refers to an increase or decrease in enzyme activity in response to exposure to compounds of this disclosure.

[0118] The term "inhibitor" as used herein refers to a molecule that exhibits inhibition of metalloenzyme activity. "Inhibition" as used herein means a reduction in metalloenzyme activity compared to the activity of the metalloenzyme in the absence of an inhibitor. In some embodiments, the term "inhibition" means a reduction in metalloenzyme activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibition means a reduction in metalloenzyme activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibition means a reduction in metalloenzyme activity of about 95% to 100%, for example, a reduction of 95%, 96%, 97%, 98%, 99%, or 100%. This reduction can be measured using various techniques recognized by those skilled in the art.

[0119] The terms “administration” or “application” refer to the means by which a compound is introduced into a target to achieve its intended function. Examples of possible routes of administration include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal administration.

[0120] The term "effective amount" refers to the amount of a compound that achieves the desired result within the necessary dosage and time period. The effective amount of a compound can vary depending on factors such as the subject's disease condition, age, and weight, as well as the compound's ability to elicit the desired response in the subject. Dosing regimens can be adjusted to provide the best therapeutic response. An effective amount is also the amount in which the beneficial therapeutic effect outweighs any toxic or harmful effects (e.g., side effects) of the inhibitory compound.

[0121] The phrases “systemic administration,” “systemic drug delivery,” “peripheral administration,” and “peripheral drug delivery” used here refer to the administration of a compound, drug, or other substance to the patient’s system, where it undergoes metabolism and other similar processes.

[0122] The term "therapeutic effective dose" refers to an amount of compound applied that is sufficient to prevent or, to some extent, alleviate the development of one or more symptoms of a disease or condition being treated.

[0123] The therapeutically effective amount (i.e., effective dose) of the compound can be from about 0.005 μg / kg body weight to about 200 mg / kg body weight, preferably from about 0.01 mg / kg body weight to about 200 mg / kg body weight, more preferably from about 0.015 mg / kg body weight to about 30 mg / kg body weight. In other embodiments, the therapeutically effective amount can be from about 1.0 pM to about 10 μM. Those skilled in the art will understand that certain factors can affect the dose required to effectively treat a subject, including but not limited to the severity of the disease or condition, prior treatment, the subject's overall health status and / or age, and other pre-existing conditions. Furthermore, treating a subject with a therapeutically effective amount of the compound can include monotherapy or preferably can include a series of treatments. In one example, a subject is treated with a compound at a concentration of about 0.005 μg / kg body weight to about 200 mg / kg body weight once daily for about 1 to 10 weeks, preferably 2 to 8 weeks, more preferably about 3 to 7 weeks, and even more preferably about 4, 5, or 6 weeks. In another example, in the case of a chronic condition or disease, the subject can be treated daily for several years. It should also be understood that the effective dose of a compound used for treatment can be increased or decreased during a particular treatment.

[0124] The term "object" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some implementations, the object is humans.

[0125] As used herein, the term "pharmaceutically acceptable" means a carrier, loading agent, diluent, excipient, and / or salt that must be compatible with other components of the formulation and not be harmful to the recipient.

[0126] As used herein, the term "pharmaceuticalally acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or animals and has no adverse effects on the composition of the pharmaceutical composition.

[0127] This article involves X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) patterns, thermogravimetric analysis (TGA) patterns, and more. 1 H and 13 12C nuclear magnetic resonance (NMR) spectra, the term “substantially as shown in” means that they are not necessarily the same as those depicted in this disclosure, but fall within the limits of experimental error or bias when considered by a person of ordinary skill in the art.

[0128] In this document, when referring to X-ray powder diffraction (XRPD) peak positions, the term "substantially identical" as used herein means taking into account typical peak positions and intensities of variability. For example, those skilled in the art will understand that peak positions (2θ) will exhibit some variability, typically up to 0.1° to 0.2°, depending on the solvent used and the apparatus used to measure the diffraction. Furthermore, those skilled in the art will understand that relative peak intensities will exhibit instrument-specific variability as well as variability caused by crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art, and should be considered only as qualitative measurements.

[0129] In this document, the term "2θ value" or "2θ" refers to the peak position in degrees based on an experimental setup for X-ray powder diffraction (XRPD) experiments and is a common unit of measurement for the horizontal axis of diffraction patterns. The experimental setup requires that the reflected beam be diffracted at an angle θ (theta) between the incident beam and a crystal plane, and the reflected beam be recorded in angle 2θ (2theta). It should be understood that the specific 2θ value for a particular crystal form mentioned herein is intended to refer to the 2θ value (in degrees) measured using the X-ray powder diffraction (XRPD) experimental conditions described herein. For example, as described herein, using CuKα... As a radiation source.

[0130] In this document, the term "amorphous" refers to a solid substance with an irregular microstructure, which may be called an amorphous solid. An amorphous solid in this document may contain only one substance or more substances. For example, when an amorphous solid contains substance A and substance B, it may be called an amorphous solid of substance A or an amorphous solid of substance B. In some embodiments, an amorphous solid may be a solid dispersion formed by two or more substances. For example, when substance A and substance B form a solid dispersion, it may be called a solid dispersion of substance A or an amorphous solid, or a solid dispersion of substance B or an amorphous solid.

[0131] In this application (including the claims), terms used without a quantifier mean "one or more". Thus, for example, reference to "sample" includes multiple samples unless the context clearly indicates otherwise (e.g., multiple samples), etc.

[0132] Throughout the specification and claims, unless the context otherwise requires, the words “comprising,” “including,” and “containing” are used in a non-exclusive sense.

[0133] As used herein, the term "about" when referring to a value means including variations based on a specific amount, within ±20% in some embodiments, within ±10% in some embodiments, within ±5% in some embodiments, within ±1% in some embodiments, within ±0.5% in some embodiments, and within ±0.1% in some embodiments, because such variations are suitable for performing the disclosed methods or using the disclosed compositions. When referring to the value of the diffraction angle 2θ, "about" can mean that the error of the value of the diffraction angle 2θ is within ±0.2°.

[0134] It should be understood that the singular article “a” (corresponding to the English words “a,” “an,” and “the”) used in this disclosure and the appended claims includes plural objects unless otherwise expressly stated herein. Thus, a pharmaceutical composition comprising, for example, a “pharmaceutical-acceptable carrier, diluent, or excipient” includes one, or two or more, pharmaceutically acceptable carriers, diluents, or excipients.

[0135] The numerical limits or ranges stated in this article include endpoints, specifically all values ​​and subranges within the numerical limits or ranges.

[0136] The present invention will be further described below through specific embodiments. Unless otherwise specified, the terminology used herein has the same meaning as commonly understood by those skilled in the art.

[0137] This invention relates to the crystalline and solid forms of compound (I), 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole (“Compound A”). Compound A has the chemical formula C. 15 N4H 10 F4, molecular weight 322.3. Compound A is a metalloenzyme inhibitor, specifically a selective inhibitor of aldosterone synthase CYP11B2. The synthetic method and biological activity of compound A can be found, for example, in WO2018 / 125800, the entire contents of which are incorporated herein by reference.

[0138] Crystal form I of compound A

[0139] This invention relates, in one aspect, to crystal form I of compound A, which exhibits characteristic peaks at diffraction angles of approximately 8.9°, 12.4°, 17.6°, 25.0°, and 25.8° in X-ray powder diffraction (XRPD) patterns. Preferably, it exhibits characteristic peaks at diffraction angles of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 25.0°±0.2°, and 25.8°±0.2°.

[0140] The present invention also relates to crystal form I of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 24.2°, 25.0°, and 25.8°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 24.2°±0.2°, 25.0°±0.2°, and 25.8°±0.2°.

[0141] The present invention also relates to crystal form I of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 24.2°, 25.0°, and 25.8°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 24.2°±0.2°, 25.0°±0.2°, and 25.8°±0.2°.

[0142] The present invention also relates to crystal form I of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 24.2°, 25.0°, 25.8°, and 26.7°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 25.8°±0.2°, and 26.7°±0.2°.

[0143] The present invention also relates to crystal form I of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 24.2°, 25.0°, 25.8°, 26.7°, and 28.0°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 26.7°±0.2°, and 28.0°±0.2°.

[0144] The present invention also relates to crystal form I of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, and 28.0°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 19.6°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 26.7°±0.2°, and 28.0°±0.2°.

[0145] The present invention also relates to crystal form I of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, 28.0°, and 28.8°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.9°±0.2°, 12.4°±0.2°, 17.6°±0.2°, 18.2°±0.2°, 19.6°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 26.7°±0.2°, 28.0°±0.2°, and 28.8°±0.2°.

[0146] The present invention also relates to crystal form I of compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.

[0147] In some specific embodiments, the crystal form I of compound A is the amorphous form.

[0148] In some specific embodiments, when the crystal form I of compound A is thermally analyzed using differential scanning calorimetry (DSC), it exhibits an endothermic peak at approximately 211.6 °C ± 2.0 °C.

[0149] In some specific embodiments, when the crystal form I of compound A is thermally analyzed using differential scanning calorimetry (DSC), it has a DSC spectrum that is essentially as shown in Figure 2. As shown in Figure 2, the crystal form I of compound A exhibits only one endothermic peak, which corresponds to the melting point of crystal form I.

[0150] In some specific embodiments, when the crystal form I of compound A is thermally analyzed using thermogravimetric analysis (TGA), it has a TGA spectrum essentially as shown in Figure 3. As shown in Figure 3, the weight loss of crystal form I of compound A is only about 0.5% in the heating range of 110-180°C, which means that crystal form I is amorphous.

[0151] In some specific embodiments, when compound A's crystal form I is analyzed using dynamic moisture adsorption (DVS), it exhibits a DVS pattern essentially as shown in Figure 6. As shown in Figure 6, the weight change of crystal form I of compound A is <0.2% during cycling at relative humidity from 0 to 90%, indicating that crystal form I is not hygroscopic.

[0152] This invention also relates to a method for preparing crystal form I of compound A, comprising the following steps:

[0153] (1) The solid of compound A is dissolved in an organic solvent or suspended in an organic solvent, wherein the organic solvent is one or more selected from organic acids, amides, sulfones, alcohols, ethers, and nitriles, preferably selected from organic acids and amides;

[0154] (2) Add water to the above solution or suspension to precipitate crystals, wherein the amount of water used is 0.1 to 100 times the volume of the organic solvent;

[0155] (3) Filter and collect the crystals and dry them to obtain crystal form I of compound A.

[0156] In some specific embodiments, in the method for preparing crystal form I of compound A, the organic solvent is selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohols or polyols, tetrahydrofuran, anisole, or acetonitrile.

[0157] In this invention, crystal form I of compound A is the dominant crystal form, which remains stable under high temperature, high humidity, light conditions and when suspended in water.

[0158] Crystal form III of compound A

[0159] Another aspect of the present invention relates to crystal form III of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, and 25.7°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 24.8°±0.2°, and 25.7°±0.2°.

[0160] The present invention also relates to crystal form III of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, 25.2°, and 25.7°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 24.8°±0.2°, 25.2°±0.2°, and 25.7°±0.2°.

[0161] The present invention also relates to crystal form III of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 23.4°, 24.8°, 25.2°, and 25.7°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, and 25.7°±0.2°.

[0162] The present invention also relates to crystal form III of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 22.1°, 23.4°, 24.8°, 25.2°, and 25.7°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, and 25.7°±0.2°.

[0163] The present invention also relates to crystal form III of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 22.1°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2°. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0164] The present invention also relates to crystal form III of compound A, which has characteristic peaks at diffraction angles of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in X-ray powder diffraction (XRPD) patterns. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0165] The present invention also relates to crystal form III of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2°. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0166] The present invention also relates to crystal form III of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.4°, 10.2°, 12.4°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2°. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 15.8°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0167] The present invention also relates to crystal form III of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 8.4°, 10.2°, 12.4°, 14.0°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2°. Preferably, it has characteristic peaks at diffraction angles 2θ of 8.4°±0.2°, 10.2°±0.2°, 12.4°±0.2°, 14.0°±0.2°, 15.8°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.7°±0.2°, and 28.2°±0.2°.

[0168] The present invention also relates to crystal form III of compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7.

[0169] In some specific embodiments, the crystal form III of compound A is an acetic acid-containing crystal form, preferably an acetic acid solvate crystal form.

[0170] In some specific embodiments, when the crystal form III of compound A is thermally analyzed using differential scanning calorimetry (DSC), it exhibits endothermic peaks at approximately 78.3, 121.4, and / or 212.2 °C ± 2 °C.

[0171] In some specific embodiments, when the crystal form III of compound A is thermally analyzed using differential scanning calorimetry (DSC), it exhibits a DSC spectrum essentially as shown in Figure 8. As shown in Figure 8, the endothermic peak of crystal form III of compound A at approximately 63-90 °C corresponds to the decomposition of the acetic acid solvate; the endothermic peak at approximately 121 °C corresponds to the boiling point of acetic acid; and the endothermic peak at approximately 212 °C corresponds to the melting point of compound A.

[0172] In some specific embodiments, when the crystal form III of compound A is thermally analyzed using thermogravimetric analysis (TGA), it has a TGA spectrum substantially as shown in Figure 9. As shown in Figure 9, the weight loss of crystal form III of compound A is approximately 15.2% in the heating range of 50-150°C, which means that the stoichiometric ratio of compound A to acetic acid in the acetic acid solvate crystal form III is 1:1, and that crystal form III of compound A is an amorphous form.

[0173] This invention also relates to a method for preparing crystal form III of compound A, comprising the following steps:

[0174] (1) The solid of compound A was added to anhydrous acetic acid and suspended under heating conditions;

[0175] (2) Filtration, and the filtrate is allowed to settle under cooling conditions;

[0176] (3) Filter and collect the crystals and dry them to obtain crystal form III of compound A.

[0177] In some specific embodiments, in the method for preparing crystal form III of compound A, the heating suspension temperature is <60°C, preferably ≤55°C, more preferably ≤50°C; and the cooling and settling temperature is ≤10°C, preferably ≤5°C.

[0178] In this invention, crystal form III of compound A remains stable at room temperature. Crystal form III transforms into crystal form I at high temperatures, such as when heated in air to >110°C. Furthermore, crystal form III remains stable in anhydrous acetic acid solvent at <60°C, preferably ≤55°C; while at temperatures ≥60°C, crystal form III spontaneously transforms into crystal form I.

[0179] Crystal form IV of compound A

[0180] Another aspect of the present invention relates to crystal form IV of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, and 24.5°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, and 24.5°±0.2°.

[0181] The present invention also relates to crystal form IV of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, and 28.1°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, and 28.1°±0.2°.

[0182] The present invention also relates to crystal form IV of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, and 28.1°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, and 28.1°±0.2°.

[0183] The present invention also relates to crystal form IV of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, and 29.0°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, and 29.0°±0.2°.

[0184] The present invention also relates to crystal form IV of compound A, which, in X-ray powder diffraction (XRPD) patterns, exhibits characteristic peaks at diffraction angles 2θ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, and 32.7°. Preferably, it exhibits characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, and 32.7°±0.2°.

[0185] The present invention also relates to crystal form IV of compound A, which has characteristic peaks at diffraction angles of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, and 32.7° in X-ray powder diffraction (XRPD) patterns. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 19.1°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, and 32.7°±0.2°.

[0186] The present invention also relates to crystal form IV of compound A, which has characteristic peaks at diffraction angles of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, and 32.7° in X-ray powder diffraction (XRPD) patterns. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 19.1°±0.2°, 21.3°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, and 32.7°±0.2°.

[0187] The present invention also relates to crystal form IV of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3°. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 19.1°±0.2°, 21.3°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, 32.7°±0.2°, and 34.3°±0.2°.

[0188] The present invention also relates to crystal form IV of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3°. Preferably, it has characteristic peaks at diffraction angles 2θ of 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 19.1°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, 32.7°±0.2°, and 34.3°±0.2°.

[0189] The present invention also relates to crystal form IV of compound A, which has characteristic peaks in X-ray powder diffraction (XRPD) patterns at diffraction angles of approximately 9.7°, 13.0°, 15.6°, 17.2°, 17.9°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3°. Preferably, it has characteristic peaks at diffraction angles 2θ of approximately 9.7°±0.2°, 13.0°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 19.1°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 28.1°±0.2°, 29.0°±0.2°, 32.7°±0.2°, and 34.3°±0.2°.

[0190] The present invention also relates to crystal form IV of compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 10.

[0191] In some specific embodiments, the crystal form IV of compound A is a hydrochloric acid-containing crystal form, preferably the crystal form of the hydrochloride salt of the compound, and more preferably an amorphous crystal form.

[0192] In some specific embodiments, when the crystal form IV of compound A is thermally analyzed using differential scanning calorimetry (DSC), it exhibits an endothermic peak at approximately 180.5 °C and 209.0 °C ± 2 °C.

[0193] In some specific embodiments, when the crystal form IV of compound A is thermally analyzed using differential scanning calorimetry (DSC), it has a DSC spectrum essentially as shown in Figure 11. As shown in Figure 11, the endothermic peak of crystal form IV of compound A at around 160-180 °C corresponds to the decomposition of the hydrochloride salt, while the endothermic peak at around 209 °C corresponds to the melting point of compound A.

[0194] In some specific embodiments, when the crystal form IV of compound A is thermally analyzed using thermogravimetric analysis (TGA), it has a TGA spectrum essentially as shown in Figure 12. As shown in Figure 12, the crystal form IV of compound A experiences a weight loss of approximately 10% within the heating range of 145-205°C, implying that the stoichiometric ratio of compound A to hydrochloric acid in the hydrochloride salt is 1:1, and that crystal form IV of compound A is an amorphous form.

[0195] This invention also relates to a method for preparing crystal form IV of compound A, comprising the following steps:

[0196] (1) Dissolve the solid of compound A in a heated organic solvent containing HCl, wherein the organic solvent preferably contains isopropyl acetate and isopropanol;

[0197] (2) Cool the solution to room temperature and stir under an inert atmosphere to allow crystals to precipitate;

[0198] (3) Filter, wash the wet filter cake with isopropyl acetate and dry to obtain crystal form IV of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium.

[0199] In some specific embodiments, in the method for preparing crystal form IV of compound A, the number of moles of HCl is 2 to 5 times the number of moles of compound A, preferably 3 to 4 times.

[0200] In some specific embodiments, in the method for preparing crystal form IV of compound A, the heating temperature in step (1) is about 65±5℃.

[0201] In this invention, crystal form IV of compound A remains stable at room temperature. At high temperatures (e.g., above 100°C), crystal form IV transforms into crystal form I.

[0202] Composition

[0203] Another aspect of the present invention relates to a composition comprising:

[0204] Crystal form I of compound A, and

[0205] At least one of crystal form III and crystal form IV of compound A.

[0206] In some specific embodiments, the above composition is a mixture of two or more crystal forms of compound A, which is a mixed crystal form prepared directly from a solution or suspension of compound A.

[0207] In some embodiments, the composition comprises any proportion of crystal form I, crystal form III, and / or crystal form IV of compound A. In some preferred embodiments, the composition comprises any proportion of crystal form I and crystal form III of compound A.

[0208] Pharmaceutical composition (crystalline form)

[0209] The present invention also provides pharmaceutical compositions comprising one or more of the above-described crystal forms of compound A.

[0210] Specifically, another aspect of the present invention relates to a pharmaceutical composition comprising:

[0211] (i) Crystal form I of compound A, and / or

[0212] Crystal form III of compound A, and / or

[0213] Crystal form IV of compound A, and

[0214] (ii) Pharmaceutically acceptable carriers, diluents or excipients.

[0215] In some embodiments, the pharmaceutical composition also includes additional therapeutic agents.

[0216] In some specific embodiments, the pharmaceutical composition may include additional therapeutic agents selected from anticancer agents, antifungal agents, cardiovascular therapeutic agents, anti-inflammatory agents, chemotherapeutic agents, anti-angiogenic agents, cytotoxic agents, antiproliferative agents, metabolic disease therapeutic agents, ophthalmic disease therapeutic agents, central nervous system (CNS) disease therapeutic agents, urinary disease therapeutic agents, and gastrointestinal disease therapeutic agents.

[0217] Amorphous solid of compound A

[0218] Another aspect of the present invention relates to an amorphous solid of compound A, which does not exhibit obvious crystal diffraction characteristic peaks in X-ray powder diffraction (XRPD) patterns.

[0219] In some specific embodiments, the amorphous solid of compound A has an X-ray powder diffraction (XRPD) pattern that is substantially as shown in Figure 15.

[0220] In some specific embodiments, the amorphous solid of compound A further comprises a pharmaceutically acceptable polymer.

[0221] In some specific embodiments, the amorphous solid of compound A is a solid dispersion of the compound and the polymer.

[0222] In some specific embodiments, in the amorphous solid of compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymers (Eudragit).

[0223] In some specific embodiments, the hydroxypropyl methylcellulose in the amorphous solid of compound A is selected from HPMC E3, HPMC E5, or HPMC E50LV;

[0224] The hydroxypropyl methylcellulose acetate succinate is selected from HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP or HPMCAS MF;

[0225] The hydroxypropyl methylcellulose phthalate is selected from HPMCP HP50;

[0226] The acrylic resin copolymer is selected from methacrylic acid / methyl methacrylate copolymer (Eudragit L100) or butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer (Euragit EPO).

[0227] Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a pharmaceutically acceptable polymer based on hydroxypropyl methylcellulose, in which the hydroxyl groups on the cellulose backbone are partially replaced by acetyl and succinyl groups. Commercially available HPMCAS products can have different solubility pH values, such as 5.5, 6.0, and 6.5, designated as -L, -M, and -H, respectively, by adjusting the chemical substitution levels of the acetyl and succinyl groups. HPMCAS can also be formulated into solid particles of different sizes, such as 5 μm, 200 μm, and 1000 μm, designated as -F, -MP, and -G, respectively. Therefore, HPMCAS with a particle size of 1000 μm and a solubility pH of 6.5 can be called HPMCAS HG; HPMCAS with a particle size of 200 μm and a solubility pH of 6.0 can be called HPMCAS MMP, and so on.

[0228] In some specific embodiments, in the amorphous solid of compound A, the polymer is selected from one or more of HPMC E3, HPMC E5, HPMC E50LV, HPMC LG, HPMC MG, HPMC HG, HPMC MMP, HPMC MF, HPMC HP50, Eudragit L100, and Euragit EPO, preferably one or more of HPMC MG, HPMC MMP, and HPMC MF.

[0229] In some specific embodiments, in the amorphous solid of compound A, compound A accounts for about 5% to 25% of the weight of the amorphous solid, preferably about 5% to 20%, more preferably about 10% to 20%, and particularly preferably about 10% to 15%.

[0230] In some specific embodiments, in the amorphous solid of compound A, the mass ratio of compound A to polymer is about 1:3 to 1:20, preferably about 1:4 to 1:20, more preferably about 1:4 to 1:9, and particularly preferably about 1:5.6 to 1:9.

[0231] In some specific embodiments, the amorphous solid of compound A is prepared by spray drying or hot melt extrusion.

[0232] The amorphous solid of compound A of the present invention, particularly the amorphous solid dispersion of compound A, can significantly improve the water solubility and bioavailability of compound A, for example, the solubility of compound A in fasting simulated intestinal fluid (FaSSIF), satiated simulated intestinal fluid (FeSSIF), and simulated gastric juice (SGF). The solubility of the amorphous solid of compound A is more than 3 times, preferably more than 5 times, that of the crystalline form of compound A.

[0233] The amorphous solid of compound A of the present invention, especially the amorphous solid dispersion of compound A, can remain stable under high temperature, high humidity and light conditions and will not undergo crystal transformation, which is beneficial for its application in pharmaceutical compositions, pharmaceutical dosage forms and pharmaceutical preparation.

[0234] The present invention also provides a method for preparing an amorphous solid of compound A, including spray drying or hot melt extrusion.

[0235] Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:

[0236] Compound A is dissolved in a solvent with a pharmaceutically acceptable polymer to form a solution;

[0237] The solution is spray-dried to form a solid dispersion, namely the amorphous solid of compound A.

[0238] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymer (Eudragit).

[0239] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the solvent is one or more selected from alcohols, haloalkanes, ketones, ethers, esters, amides, sulfones, and nitriles. In some specific embodiments, the solvent is one or more selected from C1-C6 alcohols or polyols, dichloromethane, trichloromethane, acetone, methyl ethyl ketone, tetrahydrofuran, anisole, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, and acetonitrile.

[0240] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the solvent is a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane and methanol in a volume ratio of 2:1.

[0241] In some specific embodiments, in the preparation method of compound A, the concentration of compound A in the solution is about 3-15 mg / mL, preferably about 4-12 mg / mL, and more preferably about 5-10 mg / mL.

[0242] Therefore, the present invention also relates to an amorphous solid of compound A obtained by the above-described spray drying method.

[0243] Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:

[0244] Compound A is mixed uniformly with a pharmaceutically acceptable polymer and then extruded through a hot melt extruder to obtain an amorphous solid of compound A.

[0245] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymer (Eudragit).

[0246] In some specific embodiments, in the method for preparing the amorphous solid of compound A, the heating temperature of the hot melt extruder is 150-200°C, preferably 160-180°C.

[0247] In some specific embodiments, the method for preparing the amorphous solid of compound A further includes the steps of crushing and sieving the hot melt extruded material.

[0248] Therefore, the present invention also relates to an amorphous solid of compound A obtained according to the above-described hot melt extrusion method.

[0249] Pharmaceutical composition (amorphous)

[0250] The present invention also provides a pharmaceutical composition comprising an amorphous solid of compound A.

[0251] Specifically, another aspect of the present invention relates to a pharmaceutical composition comprising:

[0252] (i) the amorphous solid of compound A, and

[0253] (ii) Pharmaceutically acceptable carriers, diluents or excipients.

[0254] In some embodiments, the pharmaceutical composition also includes additional therapeutic agents.

[0255] In some specific embodiments, the pharmaceutical composition may include additional therapeutic agents selected from anticancer agents, antifungal agents, cardiovascular therapeutic agents, anti-inflammatory agents, chemotherapeutic agents, anti-angiogenic agents, cytotoxic agents, antiproliferative agents, metabolic disease therapeutic agents, ophthalmic disease therapeutic agents, central nervous system (CNS) disease therapeutic agents, urinary disease therapeutic agents, and gastrointestinal disease therapeutic agents.

[0256] Pharmaceutical uses of the crystalline form and amorphous solid of compound A

[0257] Another aspect of the present invention relates to the use of compound A (1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole) in crystal form I, crystal form III, or crystal form IV, or a mixture of any two or more crystal forms in any proportion, or an amorphous solid of compound A, in the preparation of a pharmaceutical product.

[0258] In some specific embodiments, the drug is used to regulate the activity of metalloenzymes.

[0259] In some specific embodiments, the drug is used to regulate the activity of aldosterone synthase CYP11B2.

[0260] In some specific embodiments, the drug is used to treat metalloenzyme-related conditions or diseases, wherein the conditions or diseases are cancer, cardiovascular disease, endocrine disorders, fibrosis, kidney disease, inflammatory diseases, infectious diseases, gynecological diseases, metabolic diseases, ophthalmic diseases, central nervous system (CNS) diseases, urinary diseases, or gastrointestinal diseases.

[0261] In some specific embodiments, the condition or disease is adrenal carcinoma, adrenal adenoma, leukemia, breast cancer, hypertension, refractory hypertension, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, post-myocardial infarction syndrome, coronary artery disease, myocardial necrosis, atrial fibrillation, atherosclerosis, restenosis, endothelial dysfunction, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, vascular disease, and diseases associated with primary or secondary aldosteronism and adrenal hyperplasia. Diseases including diabetes, metabolic syndrome, insulin resistance, neuropathy, insulinopathy, diabetic nephropathy, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, diseases characterized by fibrosis and matrix remodeling after endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, renal failure, chronic renal failure, nephropathy, renal dysfunction, kidney disease, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, hypokalemia, retinopathy, sleep apnea, obstructive sleep apnea, muscular dystrophy, stroke, liver disease, non-alcoholic steatohepatitis, cirrhosis or non-alcoholic fatty liver disease.

[0262] In a preferred embodiment, the condition or disease is hypertension, refractory hypertension, pulmonary hypertension, atherosclerosis, or hypokalemia.

[0263] The various crystalline forms and amorphous solids of compound A of the present invention, as regulators and inhibitors of aldosterone synthase CYP11B2, can effectively and specifically target CYP11B2, and therefore can be used to prevent or treat various symptoms or diseases related to CYP11B2.

[0264] Treatment

[0265] The present invention also provides a treatment for a symptom or disease, comprising administering to a subject in need an effective amount of compound A (1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzis[d]imidazole) in crystal form I, crystal form III, or crystal form IV, or a mixture of any two or more crystal forms in any proportion, or an amorphous solid of compound A. The symptom or disease is as described above.

[0266] Example

[0267] The present invention will be described in detail below through embodiments, which are not intended to limit the invention. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods. All reagents and equipment used in the following embodiments are commercially available products and have no special requirements.

[0268] Example 1: Preparation of Crystal Form I of Compound A

[0269] The solid form of compound A was prepared according to the method described in WO2018 / 125800.

[0270] The solid of compound A is dissolved in or suspended in an organic solvent selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohols or polyols, tetrahydrofuran, anisole, or acetonitrile, and may be heated appropriately if necessary to obtain a solution or suspension.

[0271] Add water to the above solution or suspension to precipitate crystals, and stir at room temperature for about 2 hours. Depending on the miscibility of water with the organic solvent used, the amount of water is 0.1 to 100 times the volume of the organic solvent used.

[0272] The filter cake was filtered and washed with water. It was then dried at 50±5℃ for 16 hours to obtain crystal form I of compound A.

[0273] Example 2: X-ray powder diffraction (XRPD) test of crystal form I of compound A

[0274] X-ray powder diffraction (XRPD) patterns were measured using a Bruker XRD-D2Phaser X-ray diffractometer at room temperature. Specific data collected is as follows: the X-ray source was Cu-Kα rays. The scanning range (2θ range) was from 3° to 40°, the rotation speed was 20 rpm, the scanning speed was 0.2 seconds per step, the scanning step size was 0.02°, and the slit width was 0.01. Samples were processed by pressing a glass slide directly onto the test plate. Subsequent XRPD spectra were measured using a similar method.

[0275] The XRPD pattern of crystal form I of compound A prepared according to Example 1 was measured. Characteristic diffraction peaks were observed at 2θ = 8.87°, 12.41°, 12.97°, 13.92°, 15.39°, 17.61°, 18.20°, 19.64°, 20.37°, 24.17°, 25.06°, 25.84°, 26.65°, 28.00°, 28.79°, 31.96°, and 36.05°, as shown in Figure 1. The error range of the 2θ value is ±0.2°.

[0276] A detailed list of the characteristic X-ray diffraction peaks derived from this spectrum is provided in Table 1.

[0277] Table 1 lists the XRPD diffraction peaks in Figure 1.

[0278] Those skilled in the art will understand that these diffraction peaks do not represent an exhaustive view of the diffraction peaks exhibited by crystal form I of compound A. The 2θ values ​​of X-ray powder diffraction patterns can vary slightly with machine variations and with changes in sample preparation and batch-to-batch variations; the values ​​cited are not considered absolute values. It should also be understood that the relative intensity of peaks may vary with orientation effects; therefore, the intensities shown in the XRPD traces contained herein are exemplary and not intended for absolute comparison.

[0279] Example 3: Differential Scanning Calorimetry (DSC) Test of Crystal Form I of Compound A

[0280] The DSC spectrum of crystal form I of compound A prepared according to Example 1 was tested using a TA Instruments Discovery DSC 250 thermal analyzer. The DSC test conditions were a heating rate of 10 °C / min and a temperature range from room temperature (25 °C) to 300 °C. The obtained DSC spectrum is shown in Figure 2.

[0281] As shown in Figure 2, crystal form I of compound A exhibits only one endothermic peak in the DSC test, with an initial temperature of 210.87℃ and a peak temperature of 211.60℃. That is, the melting point of crystal form I of compound A is 211.60℃.

[0282] Example 4: Thermogravimetric analysis (TGA) test of crystal form I of compound A

[0283] The TGA spectrum of crystal form I of compound A prepared according to Example 1 was tested using a TA Instruments thermal analyzer (model: Discovery TA 55). The TGA test conditions were a heating rate of 10 °C / min and a temperature range from room temperature (25 °C) to 300 °C. The obtained TGA spectrum is shown in Figure 3.

[0284] As shown in Figure 3, the weight loss of crystal form I of compound A is only about 0.5% in the heating range of 110-180℃, which means that crystal form I is amorphous.

[0285] Example 5: Crystal form I of compound A 1 H NMR test

[0286] The crystal form I of compound A prepared in Example 1 was analyzed using an instrument (AVANCE NEO 400MHz). 1 H NMR testing was performed at a frequency of 400 MHz using DMSO-d6 as the solvent.

[0287] Test results 1 The H NMR spectrum is shown in Figure 4.

[0288] 1 H NMR(400MHz, DMSO-d6)δ10.00(d,J=2.0Hz,1H),8.56(d,J=2.0Hz,1H),7.93–7.85(m, 2H),7.43(t,J=54.0Hz,1H),4.03–3.97(m,1H),1.22–1.17(m,2H),0.83–0.79(m,2H).

[0289] Example 6: Crystal form I of compound A 13 C NMR test

[0290] The crystal form I of compound A prepared in Example 1 was analyzed using an instrument (AVANCE NEO 400MHz). 13 C NMR testing was performed at a frequency of 400 MHz using DMSO-d6 as the solvent.

[0291] Test results 13The C NMR spectrum is shown in Figure 5.

[0292] 13 C NMR(100MHz,DMSO-d6)δ155.68,155.43,155.17,151.95,149.86,149.82,149.73,149.57,149.24,149.09,147.32,147.16,146.86,146.71 ,137.92,137.81,133.56,133.45,129.95,123.13,123.10,123.07,1 16.06,113.68,111.30,107.98,107.78,100.74,100.51,26.90,8.99.

[0293] According to the NMR test results of Examples 5 and 6, the crystal form I of compound A contains only the molecules of compound A and does not contain water or other solvents.

[0294] Example 7: Dynamic water adsorption (DVS) test of crystal form I of compound A

[0295] The dynamic moisture adsorption spectrum of crystal form I of compound A, prepared according to Example 1, was determined using a ProUmid (instrument model: Vsorp-Enhanced) dynamic moisture adsorption analyzer. The sample was first dried at 40°C / 0% RH for 3 hours. The experiment was then conducted at 25°C with equilibration conditions of 0.01% / 45 min. The relative humidity (RH) was increased by 10% at each step (maximum 2 hours, minimum 50 minutes, the same below), ranging from RH 0% to 90%. After equilibration at RH 90% for a maximum of 2 hours, the relative humidity was decreased by 10% at each step (maximum 2 hours, minimum 50 minutes) until RH 0%. The weight change of the sample was recorded during the process and reported as a percentage shift relative to the lowest sample weight. The resulting dynamic moisture adsorption spectrum is shown in Figure 6.

[0296] As shown in Figure 6, the weight change of crystal form I of compound A is <0.2% during the cycle of relative humidity from 0 to 90%, indicating that crystal form I is not hygroscopic and is stable under various humidity conditions.

[0297] Example 8: Stability test of crystal form I of compound A

[0298] High-temperature stability: Crystal form I of compound A prepared according to Example 1 was placed in a 60°C oven. After 5 and 10 days, the samples were removed and subjected to XRPD tests to examine the crystal form stability of the samples to temperature. The results showed that crystal form I was stable under high-temperature conditions.

[0299] High humidity stability: Crystal form I of compound A prepared according to Example 1 was placed under 92.5% humidity for 5 and 10 days, and then subjected to XRPD tests to examine the crystal form stability of the sample to humidity. The results showed that crystal form I was stable under high humidity conditions.

[0300] Accelerated stability testing: Crystal form I of compound A prepared according to Example 1 was placed in an experimental chamber at 40°C and 75% relative humidity. After one month, the sample was removed and subjected to XRPD testing to examine the crystal form stability of the sample under high temperature and high humidity conditions. The results showed that crystal form I is stable under high temperature and high humidity conditions, which is beneficial for the preparation and storage of the active pharmaceutical ingredient and pharmaceutical formulation.

[0301] Light stability: Crystal form I of compound A prepared according to Example 1 was placed under a light intensity of 4500 lux. After 5 and 10 days, the samples were removed and subjected to XRPD tests to examine the crystal form stability of the samples under light. The results showed that crystal form I was stable under light conditions.

[0302] Example 9 Preparation of Crystal Form III of Compound A

[0303] Weigh 300 mg of crystal form I of compound A prepared in Example 1 and add it to 3 mL of anhydrous acetic acid. Mix and heat to 50 °C to obtain a suspension. Then filter, cool the filtrate to 4 °C, and let it stand. After one day, large crystal precipitates were observed. Collect the precipitated crystals, dry them with filter paper, and obtain crystal form III of compound A. Observe the crystals of crystal form III using a polarizing microscope; the particle size is approximately 100 μm.

[0304] Example 10: X-ray powder diffraction (XRPD) test of crystal form III of compound A

[0305] Using the same method as in Example 2, the XRPD pattern of crystal form III of compound A prepared according to Example 9 was measured. Characteristic diffraction peaks were observed at 2θ = 8.39°, 10.21°, 12.40°, 14.05°, 15.75°, 16.66°, 17.53°, 18.10°, 20.22°, 22.07°, 22.55°, 23.37°, 25.84°, 25.23°, 25.70°, 28.18°, 29.34°, 31.37°, 31.92°, and 34.45°, as shown in Figure 7. The error range for the 2θ value is ±0.2°.

[0306] A detailed list of the characteristic X-ray diffraction peaks derived from this spectrum is provided in Table 2.

[0307] Table 2 lists the XRPD diffraction peaks in Figure 7.

[0308] Those skilled in the art will understand that these diffraction peaks do not represent an exhaustive view of the diffraction peaks exhibited by crystal form III of compound A. The 2θ values ​​of X-ray powder diffraction patterns can vary slightly with machine and with variations in sample preparation and batch-to-batch changes; the values ​​cited are not considered absolute values. It should also be understood that the relative intensity of peaks may vary with orientation effects; therefore, the intensities shown in the XRPD traces contained herein are exemplary and not intended for absolute comparison.

[0309] Example 11 Differential Scanning Calorimetry (DSC) Test of Crystal Form III of Compound A

[0310] The DSC spectrum of crystal form III of compound A prepared according to Example 9 was tested using the same method as in Example 3. The obtained DSC spectrum is shown in Figure 8.

[0311] As shown in Figure 8, the crystal form III of compound A exhibits three endothermic peaks at approximately 63℃, 121℃, and 212℃ (initial temperatures) during DSC testing. The endothermic peak at an initial temperature of 62.7℃ and a peak temperature of 78.3℃ corresponds to the decomposition of the acetic acid solvate; the endothermic peak at an initial temperature of 121℃ and a peak temperature of 121.4℃ corresponds to the boiling point of acetic acid; and the endothermic peak at 212℃ corresponds to the melting point of compound A.

[0312] Example 12 Thermogravimetric analysis (TGA) test of crystal form III of compound A

[0313] The TGA spectrum of crystal form III of compound A prepared according to Example 9 was tested using the same method as in Example 4. The obtained TGA spectrum is shown in Figure 9.

[0314] As shown in Figure 9, the weight loss of crystal form III of compound A is about 15.2% in the heating range of 50-150℃, which corresponds to the decomposition of acetic acid solvate and the volatilization of acetic acid. This means that the stoichiometric ratio of compound A to acetic acid in crystal form III of acetic acid solvate is 1:1, and that crystal form III of compound A is an amorphous form.

[0315] Example 13 Thermal conversion test of crystal form III of compound A

[0316] Multiple samples of compound A in crystal form III, prepared according to Example 9, were heated to 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, and 150°C, respectively, and maintained for 30 minutes. After natural cooling to room temperature, the XRPD spectra of these samples were measured. The results showed that when crystal form III of compound A was heated to 110°C or higher, crystal form III spontaneously transformed into crystal form I.

[0317] Example 14: Slurry competition experiment of crystal form III and crystal form I of compound A

[0318] Weigh 10-15 mg each of crystal form I of compound A prepared according to Example 1 and crystal form III of compound A prepared according to Example 9, and add them to 0.5 mL of a solution pre-saturated with crystal form I. Suspend the solutions at room temperature (RT), 50°C, 55°C, 60°C, or 65°C for a certain period of time, filter to obtain solids, and immediately test their crystal form by XRPD. The solvents used in the experiments, suspension temperatures, test times, XRPD results, and stable crystal forms are listed in Table 3.

[0319] Table 3. Results of slurry competition experiments for crystal form III and crystal form I of compound A.

[0320] As shown in Table 3, crystal form III of compound A is a stable crystal form in an acetic acid solvent system at <60℃, preferably ≤55℃, and under these conditions, crystal form I can spontaneously transform into crystal form III. When the temperature of the acetic acid solvent system is ≥60℃, crystal form I is a stable crystal form, and under these conditions, crystal form III can spontaneously transform into crystal form I. This phenomenon basically corresponds to the decomposition temperature of the acetic acid solvate observed in DSC tests.

[0321] Furthermore, when the solvent changes from anhydrous acetic acid to an aqueous system, regardless of the temperature, crystal form III spontaneously transforms into crystal form I, which remains a stable crystal form. This indicates that the acetic acid molecules in crystal form III have a lower free energy for binding with water, and in an aqueous solvent system, they spontaneously migrate into water, disrupting the structure of the acetic acid solvate. On the other hand, crystal form I of compound A remains thermodynamically stable throughout the entire crystallization process.

[0322] Example 15 Preparation of crystal form IV of compound A

[0323] Under a nitrogen atmosphere, the solid compound A was dissolved in isopropyl acetate at 65±5℃, and a 4M HCl isopropanol solution was added so that the number of moles of HCl was three times the number of moles of compound A. The mixture was stirred for 2 hours.

[0324] Under a nitrogen atmosphere, the solution was cooled to 25±5℃ and stirred for 2 hours to allow crystals to precipitate.

[0325] The filter cake was filtered and washed with isopropyl acetate. It was then dried at 50±5℃ for 16 hours to obtain crystal form IV of compound A.

[0326] Example 16 X-ray powder diffraction (XRPD) test of crystal form IV of compound A

[0327] Using the same method as in Example 2, the XRPD pattern of crystal form IV of compound A prepared according to Example 15 was measured. Characteristic diffraction peaks were observed at 2θ = 9.70°, 10.34°, 12.97°, 15.55°, 17.18°, 17.85°, 19.13°, 20.37°, 21.31°, 23.00°, 24.06°, 24.49°, 25.15°, 28.08°, 28.54°, 29.05°, 32.71°, and 34.27°, as shown in Figure 10. The error range for the 2θ value is ±0.2°.

[0328] A detailed list of the characteristic X-ray diffraction peaks derived from this spectrum is provided in Table 4.

[0329] Table 4 lists the XRPD diffraction peaks in Figure 10.

[0330] Those skilled in the art will understand that these diffraction peaks do not represent an exhaustive view of the diffraction peaks exhibited by crystal form IV of compound A. The 2θ values ​​of X-ray powder diffraction patterns can vary slightly with machine and with variations in sample preparation and batch-to-batch changes; the values ​​cited are not considered absolute values. It should also be understood that the relative intensity of peaks may vary with orientation effects; therefore, the intensities shown in the XRPD traces contained herein are exemplary and not intended for absolute comparison.

[0331] Example 17 Differential Scanning Calorimetry (DSC) Test of Crystal Form IV of Compound A

[0332] The DSC spectrum of crystal form IV of compound A prepared according to Example 15 was tested using the same method as in Example 3. The obtained DSC spectrum is shown in Figure 11.

[0333] As shown in Figure 11, the crystal form IV of compound A exhibits a broad endothermic peak in the range of approximately 160-180℃ during DSC testing, which corresponds to the decomposition of the hydrochloride salt. In addition, the endothermic peak with an initial temperature of 205.81℃ and a peak temperature of 208.92℃ corresponds to the melting point of compound A.

[0334] Example 18 Thermogravimetric analysis (TGA) test of crystal form IV of compound A

[0335] The TGA spectrum of crystal form IV of compound A prepared according to Example 15 was tested using the same method as in Example 4. The obtained TGA spectrum is shown in Figure 12.

[0336] As shown in Figure 12, the weight loss of crystal form IV of compound A is about 9.9% in the heating range of 145-205℃, which corresponds to the decomposition of hydrochloride and the volatilization of hydrochloric acid (HCl). This means that the stoichiometric ratio of compound A to HCl in hydrochloride is 1:1, and the crystal form IV of compound A is amorphous.

[0337] Example 19: Crystal form IV of compound A 1 H NMR test

[0338] The crystal form IV of compound A prepared in Example 15 was subjected to the same method as in Example 5. 1 H NMR test. The results obtained from the test... 1 The H NMR spectrum is shown in Figure 13.

[0339] 1 H NMR (400MHz, DMSO-d6) δ10.00(d,J=2.0Hz,1H),9.00(s,1H),8.58(d,J=2.0Hz,1H),7.89 (m,2H),7.46(t,J=54.0Hz,1H),4.03–3.97(m,1H),1.22–1.17(m,2H),0.83–0.79(m,2H).

[0340] Based on the above 1 The 1H NMR test results show that the crystal form IV of compound A contains molecules of compound A and HCl in a stoichiometric ratio of 1:1, but does not contain water or other solvents.

[0341] Example 20: Slurry competition experiment of crystal form IV of compound A

[0342] Approximately 200 mg of the crystal form IV sample of compound A prepared according to Example 15 was weighed and added to 1 mL of anhydrous acetic acid. The mixture was suspended at room temperature for 3 days, and the sample was filtered to obtain a solid. Its crystal form was immediately determined by XRPD. The XRPD spectrum showed that the crystal form remained crystal form IV.

[0343] The suspension was heated to 65°C and stirred until the solid completely dissolved.

[0344] Add 1 mL of water and observe a solid precipitate. Then stir at 65 °C for 3 hours, take a sample, filter to obtain the solid, and immediately test its crystal form by XRPD. The XRPD spectrum shows that the crystal form is crystal form I+ and crystal form III (small amount).

[0345] The suspension was stirred at 65°C for another 2 days, and a sample was taken and filtered to obtain a solid. Its crystal form was immediately determined by XRPD. The XRPD spectrum showed that the crystal form was crystal form I.

[0346] The above experiments show that crystal form IV of compound A is a stable crystal form in acetic acid solvent system or anhydrous system at room temperature.

[0347] Furthermore, after crystal form IV is completely dissolved by heating, its crystallization behavior is the same as that of crystal forms I and III described in Example 14. That is, crystal form I is a thermodynamically stable crystal form in an aqueous system, and other crystal forms of compound A will eventually spontaneously transform into crystal form I.

[0348] Example 21 Solubility test of compound A

[0349] To test the equilibrium solubility of compound A in crystal form I in FaSSIF, approximately 2 mg of compound A was added to an 8 mL glass bottle, followed by 1 mL of FaSSIF. The mixture was stirred at 25 °C for 24 hours. The suspension was then centrifuged, and the concentration of compound A in the supernatant was determined by HPLC to be 5.6 μg / mL. This concentration was taken as the equilibrium solubility of compound A in FaSSIF.

[0350] Further testing was conducted on the solubility of compound A in organic solvents. Approximately 2 mg of compound A was added to a 2 mL glass vial, with organic solvent added in increments of 10 μL until the solid was completely dissolved or 1 mL of organic solvent had been added. The concentration of compound A in the solution was then determined by HPLC. The organic solvents used and the solubility of compound A are listed in Table 5.

[0351] Table 5. Solubility test of compound A in organic solvents

[0352] Based on the results of the above solubility tests, a mixture of methanol / DCM with a volume ratio of 1:2 was used as the solvent in the experiment of preparing amorphous solids by solvent method.

[0353] Example 22: Test of the inhibitory effect of pharmaceutically acceptable polymers on the crystallization of compound A

[0354] In this embodiment, the ability of the polymer to inhibit the crystallization of compound A is first screened by rapid evaporation, and then the degree of crystallization of compound A is determined by spray drying.

[0355] The tested polymers include: PVP (polyvinylpyrrolidone) K30, PVP-VA64 (ethylpyrrolidone / vinyl acetate (6:4) copolymer), SOLUPLUS (polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), HPMC E3 (molecular weight 20000), HPMC E5, HPMC E50LV, HPMC MG (particle size 1000μm, solubility pH 6.0), HPMC LG (hydroxypropyl methylcellulose acetate succinate) (particle size 1000μm, solubility pH 5.5), HPMCPHP50 (solubility pH 5.0), HPC SSL (molecular weight 40000), Eudragit L100 (methacrylic acid / methacrylate (1:1) copolymer), Euragit EPO butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1) copolymer.

[0356] When preparing a solid dispersion using a rapid evaporation method, approximately 10 mg of compound A is added to a 40 mL glass bottle, and a polymer is added at a loading ratio of 10%-20%. Then, 1 mL of a methanol / DCM (1:2) mixed solvent is added to dissolve the compound and obtain a clear solution. The bottle mouth is covered with filter paper, and the bottle is heated in a vacuum oven at 60 °C for 1 hour to rapidly evaporate the solvent, thus obtaining a solid dispersion. Polarized light microscopy is used to determine whether the obtained solid is crystalline.

[0357] Testing showed that PVP K30, PVP VA64, SOLUPLUS, HPC SSL, and Eudragit L100, with a drug loading of 10%, still exhibited a clear crystalline structure in the solids obtained by rapid evaporation. HPMC E3, HPMC E5, HPMCCP HP50, HPMCAS MG, HPMCAS HG, HPMCAS LG, Eudragit EPO, and HPMC E5, with drug loadings of 10%-15% or higher, could yield essentially amorphous solid structures via rapid evaporation. Furthermore, tests were conducted using combinations of two or more polymers, revealing that the use of HPMC E50LV facilitated the acquisition of amorphous solids at higher drug loadings.

[0358] To prepare a spray-dried dispersion (SDD) using the spray drying method, approximately 200 mg of compound A is added to a 100 mL flask, and a polymer is added at a drug loading ratio of 10%-20%. Then, 40 mL of a methanol / DCM (1:2) mixed solvent is added to dissolve the compound and obtain a clear solution. A solid dispersion is obtained by spray drying, and XRPD testing is then used to determine whether the obtained solid is crystalline.

[0359] Testing revealed that the spray-dried dispersions formed by HPMC E3, HPMC E50LV, HPMCCP HP50, HPMC MG, HPMC HG, HPMC LG, Eudragit L100, Eudragit EPO, and compound A, with a drug loading of 10%-20%, possessed amorphous or substantially amorphous structures. XRPD spectra of some of the spray-dried dispersions are shown in Figure 14.

[0360] The above experiments show that when the polymers used are selected from HPMC E3, HPMC E5, HPMC E50LV, HPMCCAS, HPMCCP HP50, Eudragit L100, Euragit EPO, etc., especially when the drug loading of the solid dispersion is 10% to 15%, an amorphous solid dispersion with virtually no X-ray diffraction characteristic peaks can be obtained by spray drying.

[0361] Example 23 Kinetic solubility test of amorphous solid dispersion of compound A

[0362] In the kinetic solubility test, the spray-dried dispersion (SDD) prepared in Example 22 was added to an 8 mL glass bottle containing 5 mL of FaSSIF at a target concentration of 0.5 mg / mL for compound A. The mixture was magnetically stirred at 150 rpm at 37°C. Samples of 0.5 mL were taken at 15, 30, 60, and 120 minutes, centrifuged, and the supernatant was collected. After appropriate dilution, HPLC analysis was performed to determine the solubility of compound A. Furthermore, the endpoint pH of the solution at 120 minutes was measured using a pH meter. The results are shown in Table 6.

[0363] Table 6. Kinetic solubility test of amorphous solid dispersion of compound A

[0364] The above experiments show that when compound A is mixed with a polymer to prepare an amorphous solid dispersion, the kinetic solubility of compound A in FaSSIF can be improved. For most amorphous solid dispersions of compound A, the solubility can be increased by 3 to 5 times compared with the crystals of compound A (crystal form I).

[0365] Example 24: Preparation of amorphous solid of compound A by spray drying

[0366] 1.5 g of compound A, 8.5 g of HPMCAS MG, and 200 mL of a methanol / DCM (1:2) mixed solvent were added to a 200 mL flask and dissolved to obtain a clear solution. An amorphous solid of compound A was prepared by spray drying. The spray-dried solid was collected and dried under vacuum at 50 °C for 3 hours to obtain 8.79 g of amorphous solid sample. The XRPD spectrum of the amorphous solid of compound A was determined using the same method as in Example 2, and its TGA spectrum was determined using the same method as in Example 4, as shown in Figures 15 and 17, respectively.

[0367] In addition, the modulation differential scanning calorimetry (mDSC) spectrum of the amorphous solid of compound A was tested using a TA Discovery Q2000 thermal analyzer. The test conditions were: temperature range from room temperature to 200 °C, modulation amplitude ±0.32 °C / min, modulation period 60 seconds, and heating rate 2 °C / min. The obtained mDSC spectrum is shown in Figure 16. In Figure 16, the three curves from top to bottom represent the reversible sample heat flow, the irreversible sample heat flow, and the total heat flow, respectively.

[0368] As shown in Figure 15, the amorphous solid of compound A obtained in this embodiment does not have characteristic X-ray diffraction peaks, proving that it is an amorphous body; as shown in Figure 16, the mDSC spectrum shows a single glass transition temperature Tg = 95.59℃, proving that compound A and polymer HPMCAS MG are uniformly distributed in the solid dispersion; as shown in Figure 17, the TGA spectrum shows that the weight loss is about 1.5% in the range of room temperature to 150℃.

[0369] Furthermore, HPLC analysis showed that the content of compound A in the solid dispersion was approximately 14.93%, highly consistent with a drug loading of 15%. GC analysis also confirmed the absence of residual solvent in the solid dispersion.

[0370] Example 25 Two-step dissolution test of amorphous solid of compound A

[0371] A two-step dissolution test simulated the dissolution process of compound A in gastric and intestinal fluids after oral administration. 50 mg of the amorphous solid of compound A prepared in Example 24 and 7.5 mg of the crystals of compound A (crystal form I) were weighed and placed in 40 mL glass bottles. 5 mL of simulated gastric fluid (SGF, pH 1.3) was added, and the mixture was magnetically stirred at 150 rpm for 30 minutes at 37°C. A 0.5 mL sample was taken, centrifuged, and the supernatant was collected. After appropriate dilution, HPLC analysis was performed to determine the solubility of compound A.

[0372] Immediately after sampling, 10 mL of fasting simulated intestinal fluid (cFaSSIF, pH 12.1) was added to the glass bottle to achieve a target concentration of compound A of 0.5 mg / mL. Stirring continued, and 0.5 mL samples were taken at 15, 30, 60, and 120 minutes. The supernatant was collected by centrifugation, appropriately diluted, and analyzed by HPLC to determine the solubility of compound A. Furthermore, the endpoint pH of the solution at 120 minutes was measured using a pH meter. The results are shown in Table 7.

[0373] Table 7 Two-step dissolution test of amorphous solids of compound A

[0374] The above results indicate that the solid dispersion of compound A with a drug loading of 15% in HPMCAS MG significantly improves the solubility and dissolution performance of compound A in gastric and intestinal fluids. Compared with compound A crystals (crystal form I), the solubility in SGF is increased by approximately 7 times, and the solubility in FaSSIF is increased by approximately 3 to 4 times.

[0375] Example 26: Stability test of the amorphous solid of compound A prepared by spray drying.

[0376] High-temperature stability: The amorphous solid of compound A prepared according to Example 24 was placed in an oven at 40°C. Samples were removed after 1, 2, and 4 weeks for XRPD testing to examine the temperature stability of the samples. The results showed that the amorphous solid of compound A remained amorphous after 4 weeks at 40°C, indicating that the amorphous solid of compound A can remain stable at temperatures above room temperature.

[0377] Environmental stability: The amorphous solid of compound A prepared according to Example 24 was placed in a test chamber at 25°C and 60% relative humidity. The samples were removed after 1, 2, and 4 weeks for XRPD testing to examine their stability under environmental conditions. The results showed that the amorphous solid of compound A remained amorphous after 4 weeks and was stable under environmental conditions.

[0378] Example 27: Preparation of amorphous solid of compound A by hot melt extrusion

[0379] First, the thermal stability of compound A was tested using TGA. Compound A was placed in a TGA analyzer and heated to 150℃, 160℃, 170℃, 180℃, 190℃, 200℃, and 210℃, respectively, and held for 30 minutes. The results showed that at heating temperatures of 170℃ or lower, compound A showed virtually no weight change over 30 minutes, and no thermal degradation was detected by HPLC. When heated to 180℃, 190℃, 200℃, and 210℃, the sample weights after 30 minutes were 97.9%, 95.3%, 95.5%, and 53.6%, respectively, but no thermal degradation was detected by HPLC, indicating that compound A has good thermal stability, only undergoing sublimation near its melting point. In the following hot melt extrusion experiments, the temperature of the hot melt extruder was set below 200℃, specifically 150℃, 160℃, 170℃, 180℃, or 190℃.

[0380] 3g of compound A and 17g of HPMCAS MF were placed in a sealed bag and manually shaken for 10 minutes. The mixture was then loaded into a hot melt extruder (Three-Tec, Model: ZE 5HMI) and hot melt extruded at set temperatures of 150℃, 160℃, 170℃, 180℃, or 190℃. The extrudate (HME) was ground into powder, and its crystal morphology was determined by XRPD (shown in Figure 18). Purity was determined by HPLC.

[0381] Visual observation of the extrudates revealed that samples extruded at temperatures between 160℃ and 190℃ were transparent, while those extruded at 150℃ were opaque, possibly due to insufficient solid solution formation of compound A. As shown in Figure 18, all five hot-melt extruded samples prepared above were amorphous. HPLC results indicated that the purity of the extrudates was above 99%.

[0382] The mDSC spectrum of the amorphous solid of compound A extruded at 170°C was determined using the same method as in Example 24, and the TGA spectrum of the amorphous solid of compound A extruded at 170°C was determined using the same method as in Example 4. These are shown in Figures 19-20, respectively. In Figure 19, the three curves from top to bottom represent the irreversible sample heat flow, the total heat flow, and the reversible sample heat flow, respectively.

[0383] As shown in Figure 19, the mDSC spectrum shows a single glass transition temperature Tg = 95.64℃, proving the uniform distribution of compound A and polymer HPMCAS MF in the solid dispersion; as shown in Figure 20, the TGA spectrum shows a weight loss of approximately 2.0% in the range of room temperature to 150℃.

[0384] Example 28 Two-step dissolution test of amorphous solid of compound A

[0385] The two-step dissolution results of the amorphous solid of compound A prepared in Example 27 were determined using the same method as in Example 25, and are shown in Table 8.

[0386] Table 8 Two-step dissolution test of amorphous solids of compound A

[0387] The above results indicate that the hot-melt extrudate of compound A with a drug loading of 15% significantly improves the solubility and dissolution performance of compound A in gastric and intestinal fluids. Compared with compound A crystals (crystal form I), the solubility in SGF is increased by nearly 4 times, and the solubility in FaSSIF is increased by about 2 to 3 times. Under the same formulation, the dissolution rate of the hot-melt extrudate is lower than that of the spray-dried solid dispersion, mainly because the particle size of the solid particles obtained by the two preparation methods is different. The hot-melt extrudate with larger particle size has a smaller specific surface area, which limits the drug dissolution rate.

[0388] Example 29: Stability test of the amorphous solid of compound A prepared by hot melt extrusion.

[0389] High-temperature stability: The amorphous solid of compound A prepared according to Example 27 was placed in an oven at 40°C or 60°C. Samples were removed after 1, 2, and 4 weeks for XRPD testing to examine the temperature stability of the samples. The results showed that the amorphous solid of compound A remained amorphous after 4 weeks of storage at 40°C and 60°C, indicating stability under high-temperature conditions.

[0390] Environmental stability: The amorphous solid of compound A prepared according to Example 24 was placed in a test chamber at 25°C and 60% relative humidity. The samples were removed after 1, 2, and 4 weeks for XRPD testing to examine their stability under environmental conditions. The results showed that the amorphous solid of compound A remained amorphous after 4 weeks and was stable under environmental conditions.

[0391] Accelerated stability testing: The amorphous solid of compound A prepared according to Example 24 was placed in a test chamber at 40°C and 75% relative humidity. Samples were removed after 1, 2, and 4 weeks for XRPD testing to examine the stability of the samples under high temperature and high humidity conditions. The results showed that the amorphous solid of compound A remained amorphous after 4 weeks and was stable under accelerated conditions.

[0392] The foregoing description of exemplary embodiments of the present invention provides a concrete example, but the invention is not limited thereto. Those skilled in the art should understand that the above embodiments are merely illustrative, and the specific embodiments and examples of the present invention should not be considered as limiting the scope of the invention. The embodiments contain important additional information, illustrations, and guidance that can be practiced in various embodiments and equivalents of this disclosure. Changes and modifications to the embodiments are possible within the scope of the spirit of the invention, and such changes and modifications should fall within the protection scope of the present invention.

Claims

1. The crystalline form I of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles of approximately 8.9°, 12.4°, 17.6°, 25.0°, and 25.8°.

2. The crystal form I of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles of approximately 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, 28.0°, and 28.8°.

3. The crystalline form I of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, It has an X-ray powder diffraction (XRPD) pattern that is essentially as shown in Figure 1.

4. The crystal form I of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 3, characterized in that, Crystal form I is the amorphous form.

5. The crystal form I of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 3, characterized in that, The crystal form I satisfies any one or more of the following: When thermal analysis is performed using differential scanning calorimetry (DSC), it has an endothermic peak at approximately 211.6 °C ± 2.0 °C, and preferably, it has a DSC spectrum substantially as shown in Figure 2. When thermal analysis is performed using thermogravimetric analysis (TGA), it has a TGA spectrum that is essentially as shown in Figure 3; and When analyzed using the Dynamic Water Adsorption (DVS) method, it exhibits a DVS spectrum that is essentially as shown in Figure 6.

6. A method for preparing crystal form I of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 5, characterized in that, Includes the following steps: (1) The solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole is dissolved in an organic solvent or suspended in an organic solvent, wherein the organic solvent is one or more selected from organic acids, amides, sulfones, alcohols, ethers, and nitriles, preferably selected from organic acids and amides; (2) Add water to the above solution or suspension to precipitate crystals, wherein the amount of water used is 0.1 to 100 times the volume of the organic solvent; (3) The crystals were collected by filtration and dried to obtain crystal form I of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium.

7. The preparation method according to claim 6, characterized in that, The organic solvent is selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohols or polyols, tetrahydrofuran, anisole, or acetonitrile.

8. Crystal form III of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, and 25.7°.

9. Crystal form III of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles of approximately 8.4°, 10.2°, 12.4°, 14.0°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2°.

10. Crystal form III of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, It has an X-ray powder diffraction (XRPD) pattern that is essentially as shown in Figure 7.

11. The crystal form III of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 10, characterized in that, The crystal form III is an acetic acid-containing crystal form, preferably an acetic acid solvate crystal form.

12. The crystal form III of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 10, characterized in that, Crystal form III satisfies any one or more of the following: When thermal analysis is performed using differential scanning calorimetry (DSC), it exhibits endothermic peaks at approximately 78.3℃±2℃, 121.4℃±2℃, and / or 212.2℃±2℃; preferably, it has a DSC spectrum substantially as shown in Figure 8; and When thermal analysis is performed using thermogravimetric analysis (TGA), it has a TGA spectrum that is essentially as shown in Figure 9.

13. The compound according to any one of claims 8 to 12, 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[a] The method for preparing [d]imidazole crystal form III is characterized by, Includes the following steps: (1) The solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium was added to anhydrous acetic acid and suspended under heating conditions; (2) Filtration, and the filtrate is allowed to settle under cooling conditions; (3) The crystals were collected by filtration and dried to obtain the crystal form III of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium.

14. The preparation method according to claim 13, characterized in that, The temperature of the heated suspension is <60℃, preferably ≤55℃, more preferably ≤50℃; and / or The cooling and settling temperature is ≤10℃, preferably ≤5℃.

15. Crystal form IV of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, and 24.5°.

16. Crystal form IV of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, In the X-ray powder diffraction (XRPD) pattern, it has characteristic peaks at diffraction angles of approximately 9.7°, 13.0°, 15.6°, 17.2°, 17.9°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3°.

17. Crystal form IV of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, It has an X-ray powder diffraction (XRPD) pattern that is essentially as shown in Figure 10.

18. The crystal form IV of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 17, characterized in that, The crystal form is a hydrochloric acid-containing crystal form, preferably a hydrochloric acid salt crystal form of the compound, and more preferably a crystal-free crystal form.

19. The crystal form IV of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 17, characterized in that, The crystal form IV satisfies any one or more of the following: When thermal analysis is performed using differential scanning calorimetry (DSC), it exhibits an endothermic peak at approximately 180.5 °C ± 2 °C and / or 209 °C ± 2 °C; preferably, it has a DSC spectrum substantially as shown in Figure 11; and When thermal analysis is performed using thermogravimetric analysis (TGA), it has a TGA spectrum that is essentially as shown in Figure 12.

20. A method for preparing crystal form IV of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 19, characterized in that, Includes the following steps: (1) The solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole is dissolved in a heated organic solvent containing HCl, wherein the organic solvent preferably comprises isopropyl acetate and isopropanol; (2) Cool the solution to room temperature and stir under an inert atmosphere to allow crystals to precipitate; (3) Filter, wash the wet filter cake with isopropyl acetate and dry to obtain crystal form IV of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazolium.

21. The preparation method according to claim 20, characterized in that, The number of moles of HCl is 2 to 5 times, preferably 3 to 4 times, the number of moles of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole.

22. A composition comprising: Crystal form I of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 5, and The crystal form III of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 12 and the crystal form IV of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 19.

23. A pharmaceutical composition comprising: (i) the crystal form I of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole as claimed in any one of claims 1 to 5, and / or Crystal form III of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 12, and / or Crystal form IV of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 15 to 19, and (ii) Pharmaceutically acceptable carriers, diluents or excipients.

24. An amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, No obvious crystal diffraction characteristic peaks were observed in the X-ray powder diffraction (XRPD) pattern.

25. The amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to claim 24, characterized in that, It has an X-ray powder diffraction (XRPD) pattern that is essentially as shown in Figure 15.

26. The amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to claim 24 or 25, characterized in that, The amorphous solid further comprises a pharmaceutically acceptable polymer; preferably, the amorphous solid is a solid dispersion of the compound and the polymer.

27. The amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to claim 26, characterized in that, The polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymers (Eudragit).

28. The amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to claim 26, characterized in that, The polymer is selected from one or more of HPMC E3, HPMC E5, HPMC E50LV, HPMC LG, HPMC MG, HPMC HG, HPMC MMP, HPMC MF, HPMC HP50, Eudragit L100, and Euragit EPO, preferably one or more of HPMC MG, HPMC MMP, and HPMC MF.

29. The amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 26 to 28, characterized in that, The compound comprises about 5% to 25% of the weight of the amorphous solid, preferably about 5% to 20%, more preferably about 10% to 20%, and particularly preferably about 10% to 15%.

30. The amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 26 to 28, characterized in that, The mass ratio of the compound to the polymer is about 1:3 to 1:19, preferably about 1:4 to 1:19, more preferably about 1:4 to 1:9, and particularly preferably about 1:5.6 to 1:

9.

31. The amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 24 to 30, characterized in that, The amorphous solid is prepared by spray drying or hot melt extrusion.

32. A method for preparing an amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, Includes the following steps: The compound is dissolved in a solvent with a pharmaceutically acceptable polymer to form a solution; The solution is spray-dried to form a solid dispersion, namely the amorphous solid.

33. The preparation method according to claim 32, characterized in that, The polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymers (Eudragit).

34. The preparation method according to claim 32 or 33, characterized in that, The solvent is selected from one or more of alcohols, haloalkanes, ketones, ethers, esters, amides, sulfones, and nitriles; preferably, the solvent is selected from one or more of C1-C6 alcohols or polyols, dichloromethane, trichloromethane, acetone, methyl ethyl ketone, tetrahydrofuran, anisole, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, and acetonitrile.

35. The preparation method according to any one of claims 32 to 34, characterized in that, The solvent is a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane and methanol in a volume ratio of 2:

1.

36. The preparation method according to any one of claims 32 to 35, characterized in that, The concentration of the compound in the solution is about 3-15 mg / mL, preferably about 4-12 mg / mL, and more preferably about 5-10 mg / mL.

37. An amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole prepared by any one of claims 32 to 36.

38. A method for preparing an amorphous solid of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, characterized in that, Includes the following steps: The compound is mixed uniformly with a pharmaceutically acceptable polymer and then extruded through a hot melt extruder to obtain the amorphous solid.

39. The preparation method according to claim 38, characterized in that, The polymer is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and acrylic resin copolymers (Eudragit).

40. The preparation method according to claim 38 or 39, characterized in that, The heating temperature of the hot melt extruder is 150-200℃, preferably 160-180℃.

41. The preparation method according to any one of claims 38 to 40, characterized in that, It also includes the steps of crushing and sieving the hot melt extruded material.

42. An amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole prepared by any one of claims 38 to 41.

43. A pharmaceutical composition comprising: (i) the amorphous solid of 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole as claimed in any one of claims 24 to 31, 37 and 42, and (ii) Pharmaceutically acceptable carriers, diluents or excipients.

44. The pharmaceutical composition according to claim 23 or 43, further comprising an additional therapeutic agent.

45. The pharmaceutical composition according to claim 44, wherein the additional therapeutic agent is selected from anticancer agents, antifungal agents, cardiovascular therapeutic agents, anti-inflammatory agents, chemotherapeutic agents, anti-angiogenic agents, cytotoxic agents, antiproliferative agents, metabolic disease therapeutic agents, ophthalmic disease therapeutic agents, central nervous system (CNS) disease therapeutic agents, urinary disease therapeutic agents, and gastrointestinal disease therapeutic agents.

46. ​​Crystal form I of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 1 to 5; crystal form III of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole according to any one of claims 8 to 12; and the compound according to any one of claims 15 to 19. Use in pharmaceutical preparation of crystalline form IV of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, or a mixture of any two or more crystalline forms in any proportion, or the amorphous solid of compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole as described in any one of claims 24 to 31, 37 and 42.

47. The use according to claim 46, wherein the drug is used to regulate metalloenzyme activity.

48. The use according to claim 46, wherein the drug is used to regulate the activity of aldosterone synthase CYP11B2.

49. The use according to claim 46, wherein the medicament is used to treat metalloenzyme-related conditions or diseases, wherein the condition or disease is cancer, cardiovascular disease, endocrine disorder, fibrosis, kidney disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urinary disease, or gastrointestinal disease.

50. The use according to claim 49, wherein the condition or disease is adrenal carcinoma, adrenal adenoma, leukemia, breast cancer, hypertension, refractory hypertension, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, post-myocardial infarction syndrome, coronary artery disease, myocardial necrosis, atrial fibrillation, atherosclerosis, restenosis, endothelial dysfunction, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, vascular disease, and primary or secondary hyperaldosteronism and adrenal hyperplasia. Related conditions, diabetes, metabolic syndrome, insulin resistance, neuropathy, insulinopathy, diabetic nephropathy, diseases characterized by increased collagen formation, fibrosis and matrix remodeling after hypertension, diseases characterized by fibrosis and matrix remodeling after endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, renal failure, chronic renal failure, nephropathy, renal dysfunction, kidney disease, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, hypokalemia, retinopathy, sleep apnea, obstructive sleep apnea, muscular dystrophy, stroke, liver disease, non-alcoholic steatohepatitis, cirrhosis or non-alcoholic fatty liver disease.

51. The use according to claim 50, wherein the condition or disease is hypertension, refractory hypertension, pulmonary hypertension, atherosclerosis, or hypokalemia.

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