Crystals of benzazepine compounds and methods of making and using the same

Abstract

The application provides a crystal of a benzazepine compound and a preparation method and application thereof. The benzazepine compound crystals I, II, III, IV and V have good stability and dissolution, improve the absorption of the drug, solve the problem of the metabolic speed, significantly reduce the toxicity, improve the safety, effectively ensure the quality and efficiency of the drug product. The crystal preparation method is simple in process, high in yield and purity, and is more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the crystalline form of tolvaptan sodium phosphate, its preparation method, pharmaceutical compositions containing it, and its use in the preparation of drugs for diseases such as heart failure, cirrhosis, syndrome of abnormal secretion of antidiuretic hormone, hyponatremia, and polycystic kidney disease. Background Technology

[0002] Tolvaptan is a non-peptide angiotensin V2 receptor antagonist that was launched in the United States and Europe in 2009. It can antagonize the antidiuretic effect of abnormally increased AVP on the kidneys in heart failure, improve water retention and hyponatremia in heart failure patients, and treat cardiogenic edema for which diuretics are not effective.

[0003] Clinically, tolvaptan is often used for patients who cannot take oral medication. However, tolvaptan has poor water solubility, which increases the technical difficulty of developing intravenous formulations. To improve solubility, existing technologies prepare the tolvaptan prodrug as tolvaptan sodium phosphate. Although tolvaptan sodium phosphate has increased water solubility compared to tolvaptan, the easy dissociation of the phosphate group makes it less stable. Impurities can easily form during composition preparation and storage, affecting drug efficacy. In addition, tolvaptan sodium phosphate may also generate turbidity and insoluble foreign matter during reconstitution, greatly affecting clinical safety.

[0004] Therefore, there is an urgent need to develop a benzo[a]azapyridine that can significantly increase water solubility, exhibit excellent drug stability, and demonstrate good drug safety. The study investigated and developed crystals and pharmaceutical compositions of these compounds suitable for preparing pharmaceutical formulations. Summary of the Invention

[0005] One aspect of the present invention provides crystalline forms I, II, III, IV, and V of compounds of formula (I) as described below:

[0006]

[0007] The tolvaptan sodium phosphate compound (compound of formula I) crystals provided by this invention not only have improved bioavailability, good in vivo metabolism, and increased dissolution rate, but also significantly reduced in vivo toxicity. They exhibit good therapeutic effects for diseases such as heart failure, cirrhosis, syndrome of abnormal antidiuretic hormone secretion, hyponatremia, polycystic kidney disease, ascites, and chronic kidney disease. Furthermore, they are highly preparable, with low solvent residue in the crystalline form, resulting in high safety and no unintended toxicity. There are no significant differences between batches of prepared products, demonstrating good stability. For example, under conditions of light, high temperature, high humidity, and time, the crystals are less prone to crystal transformation, making them easier to store and transport than existing crystals. The crystalline form of this invention is easier to prepare in large quantities with high purity, making it more suitable for preparing pharmaceutical formulations.

[0008] Another aspect of the present invention provides a method for preparing crystals of a compound of formula (I), comprising reacting a compound of formula (I) in any solid form with phosphorus oxychloride to precipitate a solid, and subsequently separating and drying the precipitated solid. The method includes, but is not limited to, slow evaporation at room temperature, slow cooling, etc.

[0009] Another aspect of the invention provides a pharmaceutical composition comprising any one or more crystals of formula (I) of the invention, namely I, II, III, IV, V, and one or more pharmaceutically acceptable carriers.

[0010] Another aspect of the present invention provides a treatment for heart failure, cirrhosis, syndrome of abnormal secretion of antidiuretic hormone, hyponatremia, polycystic kidney disease, ascites, and chronic kidney disease, comprising administering to an individual in need an effective amount of a crystal of the compound of formula (I) above.

[0011] Another aspect of the present invention provides the use of crystals I, II, III, IV, and V of the compound of formula (I) above in the preparation of medicaments for heart failure, cirrhosis, syndrome of abnormal secretion of antidiuretic hormone, hyponatremia, polycystic kidney disease, ascites, and chronic kidney disease.

[0012] Crystals I, II, III, IV, and V of the compounds of formula (I) of the present invention have the following advantageous properties:

[0013] i) The crystals of the present invention have high solubility, high dissolution rate, low hygroscopicity, high fluidity and significantly improved crystal morphology.

[0014] ii) The crystals of this invention possess excellent physicochemical stability, including but not limited to light stability, thermal stability, high humidity resistance, and flowability. This ensures the reliability of the crystals during storage and transportation, thereby guaranteeing the safety of the formulation. Furthermore, the crystals of this invention do not require special packaging to prevent light exposure, reducing costs and improving the safety and long-term effectiveness of the formulation. The crystals of this invention exhibit good thermal stability, maintaining stability over extended periods, making them suitable for standard formulation manufacturing processes; their excellent physicochemical stability facilitates production and makes them more suitable for the preparation of various formulations.

[0015] iii) The crystals of the present invention have improved in vivo metabolic performance, increased bioavailability, significantly reduced toxic side effects, improved safety, and increased dissolution rate, and have good therapeutic effects on diseases such as heart failure, cirrhosis, syndrome of abnormal secretion of antidiuretic hormone, hyponatremia, polycystic kidney disease, ascites, and chronic kidney disease.

[0016] iv) The crystals of the present invention also have good prepareability, low solvent residue in the crystals, high safety, do not cause undesirable toxicity, and there are no significant differences between batches of products, indicating good stability.

[0017] v) The crystalline form of the present invention is easier to prepare in large quantities with high purity, thus making it more suitable for the preparation of pharmaceutical formulations, facilitating industrial preparation, saving costs, and effectively ensuring the quality and efficacy of pharmaceutical products. Attached Figure Description

[0018] Figure 1 The image shows the XRPD pattern of crystal I of compound (I).

[0019] Figure 2 The XRPD pattern of crystal II of compound (I) is shown.

[0020] Figure 3 The XRPD pattern of crystal III of compound (I) is shown.

[0021] Figure 4 The image shows the XRPD pattern of crystal IV of compound (I).

[0022] Figure 5 The image shows the XRPD pattern of crystal V of compound (I). Detailed Implementation

[0023] definition

[0024] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The term "exemplary" as used herein means "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior to or better than other embodiments.

[0025] Furthermore, numerous specific details are set forth below to better illustrate the present invention. Those skilled in the art will understand that the present invention can be practiced even without certain specific details. Therefore, in some embodiments, methods, means, apparatus, and steps well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0026] In this invention, the terms "some specific / preferred embodiments," "other specific / preferred embodiments," "implementation," etc., refer to specific elements (e.g., features, structures, properties, and / or characteristics) related to the described embodiment that are included in at least one of the embodiments described herein, and may or may not be present in other embodiments. Furthermore, it should be understood that these elements may be combined in any suitable manner in various embodiments.

[0027] Unless otherwise stated, all units used in this invention are international standard units, and all numerical values ​​and / or ranges appearing in this invention should be understood to include systematic errors that are unavoidable in industrial production.

[0028] In this invention, the word "may" has two meanings: to perform a certain process and not to perform a certain process.

[0029] The terms “comprising,” “including,” “having,” “containing,” or “involving” as used in this invention, and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed.

[0030] As used herein, the term "about" means, as would be considered by one of ordinary skill in the art, to be within an acceptable standard error of the value, such as within a 95% confidence interval of the average value or within ±10% of a specified value, or a wider range, such as a range of ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3 for the specified value. It should be understood herein that when multiple values ​​or ranges are listed, each listed value or range may be subject to the definition of "about," even if only the first value or endpoint is designated as "about."

[0031] As used in this invention, the term "substantially identical" means taking into account variations in representative peak positions and / or intensities. For example, those skilled in the art will understand that for X-ray diffraction peaks, peak positions (2θ) will show some variation, typically up to 0.1-0.2 degrees, and the instrument used to measure diffraction will also cause some variation. Furthermore, those skilled in the art will understand that relative peak intensities will vary due to differences between instruments, as well as the degree of crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art, and should be considered as qualitative measurements only.

[0032] As used in this invention, the term "pharmaceutical composition" refers to an active ingredient that may optionally be combined with one or more pharmaceutically acceptable chemical components (e.g., but not limited to, a carrier and / or excipients). The active ingredient may be, for example, crystals of formula (I) I, II, III, IV, and V, or one or more of the compositions of this invention.

[0033] As used in this invention, the terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), local, and rectal administration.

[0034] In relation to pharmaceuticals or pharmacologically active agents, the term "effective amount" as used herein refers to a sufficient quantity of a non-toxic drug or agent that achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. In any given case, the appropriate effective amount can be determined by a person skilled in the art through routine testing.

[0035] As used in this invention, the terms "active ingredient," "therapeutic agent," "active substance," or "activator" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The terms used in this invention may refer to, for example, crystals of formula (I) I, II, III, IV, and V, or one or more of the compositions of this invention.

[0036] As used in this invention, the term "pharmaceutically acceptable carrier" refers to carriers that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. This includes, but is not limited to, any flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers acceptable for use in humans or animals (e.g., livestock). Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Further information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0037] The term "X-ray powder diffraction pattern (XRPD pattern)" as used in this invention refers to an experimentally observed diffraction pattern or parameters derived therefrom. XRPD patterns are typically characterized by peak position (x-axis) and / or peak intensity (y-axis).

[0038] As used in this invention, the term "substantially identical" for X-ray diffraction peak positions means that representative peak positions and intensity variations are taken into account. For example, those skilled in the art will understand that peak positions (2θ) will show some variation, typically up to 0.1-0.2 degrees, and that the instruments used to measure diffraction will also show some variation. Furthermore, those skilled in the art will understand that relative peak intensities will show variations between instruments as well as variations due to degree of crystallinity, preferred orientation, the prepared sample surface, and other factors known to those skilled in the art, and should be considered as qualitative measurements only.

[0039] The term "room temperature" as used in this invention refers to 20℃±5℃.

[0040] The "drying" in this invention can be carried out under forced draft or reduced pressure (preferably vacuum) at any temperature (preferably room temperature). The drying can be performed in a disc dryer, vacuum oven, air oven, conical vacuum dryer, rotary vacuum dryer, fluidized bed dryer, rotary flash dryer, rapid dryer, etc. The drying can be carried out at temperatures below about 100°C, below about 80°C, below about 60°C, below about 50°C, below about 30°C, or any other suitable temperature, under atmospheric pressure or reduced pressure (preferably vacuum), for any desired time (e.g., about 1, 2, 3, 5, 10, 15, 20, 24 hours, or overnight) to achieve the desired results. The drying can be performed any desired number of times until the desired product quality is achieved.

[0041] Crystals and their preparation methods

[0042] In some embodiments, the present invention relates to crystals of compounds of formula (I), wherein said compounds of formula (I) have the following structure:

[0043]

[0044] Crystal I

[0045] According to certain embodiments of the present invention, the present invention provides a crystal I of compound (I) whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of about 4.37 ± 0.2°, about 8.08 ± 0.2°, about 9.19 ± 0.2°, and about 10.42 ± 0.2°, about 11.61 ± 0.2°, and about 11.92 ± 0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal I of compound I further includes peaks at diffraction angles (2θ) of about 13.10 ± 0.2°, about 13.55 ± 0.2°, and about 15.23 ± 0.2°.

[0046] In certain embodiments of the invention, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes peaks at diffraction angles (2θ) of about 4.37 ± 0.2°, about 8.08 ± 0.2°, about 9.19 ± 0.2°, about 10.42 ± 0.2°, about 11.61 ± 0.2°, about 11.92 ± 0.2°, about 13.10 ± 0.2°, about 13.55 ± 0.2°, about 15.23 ± 0.2°, about 15.71 ± 0.2°, about 16.21 ± 0.2°, and about 16.80 ± 0.2°.

[0047] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes peaks at diffraction angles (2θ) of 4.37±0.2°, 8.08±0.2°, 9.19±0.2°, 10.42±0.2°, 11.61±0.2°, 11.92±0.2°, 13.10±0.2°, 13.55±0.2°, 15.23±0.2°, 15.71±0.2°, 16.21±0.2°, and 16.80±0.2°.

[0048] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes the following peaks at the 2θ angle:

[0049]

[0050]

[0051] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes the following peaks at the 2θ angle:

[0052] 4.37 37.98 15.71 14.83 25.91 48.20 36.89 3.32 8.08 10.49 16.21 25.70 26.61 23.38 / / 9.19 24.07 16.80 7.62 27.72 6.19 / / 10.42 100.00 17.39 44.90 29.02 16.52 / / 11.61 38.43 18.34 11.68 29.55 6.77 / / 11.92 20.43 19.61 8.23 30.86 4.08 / / 13.10 15.93 20.23 8.14 31.90 2.96 / / 13.55 55.59 21.83 10.44 32.90 3.15 / / 15.23 7.31 24.84 15.73 34.13 1.89 / /

[0053] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) includes the following: Figure 1 The peaks shown are at essentially the same diffraction angle (2θ).

[0054] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal I of compound (I) is as follows: Figure 1 The results are basically the same.

[0055] Crystal II

[0056] According to certain embodiments of the present invention, the present invention provides a crystal II of the compound of formula (I) whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of about 3.87 ± 0.2°, about 7.94 ± 0.2°, about 8.18 ± 0.2°, and about 8.85 ± 0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of the crystal I of the compound of formula I further includes peaks at diffraction angles (2θ) of about 9.86 ± 0.2°, about 11.53 ± 0.2°, and about 13.12 ± 0.2°.

[0057] In certain embodiments of the invention, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula (I) includes peaks at diffraction angles (2θ) of about 3.87 ± 0.2°, about 7.94 ± 0.2°, about 8.18 ± 0.2°, about 8.85 ± 0.2°, about 9.86 ± 0.2°, about 11.53 ± 0.2°, about 13.12 ± 0.2°, about 14.96 ± 0.2°, about 15.26 ± 0.2°, 22.65 ± 0.2°, 22.91 ± 0.2°, 25.20 ± 0.2°, 25.51 ± 0.2°, and 29.72 ± 0.2°.

[0058] In certain embodiments of the invention, the X-ray powder diffraction (XRPD) pattern of crystal II of compound (I) includes peaks at diffraction angles (2θ) of 3.87±0.2°, 7.94±0.2°, 8.18±0.2°, 8.85±0.2°, 9.86±0.2°, 11.53±0.2°, 13.12±0.2°, 14.96±0.2°, 15.26±0.2°, 22.65°±0.2°, 22.91°±0.2°, 25.20±0.2°, 25.51°±0.2°, and 29.72°±0.2°.

[0059] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal II of compound (I) includes the following peaks at the 2θ angle:

[0060] 3.87 18.67 29.19 7.94 19.79 29.72 8.18 20.00 30.83 8.85 21.22 31.94 9.86 21.77 32.76 11.53 22.19 33.72 13.12 22.65 33.96 14.96 22.91 34.39 15.26 23.60 35.11 15.59 23.99 35.99 15.94 24.73 36.66 16.99 25.20 37.14 17.76 25.52 37.88 18.10 27.08 39.03

[0061] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal II of compound (I) includes the following peaks at the 2θ angle:

[0062] 3.87 8.15 18.67 3.22 29.19 2.26 7.94 21.17 19.79 2.12 29.72 20.67 8.18 4.30 20.00 3.23 30.83 10.00 8.85 37.08 21.22 58.27 31.94 2.80 9.86 53.73 21.77 9.67 32.76 6.36 11.53 46.53 22.19 18.68 33.72 6.86 13.12 100.00 22.65 44.29 33.96 6.17 14.96 20.76 22.91 36.64 34.39 4.37 15.26 57.52 23.60 17.79 35.11 4.86 15.59 7.37 23.99 11.20 35.99 7.30 15.94 23.87 24.73 15.34 36.66 5.39 16.99 31.05 25.20 38.49 37.14 7.26 17.76 10.89 25.52 85.21 37.88 13.31 18.10 20.39 27.08 8.74 39.03 3.14

[0063] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal II of compound (I) includes the following: Figure 2 The peaks shown are at essentially the same diffraction angle (2θ).

[0064] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula (I) is as follows: Figure 2 The results are basically the same.

[0065] Crystal III

[0066] According to certain embodiments of the present invention, the present invention provides a crystal III of the compound of formula (I) whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of about 4.74 ± 0.2°, about 8.18 ± 0.2°, about 9.49 ± 0.2°, about 10.88 ± 0.2°, and about 11.76 ± 0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of the crystal III of the compound of formula I further includes peaks at diffraction angles (2θ) of about 12.48 ± 0.2°, about 13.31 ± 0.2°, about 13.58 ± 0.2°, about 13.95 ± 0.2°, about 14.34 ± 0.2°, and about 14.99 ± 0.2°.

[0067] In certain embodiments of the invention, the X-ray powder diffraction (XRPD) pattern of crystal III of the compound of formula (I) includes peaks at diffraction angles (2θ) of about 4.74 ± 0.2°, about 8.18 ± 0.2°, about 9.49 ± 0.2°, about 10.88 ± 0.2°, about 11.76 ± 0.2°, about 12.48 ± 0.2°, about 13.31 ± 0.2°, about 13.58 ± 0.2°, about 13.95 ± 0.2°, about 14.34 ± 0.2°, about 14.99 ± 0.2°, about 15.32 ± 0.2°, about 16.41 ± 0.2°, and about 16.63 ± 0.2°.

[0068] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal III of compound (I) includes peaks at diffraction angles (2θ) of 4.74±0.2°, 8.18±0.2°, 9.49±0.2°, 10.88±0.2°, and 11.76±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal III of compound (I) further includes peaks at diffraction angles (2θ) of 12.48±0.2°, 13.31±0.2°, 13.58±0.2°, 13.95±0.2°, 14.34±0.2°, and 14.99±0.2°.

[0069] In some embodiments of the invention, the X-ray powder diffraction (XRPD) pattern of crystal III of the compound of formula (I) includes peaks at diffraction angles (2θ) of 4.74±0.2°, 8.18±0.2°, 9.49±0.2°, 10.88±0.2°, 11.76±0.2°, 12.48±0.2°, 13.31±0.2°, 13.58±0.2°, 13.95±0.2°, 14.34±0.2°, 14.99±0.2°, 15.32±0.2°, 16.41±0.2°, and 16.63±0.2°.

[0070] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal III of compound (I) includes the following peaks at the 2θ angle:

[0071]

[0072]

[0073] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal III of compound (I) includes the following peaks at the 2θ angle:

[0074] 4.74 34.46 16.41 30.76 23.56 52.81 31.42 11.87 8.18 26.25 16.63 25.50 24.26 19.80 32.08 6.70 9.49 100.00 17.11 6.27 24.54 19.70 32.90 3.50 10.88 38.87 18.44 20.02 25.32 20.98 33.87 4.58 11.76 5.86 19.18 14.77 25.76 11.99 34.38 7.60 12.48 31.81 19.48 13.16 26.49 59.68 35.10 7.24 13.31 22.51 19.98 19.55 26.81 55.31 35.80 2.55 13.58 53.72 20.35 8.63 27.35 20.06 36.42 4.35 13.95 54.20 20.97 5.79 28.71 17.30 37.37 5.44 14.34 18.72 22.18 55.09 29.69 3.62 38.07 5.65 14.99 63.00 22.66 16.08 30.08 8.43 38.96 4.32 15.32 13.27 23.16 46.50 30.64 6.36 39.44 3.10

[0075] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal III of compound (I) includes the following: Figure 3 The peaks shown are at essentially the same diffraction angle (2θ).

[0076] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal III of the compound of formula (I) is as follows: Figure 3 The results are basically the same.

[0077] Crystal IV

[0078] According to certain embodiments of the present invention, the present invention provides a crystal IV of the compound of formula (I) whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of about 4.50 ± 0.2°, about 7.46 ± 0.2°, about 7.97 ± 0.2°, about 9.00 ± 0.2°, and about 9.40 ± 0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of the crystal IV of the compound of formula I further includes peaks at diffraction angles (2θ) of about 10.15 ± 0.2°, about 10.35 ± 0.2°, about 10.82 ± 0.2°, about 11.60 ± 0.2°, about 12.16 ± 0.2°, and about 12.89 ± 0.2°.

[0079] In certain embodiments of the invention, the X-ray powder diffraction (XRPD) pattern of crystal IV of the compound of formula (I) includes peaks at diffraction angles (2θ) of about 4.50 ± 0.2°, about 7.46 ± 0.2°, about 7.97 ± 0.2°, about 9.00 ± 0.2°, about 9.40 ± 0.2°, about 10.15 ± 0.2°, about 10.35 ± 0.2°, about 10.82 ± 0.2°, about 11.60 ± 0.2°, about 12.16 ± 0.2°, about 12.89 ± 0.2°, about 14.25 ± 0.2°, about 14.94 ± 0.2°, and about 15.57 ± 0.2°.

[0080] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal IV of compound (I) includes peaks at diffraction angles (2θ) of 4.50±0.2°, 7.46±0.2°, 7.97±0.2°, 9.00±0.2°, and 9.40±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal IV of compound (I) further includes peaks at diffraction angles (2θ) of 10.15±0.2°, 10.35±0.2°, 10.82±0.2°, 11.60±0.2°, 12.16±0.2°, and 12.89±0.2°.

[0081] In certain embodiments of the invention, the X-ray powder diffraction (XRPD) pattern of crystal IV of the compound of formula (I) includes peaks at diffraction angles (2θ) of 4.50±0.2°, 7.46±0.2°, 7.97±0.2°, 9.00±0.2°, 9.40±0.2°, 10.15±0.2°, 10.35±0.2°, 10.82±0.2°, 11.60±0.2°, 12.16±0.2°, 12.89±0.2°, 14.25±0.2°, 14.94±0.2°, and 15.57±0.2°.

[0082] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal IV of the compound of formula (I) includes the following peaks at the 2θ angle:

[0083] 4.50 10.82 16.32 25.66 7.46 11.60 17.08 26.33 7.97 12.16 18.41 27.36 9.00 12.89 19.11 28.73 9.40 14.25 20.91 31.69 10.15 14.94 22.02 / 10.35 15.57 23.01 /

[0084] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal IV of the compound of formula (I) includes the following peaks at the 2θ angle:

[0085] 4.50 100.00 10.82 5.36 16.32 10.67 25.66 16.96 7.46 4.67 11.60 4.91 17.08 8.79 26.33 10.76 7.97 18.75 12.16 5.93 18.41 3.93 27.36 4.27 9.00 28.16 12.89 13.64 19.11 2.79 28.73 3.85 9.40 13.17 14.25 10.01 20.91 8.20 31.69 7.78 10.15 4.01 14.94 2.20 22.02 10.03 / / 10.35 37.91 15.57 3.18 23.01 20.88 / /

[0086] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal IV of the compound of formula (I) includes the following: Figure 4 The peaks shown are at essentially the same diffraction angle (2θ).

[0087] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal IV of the compound of formula (I) is as follows: Figure 4 The results are basically the same.

[0088] Crystal V

[0089] According to certain embodiments of the present invention, the present invention provides a crystal V of compound (I) whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of about 4.63 ± 0.2°, about 8.12 ± 0.2°, about 9.27 ± 0.2°, about 10.67 ± 0.2°, and about 11.60 ± 0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal V of compound I further includes peaks at diffraction angles (2θ) of about 12.34 ± 0.2°, about 13.11 ± 0.2°, about 13.76 ± 0.2°, about 14.75 ± 0.2°, about 15.25 ± 0.2°, and about 16.30 ± 0.2°.

[0090] In certain embodiments of the invention, the X-ray powder diffraction (XRPD) pattern of crystal V of compound (I) includes peaks at diffraction angles (2θ) of about 4.63 ± 0.2°, about 8.12 ± 0.2°, about 9.27 ± 0.2°, about 10.67 ± 0.2°, about 11.60 ± 0.2°, about 12.34 ± 0.2°, about 13.11 ± 0.2°, about 13.76 ± 0.2°, about 14.75 ± 0.2°, about 15.25 ± 0.2°, about 16.30 ± 0.2°, about 16.92 ± 0.2°, about 18.08 ± 0.2°, and about 18.96 ± 0.2°.

[0091] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal V of compound (I) includes peaks at diffraction angles (2θ) of 4.63±0.2°, 8.12±0.2°, 9.27±0.2°, 10.67±0.2°, and 11.60±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal V of compound (I) further includes peaks at diffraction angles (2θ) of 12.34±0.2°, 13.11±0.2°, 13.76±0.2°, 14.75±0.2°, 15.25±0.2°, and 16.30±0.2°.

[0092] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal V of compound (I) includes peaks at diffraction angles (2θ) of 4.63±0.2°, 8.12±0.2°, 9.27±0.2°, 10.67±0.2°, 11.60±0.2°, 12.34±0.2°, 13.11±0.2°, 13.76±0.2°, 14.75±0.2°, 15.25±0.2°, 16.30±0.2°, 16.92±0.2°, 18.08±0.2°, and 18.96±0.2°.

[0093] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal V of compound (I) includes the following peaks at the 2θ angle:

[0094] 4.63 13.76 19.60 30.76 8.12 14.75 21.87 32.78 9.27 15.25 23.06 37.14 10.67 16.30 24.09 38.78 11.60 16.92 26.33 / 12.34 18.08 28.29 / 13.11 18.96 29.58 /

[0095] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal V of compound (I) includes the following peaks at the 2θ angle:

[0096] 4.63 77.04 13.76 45.48 19.60 9.13 30.76 7.15 8.12 9.33 14.75 38.01 21.87 17.46 32.78 3.90 9.27 51.08 15.25 18.92 23.06 81.35 37.14 3.96 10.67 100.00 16.30 55.80 24.09 21.77 38.78 2.88 11.60 10.12 16.92 10.94 26.33 56.90 / / 12.34 32.94 18.08 23.20 28.29 15.63 / / 13.11 34.38 18.96 8.72 29.58 7.36 / /

[0097] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal V of compound (I) includes the following: Figure 5 The peaks shown are at essentially the same diffraction angle (2θ).

[0098] In a preferred embodiment, the X-ray powder diffraction (XRPD) pattern of crystal V of compound (I) is as follows: Figure 5 The results are basically the same.

[0099] Crystal preparation methods

[0100] Another object of the present invention is to provide a method for preparing crystals of the compound of formula (I) of the present invention.

[0101] #imgpt8#

[0102] The present invention provides a method for preparing crystals of a compound of formula (I), which includes reacting a compound of formula (I) in any solid form with phosphorus oxychloride to precipitate a solid, and then separating and drying the precipitated solid.

[0103] The method for preparing crystals of compound (I) provided by the present invention includes, but is not limited to, slow volatilization at room temperature and cooling method.

[0104] In some embodiments, the present invention provides a method for preparing the above-described crystal I, the method including but not limited to:

[0105] (1) Dissolve the compound of formula (I) in a solvent to form a clear solution.

[0106] (2) Crystals precipitate under stirring or static conditions;

[0107] Preferably, the solvent is selected from one or two of water and ketones;

[0108] Preferably, the solvent is selected from one or both of water and acetone;

[0109] Preferably, the weight-to-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:5-1:20, more preferably 1:10-1:15;

[0110] Preferably, the volume ratio of water to acetone in the solvent is 1:5 to 1:20; more preferably, the volume ratio of water to acetone is 1:10 to 1:15.

[0111] Preferably, the dissolution of the compound of formula (I) in a solvent can be carried out at a rising temperature; more preferably, the temperature is the reflux temperature;

[0112] Preferably, the compound of formula (I) can crystallize under cooling conditions; preferably, the temperature can be selected from -5 to 20°C, and more preferably from 0 to 10°C;

[0113] Preferably, the crystals of the compound of formula (I) are dried at 20-80°C;

[0114] Preferably, the crystals of the compound of formula (I) are first dried at 20-30°C and then dried at 65-75°C.

[0115] In some embodiments, the present invention provides a method for preparing the above-described crystal II, the method including but not limited to:

[0116] The compound of formula (I) was dissolved in a solvent, and then slowly evaporated at room temperature to precipitate crystals. The precipitated crystals were then separated and dried to obtain the target crystals.

[0117] Preferably, the solvent is selected from one or two of water and ketones;

[0118] Preferably, the solvent is selected from one or both of water and acetone;

[0119] Preferably, when the solvent is water or acetone, the volume ratio of water to acetone in the solvent is 1:1 to 1:5;

[0120] Preferably, the weight-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:5-1:15; preferably, the weight-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:10.

[0121] Preferably, the compound of formula (I) can crystallize under cooling or room temperature conditions; preferably, the temperature can be selected from room temperature;

[0122] Preferably, the crystals of the compound of formula (I) are dried at 35-45°C.

[0123] In some embodiments, the present invention provides a method for preparing the above-described crystal III, the method including but not limited to:

[0124] The compound of formula (I) was dissolved in a solvent, and then slowly evaporated at room temperature or precipitated by cooling. The precipitated crystals were then separated and dried to obtain the target crystal.

[0125] Preferably, the solvent is selected from one or more of water, alcohols, esters, and ketones;

[0126] Preferably, the solvent is selected from one or more of water, methanol, ethanol, tert-butanol, acetone, butanone, and isopropyl acetate;

[0127] Preferably, when the solvent is water or acetone, the volume ratio of water to acetone in the solvent is 1:1 to 1:5;

[0128] Preferably, the weight-to-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:1 to 1:10;

[0129] Preferably, the compound of formula (I) can crystallize under cooling or room temperature conditions; preferably, the temperature can be selected from 10-20°C;

[0130] Preferably, the crystals of the compound of formula (I) are dried at 20-30°C.

[0131] In some embodiments, the present invention provides a method for preparing the above-described crystal IV, the method including but not limited to:

[0132] The compound of formula (I) was dissolved in a solvent, and then crystals were precipitated by cyclic shaking with heating and cooling. The precipitated crystals were then separated and dried to obtain the target crystal.

[0133] Preferably, the solvent is selected from alcohols;

[0134] Preferably, the solvent is selected from one or more of methanol, ethanol, isopropanol, and tert-butanol;

[0135] Preferably, the weight-to-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:8-1:20;

[0136] Preferably, the crystallization temperature is achieved by cyclic shaking at (35-45℃) / (10-20℃); preferably, the crystallization temperature is achieved by cyclic shaking at 40℃ / 15℃.

[0137] Preferably, the crystals IV of compound (I) are dried at 20-30°C.

[0138] In some embodiments, the present invention provides a method for preparing the above-described crystal V, the method including but not limited to:

[0139] (1) Dissolve the compound of formula (I) in a solvent to form a clear solution.

[0140] (2) Crystals precipitate under stirring or static conditions;

[0141] Preferably, the solvent is selected from one or two of water and ketones;

[0142] Preferably, the solvent is selected from one or two of water and acetone; more preferably, the solvent is water or acetone.

[0143] Preferably, the weight-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:10-1:35, more preferably 1:15-1:20;

[0144] Preferably, the volume ratio of water to acetone in the solvent is 1:10-1:20; more preferably, the volume ratio of water to acetone is 1:15-1:20.

[0145] Preferably, the dissolution of the compound of formula (I) in a solvent can be carried out at a rising temperature; more preferably, the temperature is the reflux temperature;

[0146] Preferably, the compound of formula (I) can crystallize under cooling conditions; preferably, the temperature can be selected from -5 to 20°C, and more preferably from 0 to 10°C;

[0147] Preferably, the crystal V of compound (I) is first dried at 20-30°C and then dried at 45-55°C.

[0148] Pharmaceutical Compositions and Uses

[0149] Another object of the present invention is to provide a pharmaceutical composition comprising any one or more of crystal I, crystal II, crystal III, crystal IV, and crystal V of the present invention, and one or more pharmaceutically acceptable carriers.

[0150] Another object of the present invention is to provide crystals or pharmaceutical compositions of the compounds of formula (I) of the present invention for use in the preparation of medicaments for non-peptide vasopressin V2 receptor antagonists. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention or salts thereof with a suitable pharmaceutically acceptable carrier.

[0151] Another object of the present invention is to provide any one or more of the crystals I, II, III, IV, V or pharmaceutical compositions of the compound of formula (I) of the present invention in the preparation of medicaments for heart failure, cirrhosis, syndrome of abnormal secretion of antidiuretic hormone, hyponatremia, polycystic kidney disease, ascites, and chronic kidney disease.

[0152] As used herein, the term "pharmaceuticalally acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with reasonable benefits / risks.

[0153] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The compositions may also contain small amounts of wetting agents, emulsifiers, or pH buffers as needed.

[0154] The pharmaceutical compositions of the present invention can be manufactured using methods well known in the art, such as conventional mixing methods, etc.

[0155] Typical routes of administration for the compounds or pharmaceutical compositions thereof of the present invention include, but are not limited to, oral, injection, intravenous, intra-arterial, rectal, transmucosal, enteric administration, or local, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0156] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention.

[0157] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available standard products.

[0158] Information on the testing instruments and methods used in the experiment

[0159] XRPD powder diffraction pattern. Panalytical X'Pert3 Powder X-ray diffraction analyzer. This instrument uses copper target irradiation, Cu Kα1=1.5406A, monochromatic radiation; voltage: 40kV; current: 40mA.

[0160] The high humidity test and light irradiation test of the present invention were carried out in accordance with the high humidity test method or strong light irradiation test method in the 2020 edition of the Pharmacopoeia 9001 "Guiding Principles for Stability Testing of Raw Materials and Preparations".

[0161] Example 1 Crystal of compound (I)

[0162] 450.00 g of tolvaptan and 3.6 L of ethylene glycol dimethyl ether were added to a reaction flask. 912.80 g of triethylamine was added with stirring, the mixture was purged with nitrogen, and the temperature was lowered to -15 °C. Phosphorus oxychloride was added dropwise at -20 to -10 °C. After the addition was complete, the reaction was maintained at -20 to -10 °C. After the reaction was complete, 400.00 g of sodium hydroxide was dissolved in 6.25 L of purified water to prepare a sodium hydroxide solution. The reaction mixture was added to the sodium hydroxide solution, followed by 2.5 L of toluene. The mixture was heated to 50 °C, separated, and filtered. The filter cake and 5.4 L of acetone were added to the reaction flask, and the mixture was heated to reflux. 450 mL of purified water was added, and the mixture was cooled to 0 to -10 °C to crystallize. The crystals were filtered, dried at 25 ± 5 °C, and then dried again at 70 ± 5 °C to obtain tolvaptan sodium phosphate crystals I. The XRPD chromatogram is shown below. Figure 1 As shown.

[0163] Example 2. Crystal of compound of formula (I) II

[0164] 10.02 g of tolvaptan sodium phosphate was weighed and added to a round-bottom flask, along with 60 ml of acetone and 40 ml of water. The mixture was stirred at room temperature, filtered, and the filter cake was dried at 40 °C to obtain the title product. The obtained XRPD spectrum is shown below. Figure 2 As shown.

[0165] Example 3. Crystals of compound (I) II

[0166] 10.02 g of tolvaptan sodium phosphate was weighed and added to a round-bottom flask, along with 50 ml of acetone and 50 ml of water. The mixture was stirred at room temperature, filtered, and the filter cake was dried at 40 °C to obtain the product in question. Analysis showed that its crystals were consistent with those of Example 2.

[0167] Example 4. Crystals of compound (I) III

[0168] Weigh 15.03 g of tolvaptan sodium phosphate and add it to a round-bottom flask. Add 80 ml of acetone and 20 ml of water, stir at room temperature, filter, and dry the filter cake at 25°C to obtain the product. The obtained XRPD spectrum is shown below. Figure 3 As shown.

[0169] Example 5. Crystals of compound (I) III

[0170] Weigh 5.0 g of tolvaptan sodium phosphate and add it to a round-bottom flask. Add 50 ml of ethanol, heat to 40 °C and stir, then cool to 15 °C and stir again. Filter, and dry the filter cake at 25 °C to obtain the product. Testing showed that its crystals were consistent with those of Example 4.

[0171] Example 6. Crystals of compound (I) III

[0172] Weigh 5.0 g of tolvaptan sodium phosphate and add it to a round-bottom flask. Add 50 ml of isopropyl acetate, heat to 40 °C, stir, then cool to 15 °C and stir again. Filter, and dry the filter cake at 25 °C to obtain the product. Testing showed that its crystals were consistent with those of Example 4.

[0173] Example 7. Crystals of compound (I) IV

[0174] Weigh 55 mg of tolvaptan sodium phosphate and add it to a glass bottle. Add 0.5 ml of tert-butanol, and shake continuously at 40°C / 15°C. Filter, and dry the filter cake at 25°C to obtain the product. The obtained XRPD spectrum is as follows. Figure 4 As shown.

[0175] Example 8. Preparation of crystal V of compound (I)

[0176] 7.00 g of tolvaptan and 56 mL of ethylene glycol dimethyl ether were added to a reaction flask. 14.20 g of triethylamine was added with stirring, the mixture was purged with nitrogen, and the temperature was lowered to -15°C. Phosphorus oxychloride was added dropwise at -20 to -10°C. After the addition was complete, the reaction was maintained at -20 to -10°C. After the reaction was complete, 11.23 g of sodium hydroxide was dissolved in 175 mL of purified water to prepare a sodium hydroxide solution. The reaction mixture was added to the sodium hydroxide solution, followed by 700 mL of toluene. The mixture was heated to 50°C, separated, and filtered. The filter cake and 112 mL of acetone were added to a flask, and the mixture was heated to reflux. 7 mL of purified water was added, and the mixture was cooled to 0 to -10°C to crystallize. The crystals were filtered, dried at 25±5°C, and then dried at 50±5°C to obtain tolvaptan sodium phosphate crystals V. The obtained XRPD spectrum is shown below. Figure 5 As shown.

[0177] Experimental Example 9. Crystals I, II, and III of the compound of formula (I) obtained in the embodiments of the present invention were packaged in pharmaceutical low-density polyethylene bags as inner packaging materials and polyester / aluminum / polyethylene composite films as outer packaging materials. They were then placed under a relative humidity of 92.5% and the changes in crystals and chemical purity were observed after 5 days and 10 days.

[0178] Crystal I Crystal I / 99.47% Crystal I / 99.47% Crystal I / 99.47% Crystal II Crystal II / 99.97% Crystal II / 99.97% Crystal II / 99.97% Crystal III Crystal III / 99.97% Crystal III / 99.97% Crystal III / 99.97%

[0179] As can be seen from the data in the table above, the crystals of the present invention have excellent stability under high humidity conditions, do not undergo crystal transformation, and do not increase impurities. They can maintain their purity unchanged after being placed under high humidity conditions for 10 days.

[0180] Experimental Example 10. Crystal A was prepared according to the methods of CN113383001A and CN119684210A respectively. Crystal A of the prior art and crystal of the compound of formula (I) of the present invention were placed in open petri dishes and observed for 5 days at a relative humidity of 75% to observe the changes in crystals and chemical purity.

[0181] Crystal A Crystal A / 99.47% Crystal II / 99.47% Crystal II Crystal II / 99.97% Crystal II / 99.97%

[0182] As shown in the table above, crystal II of the present invention, when left exposed without any outer packaging, maintains excellent stability even in a high humidity environment of 75%, without any decrease in purity or crystal transformation. Furthermore, crystals IV and V of the present invention maintain 99.70% (crystal IV) and 99.51% (crystal V) purity under the same high humidity conditions. However, crystal A prepared by prior art, after being placed under the same humidity conditions for 5 days, completely transformed into crystal II of the present invention.

[0183] Experimental Example 11. Crystals I, III, and B (referred to as crystal B in this invention) of compound (I) were placed open under light conditions without outer packaging to investigate changes in crystals and chemical purity.

[0184] Crystal I Crystal I / 99.47% Crystal I / 99.47% Crystal III Crystal III / 99.97% Crystal III / 99.97% Crystal B Crystal B / 99.97% Crystal III / 99.97%

[0185] As can be seen from the table above, the crystals of the present invention maintain excellent stability when placed under light conditions without outer packaging, and the purity of the crystals hardly changes and no crystal transformation occurs; however, the crystal B of the prior art completely transforms into the crystal III of the present invention after being placed under the same light conditions for 13 days.

[0186] Experimental Example 12. Crystals I, II, and III of compound (I) were placed in a high-temperature environment of 60°C with pharmaceutical low-density polyethylene bags as inner packaging materials and polyester / aluminum / polyethylene composite films as outer packaging materials to investigate crystal changes and chemical purity changes.

[0187] Crystal I Crystal I / 99.47% Crystal I / 99.47% Crystal I / 99.47% Crystal II Crystal II / 99.97% Crystal II / 99.97% Crystal II / 99.97% Crystal III Crystal III / 99.97% Crystal III / 99.97% Crystal III / 99.92%

[0188] As can be seen from the table above, the crystals of the present invention maintain excellent stability when placed under high temperature conditions, the purity of the crystals hardly changes, and no crystal transformation occurs.

[0189] Experimental Example 13. Crystal III of the compound of formula (I) of the present invention and the above-mentioned prior art crystals A and B were placed in petri dishes and placed open at a high temperature of 60°C to investigate the changes in crystals and chemical purity.

[0190] Crystal A Crystal A / 99.47% Crystal III / 99.45% / Crystal B Crystal B / 99.97% Crystal III / 99.90% / Crystal III Crystal III / 99.97% Crystal III / 99.95% Crystal III / 99.76%

[0191] * In this experiment, crystals A and B were completely transformed into crystal III of this invention in just 10 days, so there is no need to continue to investigate the changes over 30 days.

[0192] As shown in the table above, the crystal of the present invention maintains excellent stability even after being placed in high-temperature conditions without outer packaging for 30 days, with almost no change in crystal purity and no crystal transformation. However, crystals A and B of the prior art completely transformed into crystal III of the present invention after being left exposed in high-temperature conditions without outer packaging for 10 days.

[0193] Experimental Example 14. Crystals A and B of the prior art compound of formula (I) and crystal III of the present invention were placed in petri dishes and exposed to a high temperature of 40°C to observe changes in crystals and chemical purity.

[0194] Crystal A Crystal A / 99.47% Crystal III / 99.55% / Crystal B Crystal B / 99.97% Crystal III / 99.91% / Crystal III Crystal III / 99.97% Crystal III / 99.95% Crystal III / 99.95%

[0195] * In this experiment, crystals A and B were completely transformed into crystal III of this invention in just 10 days, so there is no need to continue to investigate the changes over 30 days.

[0196] As shown in the table above, the crystals of this invention maintain excellent stability even after being placed under high-temperature conditions without outer packaging for 30 days, with almost no change in crystal purity and no crystal transformation. However, prior art crystals A and B completely transform into the crystal III of this invention after only 10 days of placement under high-temperature conditions without outer packaging.

[0197] Example 15. The flowability of crystals I, II, III, IV and V of compound (I) was evaluated according to the "Determination of bulk density and tap density" in Pharmacopoeia 0093 of 2020.

[0198] Analysis shows that the crystals I, II, III, IV and V of the compound of formula (I) of this invention have excellent flowability, which is effective in improving industrial operability and productivity. The product quality is uniform, and there is less adhesion to the grinding mill during crystallization and crushing. The charge is low, and it has excellent operation performance.

Claims

1. Crystal I of compound (I), wherein, The compound of formula (I) has the following structure: Its X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of 4.37±0.2°, 8.08±0.2°, 9.19±0.2°, 10.42±0.2°, 11.61±0.2°, and 11.92±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal I of compound I also includes peaks at diffraction angles (2θ) of 13.10±0.2°, 13.55±0.2°, and 15.23±0.2°; more preferably, the X-ray powder diffraction (XRPD) pattern of crystal I of compound I also includes peaks at diffraction angles (2θ) of 15.71±0.2°, 16.21±0.2°, and 16.80±0.2°.

2. Crystal II of compound of formula (I), wherein, The compound of formula (I) has the following structure: Its X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of approximately 3.87±0.2°, 7.94±0.2°, 8.18±0.2°, and 8.85±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula I also includes peaks at diffraction angles (2θ) of 9.86±0.2°, 11.53±0.2°, and 13.12±0.2°; more preferably, the X-ray powder diffraction (XRPD) pattern of crystal II of the compound of formula I also includes peaks at diffraction angles (2θ) of 14.96±0.2°, 15.26±0.2°, 22.65°±0.2°, 22.91°±0.2°, 25.20±0.2°, 25.51°±0.2°, and 29.72°±0.2°.

3. Crystalline form III of compound (I), wherein, The compound of formula (I) has the following structure: The X-ray powder diffraction (XRPD) pattern of the compound includes peaks at diffraction angles (2θ) of approximately 4.74±0.2°, 8.18±0.2°, 9.49±0.2°, 10.88±0.2°, and 11.76±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal III of the compound of formula I also includes peaks at diffraction angles (2θ) of 12.48±0.2°, 13.31±0.2°, 13.58±0.2°, 13.95±0.2°, 14.34±0.2°, and 14.99±0.2°; more preferably, the X-ray powder diffraction (XRPD) pattern of crystal III of the compound of formula I also includes peaks at diffraction angles (2θ) of 15.32±0.2°, 16.41±0.2°, and 16.63±0.2°.

4. Crystalline form IV of compound (I), wherein, The compound of formula (I) has the following structure: The X-ray powder diffraction (XRPD) pattern of the compound includes peaks at diffraction angles (2θ) of 4.50±0.2°, 7.46±0.2°, 7.97±0.2°, 9.00±0.2°, and 9.40±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal IV of the compound of formula I also includes peaks at diffraction angles (2θ) of 10.15±0.2°, 10.35±0.2°, 10.82±0.2°, 11.60±0.2°, 12.16±0.2°, and 12.89±0.2°; more preferably, the X-ray powder diffraction (XRPD) pattern of crystal IV of the compound of formula I also includes peaks at diffraction angles (2θ) of 14.25±0.2°, 14.94±0.2°, and 15.57±0.2°.

5. Crystal V of compound of formula (I), wherein, The compound of formula (I) has the following structure: The X-ray powder diffraction (XRPD) pattern of the compound includes peaks at diffraction angles (2θ) of 4.63±0.2°, 8.12±0.2°, 9.27±0.2°, 10.67±0.2°, and 11.60±0.2°; preferably, the X-ray powder diffraction (XRPD) pattern of crystal V of the compound of formula I also includes peaks at diffraction angles (2θ) of 12.34±0.2°, 13.11±0.2°, 13.76±0.2°, 14.75±0.2°, 15.25±0.2°, and 16.30±0.2°; more preferably, the X-ray powder diffraction (XRPD) pattern of crystal V of the compound of formula I also includes peaks at diffraction angles (2θ) of 16.92±0.2°, 18.08±0.2°, and 18.96±0.2°.

6. A method for preparing crystals of compound (I), said method including but not limited to: (1) Dissolve the compound of formula (I) in a solvent to form a clear solution. (2) Crystals precipitate under stirring or static conditions; Preferably, the solvent is selected from one or two of water and ketones; Preferably, the solvent is selected from one or both of water and acetone; Preferably, the weight-to-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:5-1:20, more preferably 1:10-1:15; Preferably, the volume ratio of water to acetone in the solvent is 1:5 to 1:20; more preferably, the volume ratio of water to acetone is 1:10 to 1:

15. Preferably, the dissolution of the compound of formula (I) in a solvent can be carried out at a rising temperature; more preferably, the temperature is the reflux temperature; Preferably, the compound of formula (I) can crystallize under cooling conditions; preferably, the temperature can be selected from -5 to 20°C, and more preferably from 0 to 10°C; Preferably, the crystals of the compound of formula (I) are dried at 20-80°C; Preferably, the crystals of the compound of formula (I) are first dried at 20-30°C and then dried at 65-75°C.

7. A method for preparing crystals of a compound of formula (I) II, said method including but not limited to: The compound of formula (I) was dissolved in a solvent, and then slowly evaporated at room temperature to precipitate crystals. The precipitated crystals were then separated and dried to obtain the target crystals. Preferably, the solvent is selected from one or two of water and ketones; Preferably, the solvent is selected from one or both of water and acetone; Preferably, when the solvent is water or acetone, the volume ratio of water to acetone in the solvent is 1:1 to 1:5; Preferably, the weight-to-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:5-1:15; preferably, the weight-to-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:

10. Preferably, the compound of formula (I) can crystallize under cooling or room temperature conditions; preferably, the temperature can be selected from room temperature; Preferably, the crystals of the compound of formula (I) are dried at 35-45°C.

8. A method for preparing crystals III of a compound of formula (I), said method including but not limited to: The compound of formula (I) is dissolved in a solvent, and then slowly evaporated at room temperature or crystals are precipitated by cooling. The precipitated crystals are then separated and dried to obtain the target crystal. Preferably, the solvent is selected from one or more of water, alcohols, esters, and ketones; Preferably, the solvent is selected from one or more of water, methanol, ethanol, tert-butanol, acetone, butanone, and isopropyl acetate; Preferably, when the solvent is water or acetone, the volume ratio of water to acetone in the solvent is 1:1 to 1:5; Preferably, the weight-to-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:1 to 1:10; Preferably, the compound of formula (I) can crystallize under cooling or room temperature conditions; preferably, the temperature can be selected from 10-20°C; Preferably, the crystals of the compound of formula (I) are dried at 20-30°C.

9. A method for preparing crystals IV of a compound of formula (I), said method including but not limited to: The compound of formula (I) was dissolved in a solvent, and then crystals were precipitated by cyclic shaking with heating and cooling. The precipitated crystals were then separated and dried to obtain the target crystal. Preferably, the solvent is selected from alcohols; Preferably, the solvent is selected from one or more of methanol, ethanol, isopropanol, and tert-butanol; Preferably, the weight-to-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:8-1:20; Preferably, the crystallization temperature is achieved by cyclic shaking at (35-45℃) / (10-20℃); preferably, the crystallization temperature is achieved by cyclic shaking at 40℃ / 15℃. Preferably, the crystals IV of compound (I) are dried at 20-30°C.

10. A method for preparing crystals V of a compound of formula (I), said method including but not limited to: (1) Dissolve the compound of formula (I) in a solvent to form a clear solution. (2) Crystals precipitate under stirring or static conditions; Preferably, the solvent is selected from one or two of water and ketones; Preferably, the solvent is selected from one or two of water and acetone; more preferably, the solvent is water or acetone. Preferably, the weight-volume ratio (g / mL) of the compound of formula (I) to the solvent is 1:10-1:35, more preferably 1:15-1:20; Preferably, the volume ratio of water to acetone in the solvent is 1:10-1:20; more preferably, the volume ratio of water to acetone is 1:15-1:

20. Preferably, the dissolution of the compound of formula (I) in a solvent can be carried out at a rising temperature; more preferably, the temperature is the reflux temperature; Preferably, the compound of formula (I) can crystallize under cooling conditions; preferably, the temperature can be selected from -5 to 20°C, and more preferably from 0 to 10°C; Preferably, the crystal V of compound (I) is first dried at 20-30°C and then dried at 45-55°C.

11. A pharmaceutical composition, characterized in that, It contains any one or more of crystal I, crystal II, crystal III, crystal IV, and crystal V as described in claims 1-5, and one or more pharmaceutically acceptable carriers.

12. Use of any one or more of the crystals I, II, III, IV or V of the compound of formula (I) according to any one of claims 1-5 or 9, or a pharmaceutical composition thereof, in the preparation of a medicament for heart failure, cirrhosis, syndrome of abnormal secretion of antidiuretic hormone, hyponatremia, polycystic kidney disease, ascites, and chronic kidney disease.

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