Crystalline forms of emracidine, their preparation method and use

Abstract

The present invention relates to a crystalline form of emraclidine (hereinafter referred to as "Compound I"), a process for its preparation, pharmaceutical compositions containing the crystalline form, and the use of the crystalline form in the preparation of M4 receptor modulator drugs and medicaments for treating schizophrenia. TIFF2025530462000027.tif29168

Description

[Technical Field]

[0001] The present invention relates to the field of crystal chemistry. In particular, the present invention relates to crystalline forms of emracidine, and methods for their preparation and use. [Background technology]

[0002] Schizophrenia is a serious, complex, and debilitating mental health disorder characterized by a range of symptoms including delusions, hallucinations, speech or behavioral disorders, slowness of mind, and blunted affect.

[0003] Emracidine (CVL-231), developed by Cerevel Therapeutics, is a positive allosteric modulator (PAM) that selectively targets the muscarinic acetylcholine 4 (M4) receptor for the treatment of schizophrenia. Following its Phase 1b clinical results, emracidine has demonstrated clinically significant antipsychotic activity compared to placebo.

[0004] Emracidine has the chemical name 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethanone (hereinafter referred to as "Compound I"), and the compound is disclosed in WO2018002760A1. Compound I has the following chemical formula:

[0005] [ka]

[0006] The occurrence of drug polymorphism in the development of small molecule drugs is well known in the art. Drug polymorphism is a common phenomenon in drug development and research and is an important factor affecting drug quality. A crystal is a solid, and a crystal lattice is formed by a three-dimensional ordered arrangement of compound molecules in the microstructure. Polymorphism refers to the phenomenon in which a compound has multiple crystalline forms. A compound may exist in one or more crystalline forms, but the existence and properties of crystalline forms cannot be clearly predicted. Drug substances with different crystalline forms have different physicochemical properties, including chemical stability, thermal stability, solubility, hygroscopicity, and / or particle size. These different physicochemical properties may result in different dissolution and absorption of the drug in vivo, thereby affecting the clinical efficacy of the drug to some extent. Furthermore, drug substances with different crystalline forms have different manufacturability, including yield, purification, filtration, drying, and grinding properties, and stability under pressure during tableting, which may affect processing during drug production. As a result, polymorphism is important in drug research and quality control. For these reasons, there is a need to find solid forms of Compound I.

[0007] The inventors of the present application have unexpectedly found that the crystals of Compound I provided by the present invention have good physicochemical stability under mechanical force, good stability and low hygroscopicity, which are important for developing drugs containing Compound I. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2018 / 002760 Summary of the Invention [Problem to be solved by the invention]

[0009] (Summary of the Invention) The present invention provides crystals of Compound I, methods for their preparation, pharmaceutical compositions containing the crystals, and uses thereof. [Means for solving the problem]

[0010] In accordance with the objectives of the present invention, the present invention provides crystalline form CSI of Compound I (hereinafter referred to as "crystalline form CSI").

[0011] In one embodiment, the powder X-ray diffraction pattern of crystalline form CSI using Cu-Kα radiation contains characteristic peaks at one, two, or three of the following diffraction angle 2θ values: 11.9°±0.2°, 5.9°±0.2°, and 9.5°±0.2°; and preferably, the powder X-ray diffraction pattern of crystalline form CSI contains characteristic peaks at diffraction angle 2θ values: 11.9°±0.2°, 5.9°±0.2°, and 9.5°±0.2°.

[0012] Furthermore, the powder X-ray diffraction pattern of crystalline form CSI using Cu-Kα radiation contains characteristic peaks at one, two, or three of the diffraction angle 2θ values ​​of 10.7°±0.2°, 14.1°±0.2°, and 22.2°±0.2°, and preferably the powder X-ray diffraction pattern of crystalline form CSI contains characteristic peaks at the diffraction angle 2θ values ​​of 10.7°±0.2°, 14.1°±0.2°, and 22.2°±0.2°.

[0013] Furthermore, the powder X-ray diffraction pattern of crystalline form CSI using Cu-Kα radiation contains characteristic peaks at one, two, or three of the diffraction angle 2θ values ​​of 10.4°±0.2°, 16.3°±0.2°, and 19.1°±0.2°, and preferably the powder X-ray diffraction pattern of crystalline form CSI contains characteristic peaks at the diffraction angle 2θ values ​​of 10.4°±0.2°, 16.3°±0.2°, and 19.1°±0.2°.

[0014] In another embodiment, the powder X-ray diffraction pattern of crystalline form CSI using Cu-Kα radiation comprises characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or ten, or eleven, or twelve, or thirteen of the following diffraction angle 2θ values: 11.9±0.2°, 5.9°±0.2°, 9.5°±0.2°, 10.7°±0.2°, 14.1°±0.2°, 22.2°±0.2°, 10.4°±0.2°, 16.3°±0.2°, 19.1°±0.2°, 27.1°±0.2°, 21.0°±0.2°, 26.7°±0.2°, and 21.5°±0.2°.

[0015] Without limitation, the powder X-ray diffraction pattern of crystalline form CSI using Cu-Kα radiation is substantially as shown in FIG.

[0016] In accordance with the objectives of the present invention, the present invention also provides a method for preparing crystalline form CSI, which method comprises dissolving Compound I in a ketone solvent and obtaining crystalline form CSI via volatilization.

[0017] Furthermore, the volatilization temperature is preferably -20°C to 50°C.

[0018] In accordance with the objectives of the present invention, the present invention provides a crystalline form of Compound I, including, but not limited to, Compound I being crystalline form CSII (hereinafter referred to as "crystalline form CSII").

[0019] In one embodiment, the powder X-ray diffraction pattern of crystalline form CSII using Cu-Kα radiation contains characteristic peaks at one, two, or three of the following diffraction angle 2θ values: 12.8°±0.2°, 19.8°±0.2°, and 24.4°±0.2°; and preferably, the powder X-ray diffraction pattern of crystalline form CSII contains characteristic peaks at the diffraction angle 2θ values ​​of 12.8°±0.2°, 19.8°±0.2°, and 24.4°±0.2°.

[0020] Furthermore, the powder X-ray diffraction pattern of crystalline form CSII using Cu-Kα radiation contains characteristic peaks at one, two, or three of the diffraction angle 2θ values ​​of 21.5°±0.2°, 22.5°±0.2°, and 23.3°±0.2°, and preferably the powder X-ray diffraction pattern of crystalline form CSII contains characteristic peaks at the diffraction angle 2θ values ​​of 21.5°±0.2°, 22.5°±0.2°, and 23.3°±0.2°.

[0021] Furthermore, the powder X-ray diffraction pattern of crystalline form CSII using Cu-Kα radiation contains characteristic peaks at one, two, or three of the diffraction angle 2θ values ​​of 19.2°±0.2°, 20.8°±0.2°, and 25.8°±0.2°, and preferably the powder X-ray diffraction pattern of crystalline form CSII contains characteristic peaks at the diffraction angle 2θ values ​​of 19.2°±0.2°, 20.8°±0.2°, and 25.8°±0.2°.

[0022] In another embodiment, the powder X-ray diffraction pattern of crystalline form CSII using Cu-Kα radiation comprises characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or ten, or eleven, or twelve, or thirteen of the following diffraction angle 2θ values: 12.8°±0.2°, 19.8°±0.2°, 24.4°±0.2°, 21.5°±0.2°, 22.5°±0.2°, 23.3°±0.2°, 19.2°±0.2°, 20.8°±0.2°, 25.8°±0.2°, 6.4°±0.2°, 9.0°±0.2°, 14.6°±0.2°, and 16.3°±0.2°.

[0023] Without limitation, the powder X-ray diffraction pattern of crystalline form CSII using Cu-Kα radiation is substantially as shown in FIG.

[0024] Without limitation, the thermogravimetric analysis thermogram of crystalline form CSII shows essentially no weight loss when heated from room temperature to 180° C. as shown in FIG.

[0025] Without limitation, the differential scanning calorimetry thermogram of crystalline form CSII is substantially as shown in Figure 4, with an endothermic peak beginning at about 183°C, which is the melting endothermic peak.

[0026] Without limitation, crystalline form CSII is anhydrous.

[0027] According to the object of the present invention, the present invention also provides a method for preparing crystalline form CSII, which method includes: putting compound I into a mixed system of methyl t-butyl ether and alcohol, and stirring to obtain crystalline form CSII.

[0028] Furthermore, the alcohol is preferably methanol, the stirring temperature is preferably 0°C to 50°C, and the stirring time is preferably 1 to 10 days.

[0029] In accordance with the objectives of the present invention, the present invention provides a crystalline form of Compound I, including, but not limited to, Compound I being crystalline form CSIII (hereinafter referred to as "crystalline form CSIII").

[0030] In one embodiment, the powder X-ray diffraction pattern of crystalline form CSIII using Cu-Kα radiation contains characteristic peaks at one, two, or three of the following diffraction angle 2θ values: 12.5°±0.2°, 6.2°±0.2°, 18.8°±0.2°, and 17.5°±0.2°; and preferably, the powder X-ray diffraction pattern of crystalline form CSIII contains characteristic peaks at the following diffraction angle 2θ values: 12.5°±0.2°, 6.2°±0.2°, 18.8°±0.2°, and 17.5°±0.2°.

[0031] Furthermore, the powder X-ray diffraction pattern of crystalline form CSIII using Cu-Kα radiation contains characteristic peaks at one or two of the diffraction angle 2θ values ​​of 18.1°±0.2° and 21.7°±0.2°, and preferably the powder X-ray diffraction pattern of crystalline form CSIII contains characteristic peaks at the diffraction angle 2θ values ​​of 18.1°±0.2° and 21.7°±0.2°.

[0032] In another embodiment, the powder X-ray diffraction pattern of crystalline form CSIII using Cu-Kα radiation comprises characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight diffraction angle 2θ values ​​of 12.5°±0.2°, 6.2°±0.2°, 18.8°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 21.7°±0.2°, 11.6°±0.2°, and 24.2±0.2°.

[0033] Without limitation, the powder X-ray diffraction pattern of crystalline form CSIII using Cu-Kα radiation is substantially as shown in FIG.

[0034] Without limitation, the thermogravimetric analysis thermogram of crystalline form CSIII shows essentially no weight loss when heated from room temperature to 170° C. as shown in FIG.

[0035] Without limitation, crystalline form CSIII is anhydrous.

[0036] According to the object of the present invention, the present invention also provides a method for preparing crystalline form CSIII, which method comprises dissolving compound I in a mixed solvent of ether and alkane, and obtaining crystalline form CSIII through volatilization.

[0037] Furthermore, the ether is preferably tetrahydrofuran, the alkane is preferably n-heptane, and the evaporation temperature is preferably 40 to 60°C.

[0038] In accordance with the purpose of the present invention, the present invention provides a crystalline form of Compound I, including, but not limited to, Compound I being crystalline form CSIV (hereinafter referred to as "crystalline form CSIV").

[0039] In one aspect, the powder X-ray diffraction pattern of crystalline form CSIV using Cu-Kα radiation contains characteristic peaks at one, two, three, or four of the following diffraction angle 2θ values: 13.0°±0.2°, 16.4°±0.2°, 23.1°±0.2°, and 22.0°±0.2°; and preferably, the powder X-ray diffraction pattern of crystalline form CSIV contains characteristic peaks at the following diffraction angle 2θ values: 13.0°±0.2°, 16.4°±0.2°, 23.1°±0.2°, and 22.0°±0.2°.

[0040] Furthermore, the powder X-ray diffraction pattern of crystalline form CSIV using Cu-Kα radiation contains characteristic peaks at one, two, or three of the diffraction angle 2θ values ​​of 24.0°±0.2°, 14.2°±0.2°, and 17.2°±0.2°, and preferably the powder X-ray diffraction pattern of crystalline form CSIV contains characteristic peaks at the diffraction angle 2θ values ​​of 24.0°±0.2°, 14.2°±0.2°, and 17.2°±0.2°.

[0041] Furthermore, the powder X-ray diffraction pattern of crystalline form CSIV using Cu-Kα radiation exhibits characteristic peaks at one, two, or three of the diffraction angle 2θ values ​​of 18.1°±0.2°, 20.8°±0.2°, and 27.2°±0.2°, and preferably the powder X-ray diffraction pattern of crystalline form CSIV includes characteristic peaks at the diffraction angle 2θ values ​​of 18.1°±0.2°, 20.8°±0.2°, and 27.2°±0.2°.

[0042] In another embodiment, the powder X-ray diffraction pattern of crystalline form CSIV comprises characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or ten diffraction angle 2θ values ​​of 13.0°±0.2°, 16.4°±0.2°, 23.1°±0.2°, 22.0°±0.2°, 24.0°±0.2°, 14.2°±0.2°, 17.2°±0.2°, 18.1°±0.2°, 20.8°±0.2°, 27.2°±0.2°, 6.5°±0.2°, 8.6°±0.2°, 11.5, 20.0°±0.2°, 20.4°±0.2°, and 26.4°±0.2°.

[0043] Without limitation, the powder X-ray diffraction pattern of crystalline form CSIV using Cu-Kα radiation is substantially as shown in FIG.

[0044] Without limitation, the thermogravimetric analysis thermogram of crystalline form CSIV shows essentially no weight loss when heated from room temperature to 180° C. as shown in FIG.

[0045] Without limitation, crystalline form CSIV is anhydrous.

[0046] In accordance with the objectives of the present invention, the present invention also provides a method for preparing crystalline form CSIV, the method comprising heating compound I to 185°C-190°C to obtain crystalline form CSIV.

[0047] In accordance with the purpose of the present invention, the present invention provides a crystalline form of Compound I, which is, but is not limited to, crystalline form CSV (hereinafter referred to as "crystalline form CSV").

[0048] In one embodiment, the powder X-ray diffraction pattern of crystalline form CSV using Cu-Kα radiation contains characteristic peaks at one, two, three, or four of the following diffraction angle 2θ values: 10.3°±0.2°, 19.2°±0.2°, 13.5°±0.2°, and 14.5°±0.2°; and preferably, the powder X-ray diffraction pattern of crystalline form CSV contains characteristic peaks at the following diffraction angle 2θ values: 10.3°±0.2°, 19.2°±0.2°, 13.5°±0.2°, and 14.5°±0.2°.

[0049] Furthermore, the powder X-ray diffraction pattern of crystalline form CSV using Cu-Kα radiation contains characteristic peaks at one or two of the diffraction angle 2θ values ​​of 18.1°±0.2° and 20.0°±0.2°, and preferably the powder X-ray diffraction pattern of crystalline form CSV contains characteristic peaks at the diffraction angle 2θ values ​​of 18.1°±0.2° and 20.0°±0.2°.

[0050] Furthermore, the powder X-ray diffraction pattern of crystalline form CSV using Cu-Kα radiation contains characteristic peaks at one or two of the diffraction angle 2θ values ​​of 20.6°±0.2° and 12.5°±0.2°, and preferably the powder X-ray diffraction pattern of crystalline form CSV contains characteristic peaks at diffraction angle 2θ values ​​of 20.6°±0.2° and 12.5°±0.2°.

[0051] In another embodiment, the powder X-ray diffraction pattern of crystalline form CSV comprises characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine diffraction angle 2θ values ​​of 10.3°±0.2°, 19.2°±0.2°, 13.5°±0.2°, 14.5°±0.2°, 18.1°±0.2°, 20.0°±0.2°, 20.6°±0.2°, 12.5°±0.2°, 11.5°±0.2°, 24.9°±0.2°, 25.4°±0.2°, 22.5°±0.2°, 22.0°±0.2°, 23.2°±0.2°, and 30.7°±0.2°.

[0052] Although not limiting, the powder X-ray diffraction pattern of crystalline form CSV using Cu-Kα radiation is substantially as shown in FIG.

[0053] Without limitation, the thermogravimetric analysis thermogram of crystalline form CSV, as shown in Figure 10, shows a substantial weight loss of about 3.8% when heated from 35°C to 150°C.

[0054] According to the object of the present invention, the present invention also provides a method for preparing crystalline form CSV, which method comprises: placing Compound I in a mixed system of dimethyl sulfoxide and water, and stirring it to obtain crystalline form CSV.

[0055] Furthermore, the stirring temperature is preferably 0° C. to 50° C., more preferably 25° C. to 50° C. The stirring time is preferably 1 to 10 days, more preferably 4 to 6 days.

[0056] In accordance with the objectives of the present invention, the present invention provides the use of crystalline forms CSI, CSII, CSIII, CSIV and / or CSV in the preparation of other crystalline forms or co-crystals of Compound I and salts thereof.

[0057] Additionally, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of crystalline forms CSI, CSII, CSIII, CSIV and / or CSV and a pharmaceutically acceptable excipient.

[0058] Further, in accordance with the object of the present invention, the present invention provides the use of crystalline forms CSI, CSII, CSIII, CSIV and / or CSV in the preparation of an M4 receptor modulator drug.

[0059] Further, in accordance with the object of the present invention, the present invention provides the use of crystalline forms CSI, CSII, CSIII, CSIV and / or CSV in the preparation of a medicament for the treatment of schizophrenia.

[0060] Advantageous Properties of the Crystalline Forms Provided by the Invention The crystalline form CSI provided by the present invention has the following excellent properties:

[0061] (1) Both the crystalline form CSI drug substance and formulations provided in the present invention have good physicochemical stability. The crystalline form CSI drug substance provided in the present invention is stable for at least six months under conditions of 40°C / 75% RH and has a purity that remains substantially unchanged during storage. A formulation formed by combining and stirring the crystalline form CSI of the present invention with excipients is stable for at least one month under conditions of 25°C / 60% RH and 40°C / 75% RH and has a purity that remains substantially unchanged during storage. The crystalline form CSI drug substance shows no significant changes in sample properties and no change in crystalline form after humidity cycling of 30%-90%-0%-90% RH.

[0062] Environmental factors, such as high temperature and humidity caused by seasonal variations and differences in climate in different regions, can affect the storage, transportation, and production of active ingredients, as well as formulations. The crystalline CSI active ingredients and formulations have good physicochemical stability, which is effective in preventing the impact on drug quality caused by crystal transformation or a decrease in purity during drug storage.

[0063] (2) The crystalline form CSI provided by the present invention allows for a small amount of weight gain due to hygroscopicity. The weight gain due to hygroscopicity of crystalline form CSI under conditions of 30% to 80% RH is 0.36%. Strong hygroscopicity tends to cause chemical decomposition and crystalline transformation of the drug substance, thereby affecting the physicochemical stability of the drug substance. At the same time, highly hygroscopic drugs impose higher demands on manufacturing. A crystalline form with low hygroscopicity does not require strict environmental requirements, thereby reducing the costs of substance manufacturing, storage, and quality control, and is economically beneficial.

[0064] (3) The crystalline form CSI provided by the present invention provides good physical stability under mechanical force. The crystalline form of the crystalline form CSI drug substance remains unchanged even after grinding and formulation. The drug substance is often ground or pulverized during formulation processing, and good physical stability can reduce the risk of a decrease in crystallinity and crystalline transformation of the drug substance during formulation processing. Furthermore, the crystalline form CSI drug substance also has good physical stability under pressure, which is effective for stabilizing the crystalline form during the tableting process of the formulation.

[0065] Crystalline Form CSII provided by the present invention has the following excellent properties:

[0066] (1) Both the crystalline form CSII drug substance and formulations provided by the present invention have good physicochemical stability. Crystalline form CSII drug substance is stable for at least six months under conditions of 25°C / 60% RH and 40°C / 75% RH, and for at least one month under conditions of 60°C / 75% RH, and has substantially unchanged purity during storage. Formulations formed by combining crystalline form CSII of the present invention with excipients and stirring them are stable for at least one month under conditions of 25°C / 60% RH and 40°C / 75% RH, and have substantially unchanged purity during storage. Crystalline form CSII drug substance shows no significant changes in sample properties, and no change in crystalline form after humidity cycling of 0%-90%-0% RH.

[0067] Environmental factors, such as high temperature and humidity caused by seasonal variations and differences in climate in different regions, can affect the storage, transportation, and production of the drug substance, as well as the formulation. Crystalline Form CSII drug substance and formulations have good physicochemical stability, which is effective in preventing the impact on drug quality due to crystal transformation or a decrease in purity during drug storage.

[0068] (2) The crystalline form CSII provided by the present invention allows for a small amount of weight gain due to hygroscopicity. The weight gain due to hygroscopicity of crystalline form CSII under conditions of 0% to 80% RH is 0.28%. Strong hygroscopicity tends to cause chemical decomposition and crystalline transformation of the drug substance, thereby affecting the physicochemical stability of the drug substance. At the same time, highly hygroscopic drugs impose higher requirements on manufacturing. A crystalline form with low hygroscopicity does not require strict environmental requirements, thereby reducing the costs of substance manufacturing, storage, and quality control, and is economically beneficial.

[0069] (3) Crystalline Form CSII provided by the present invention provides good physical stability under mechanical force. The crystalline form of crystalline Form CSII drug substance remains unchanged even after grinding and formulation. Drug substances are often ground or pulverized during formulation processing, and good physical stability can reduce the risk of a decrease in crystallinity and crystalline transformation of the drug substance during formulation processing. Furthermore, crystalline Form CSII drug substance also has good physical stability under pressure, which is effective for stabilizing the crystalline form during the tableting process of the drug substance.

[0070] Crystalline form CSIII provided by the present invention has the following excellent properties:

[0071] (1) The crystalline form CSIII drug substance provided by the present invention has good physicochemical stability. The crystalline form CSIII drug substance provided by the present invention is stable for at least two months under conditions of 40°C / 75% RH. The crystalline form CSI drug substance shows no significant changes in sample properties and no change in crystalline form after humidity cycling from 0%-90%-0% RH.

[0072] Environmental factors, such as high temperature and humidity caused by seasonal variations and differences in climate in different regions, can affect the storage, transportation, production, and formulation of the drug substance. Crystalline Form CSIII drug substance has good physicochemical stability, which is effective in preventing the impact on drug quality caused by crystal transformation or a decrease in purity during drug storage.

[0073] (2) The crystalline form CSIII provided by the present invention allows for a small amount of weight gain due to hygroscopicity. The weight gain due to hygroscopicity of crystalline form CSIII under conditions of 0% to 80% RH is 0.21%. Strong hygroscopicity tends to cause chemical decomposition and crystal transformation of the drug substance, thereby affecting the physicochemical stability of the drug substance. At the same time, strongly hygroscopic drugs impose higher requirements on manufacturing. A crystalline form with low hygroscopicity does not require strict environmental requirements, thereby reducing the costs of substance production, storage, and quality control, and is economically beneficial.

[0074] (3) Crystalline Form CSIII provided by the present invention provides good physical stability under mechanical force. The crystalline form of Crystalline Form CSIII drug substance remains unchanged even after grinding. Drug substances are often ground or pulverized during pharmaceutical processing, and good physical stability can reduce the risk of a decrease in crystallinity and crystal transformation of the drug substance during pharmaceutical processing.

[0075] Crystalline Form CSIV provided by the present invention has the following excellent properties:

[0076] (1) The crystalline form CSIV drug substance provided by the present invention has good physicochemical stability. The crystalline form CSIV drug substance of the present invention is stable for at least six months under conditions of 25°C / 60% RH and 40°C / 75% RH, and for at least one month under conditions of 60°C / 75% RH. The crystalline form CSIV drug substance shows no significant changes in sample properties and no change in crystalline form after humidity cycling of 0%-90%-0% RH.

[0077] Environmental factors, such as high temperature and humidity caused by seasonal variations and differences in climate in different regions, can affect the storage, transportation, production, and formulation of the drug substance. Crystalline Form CSIV drug substance has good physicochemical stability, which is effective in preventing the impact on drug quality caused by crystal transformation or a decrease in purity during drug storage.

[0078] (2) The crystalline form CSIV provided by the present invention allows for a small amount of weight gain due to hygroscopicity. The weight gain due to hygroscopicity of crystalline form CSIV at 0% to 80% RH is 0.11%. Strong hygroscopicity tends to cause chemical decomposition and crystalline transformation of the drug substance, thereby affecting the physicochemical stability of the drug substance. At the same time, strongly hygroscopic drugs impose higher requirements on manufacturing. A crystalline form with low hygroscopicity does not require strict environmental requirements, thereby reducing the costs of substance manufacturing, storage, and quality control, and is economically beneficial.

[0079] (3) Crystalline Form CSIV provided by the present invention provides good physical stability under mechanical force. The crystalline form of the drug substance of Crystalline Form CSIV remains unchanged even after grinding. Drug substances are often ground or pulverized during pharmaceutical processing, and good physical stability can reduce the risk of a decrease in crystallinity and crystal transformation of the drug substance during pharmaceutical processing.

[0080] The crystalline form CSV provided by the present invention has the following excellent properties:

[0081] (1) Both the crystalline CSV drug substance and formulations provided by the present invention have good physicochemical stability. The crystalline CSV drug substance of the present invention is stable for at least six months under conditions of 25°C / 60% RH and 40°C / 75% RH, and for at least two months under conditions of 60°C / 75% RH. Formulations formed by combining the crystalline CSV drug substance of the present invention with excipients and stirring them are stable for at least one month under conditions of 25°C / 60% RH and 40°C / 75% RH, and have substantially unchanged purity during storage. The crystalline CSV drug substance shows no significant changes in sample properties, and no change in crystalline form after humidity cycling of 30%-90%-0%-90% RH.

[0082] Environmental factors, such as high temperature and humidity caused by seasonal variations and differences in climate in different regions, can affect the storage, transportation, production, and formulation of the drug substance. The crystalline CSV drug substance has good physicochemical stability, which is effective in preventing the impact on drug quality due to crystal transformation or a decrease in purity during drug storage.

[0083] (2) The crystalline form CSV provided by the present invention allows for a small amount of weight gain due to hygroscopicity. The weight gain due to hygroscopicity of the crystalline form CSV at 30% to 80% RH is 0.29%. Strong hygroscopicity tends to cause chemical decomposition and crystalline transformation of the drug substance, thereby affecting the physicochemical stability of the drug substance. At the same time, highly hygroscopic drugs impose higher requirements on manufacturing. A crystalline form with low hygroscopicity does not require strict environmental requirements, thereby reducing the costs of substance production, storage, and quality control, and is economically beneficial.

[0084] (3) The CSV crystalline form provided by the present invention provides good physical stability under mechanical force. The crystalline form of the CSV crystalline form drug substance remains unchanged even after grinding and formulation. Drug substances are often ground or pulverized during formulation processing, and good physical stability can reduce the risk of a decrease in crystallinity and crystalline transformation of the drug substance during formulation processing. Furthermore, the CSV crystalline form drug substance also has good physical stability under pressure, which is effective for stabilizing the crystalline form during the tableting process of the drug substance. [Brief explanation of the drawings]

[0085] [Figure 1] 1 shows the XRPD pattern of crystalline form CSI. [Figure 2] 1 shows the XRPD pattern of crystalline form CSII. [Figure 3] 1 shows a TGA thermogram of crystalline form CSII. [Figure 4] 1 shows a DSC thermogram of crystalline form CSII. [Figure 5] 1 shows the XRPD pattern of crystalline form CSIII. [Figure 6] 1 shows a TGA thermogram of crystalline form CSIII. [Figure 7] 1 shows the XRPD pattern of crystalline form CSIV. [Figure 8] 1 shows a TGA thermogram of crystalline form CSIV. [Figure 9] 1 shows the XRPD pattern of crystalline form CSV. [Figure 10] 1 shows a TGA thermogram of crystalline form CSV. [Figure 11] 1 shows a comparison of the XRPD patterns of crystalline form CSI before and after storage at 40° C. / 75% RH for a period of time (from bottom to top: pattern before and pattern after storage (open package) at 40° C. / 75% RH for 6 months). [Figure 12] 1 shows a comparison of the XRPD patterns of crystalline form CSI before and after ball milling (from bottom to top: pattern before ball milling and pattern after ball milling). [Figure 13] 1 shows the DVS pattern of crystalline form CSI. [Figure 14] 1 shows the XRPD patterns of crystalline form CSI and the formulation (from bottom to top: the pattern of crystalline form CSI bulk substance, the pattern of crystalline form CSI after formulation processing, and the pattern after excipient mixing and formulation processing). [Figure 15] 1 shows a comparison of XRPD patterns of crystalline form CSI formulations stored under different conditions (from bottom to top: pattern before storage, pattern after 1 month storage at 25° C. / 60% RH, and pattern after 1 month storage at 40° C. / 75% RH). [Figure 16] A comparison of the XRPD patterns of crystalline form CSII before and after storage under different conditions for different periods of time is shown (from bottom to top: pattern before storage, pattern after 6 months of storage at 25°C / 60%RH, pattern after 6 months of storage at 40°C / 75%RH, and pattern after 1 month of storage at 60°C / 75%RH). [Figure 17] 1 shows a comparison of the XRPD patterns of crystalline form CSII before and after ball milling (from bottom to top: pattern before ball milling and pattern after ball milling). [Figure 18] 1 shows the DVS pattern of crystalline form CSII. [Figure 19] 1 shows the XRPD patterns of crystalline form CSII and the formulation (from bottom to top: the pattern of crystalline form CSII drug substance, the pattern of crystalline form CSII after formulation processing, and the pattern after excipient mixing and formulation processing). [Figure 20] 1 shows a comparison of XRPD patterns of crystalline form CSII formulations stored under different conditions (from bottom to top: pattern before storage, pattern after 1 month storage at 25° C. / 60% RH, and pattern after 1 month storage at 40° C. / 75% RH). [Figure 21] 1 shows a comparison of the XRPD patterns of crystalline form CSIII before and after storage at 40° C. / 75% RH for a period of time (from bottom to top: pattern before storage and pattern after storage at 40° C. / 75% RH for 2 months (sealed packaging)). [Figure 22] 1 shows a comparison of the XRPD patterns of crystalline form CSIII before and after ball milling (from bottom to top: pattern before ball milling and pattern after ball milling). [Figure 23] DVS pattern of crystalline form CSIII is shown. [Figure 24] A comparison of the XRPD patterns of crystalline form CSIV before and after storage under different conditions for different periods of time is shown (from bottom to top: pattern before storage, pattern after 6 months of storage at 25°C / 60%RH, pattern after 6 months of storage at 40°C / 75%RH, and pattern after 1 month of storage at 60°C / 75%RH). [Figure 25] 1 shows a comparison of the XRPD patterns of crystalline form CSIV before and after ball milling (from bottom to top: pattern before ball milling and pattern after ball milling). [Figure 26] 1 shows the DVS pattern of crystalline form CSIV. [Figure 27] A comparison of the XRPD patterns of crystalline form CSV before and after storage for different periods under different conditions is shown (from bottom to top: pattern before storage, pattern after 6 months of storage at 25°C / 60%RH, pattern after 6 months of storage at 40°C / 75%RH, and pattern after 2 months of storage at 60°C / 75%RH (sealed packaging)). [Figure 28] A comparison of the XRPD patterns of crystalline form CSV before and after ball milling is shown (from bottom to top: pattern before ball milling and pattern after ball milling). [Figure 29]1 shows the DVS pattern of the crystalline form CSV. [Figure 30] 1 shows the XRPD patterns of crystalline form CSV and the formulation (from bottom to top: the pattern of crystalline form CSV bulk substance, the pattern of crystalline form CSI after formulation processing, and the pattern after excipient mixing and formulation processing). [Figure 31] A comparison of XRPD patterns of crystalline CSV formulations stored under different conditions is shown (from bottom to top: pattern before storage, pattern after 1 month storage at 25°C / 60% RH, and pattern after 1 month storage at 40°C / 75% RH). DETAILED DESCRIPTION OF THE INVENTION

[0086] The present invention will now be described in detail with reference to the following embodiments, which provide detailed descriptions of methods for preparing and using the crystalline forms of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the invention.

[0087] The abbreviations used in this invention are explained below.

[0088] XRPD: X-ray powder diffraction TGA: Thermogravimetric analysis DSC: Differential scanning calorimetry DVS: Dynamic Water Sorption HPLC: High-performance liquid chromatography RH: Relative humidity

[0089] Apparatus and method for collecting data The powder X-ray diffraction patterns described in this invention are collected by a Bruker powder X-ray diffractometer. The parameters of the powder X-ray diffraction method according to this invention are as follows:

[0090] X-ray light source: Cu, Kα Kα1(Å)>1.54060:Kα2(Å)1.54439 Kα2 / Kα1 intensity ratio: 0.50

[0091] The thermogravimetric analysis (TGA) patterns described in this invention are collected by a TA Q500. The parameters of the thermogravimetric analysis (TGA) method described in this invention are as follows:

[0092] Scan speed: 10℃ / min Protective gas: N2

[0093] The differential scanning calorimetry (DSC) pattern of the present invention is collected by a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) according to the present invention are as follows:

[0094] Scan rate: 10°C / min Protective gas: N2

[0095] The experimental dynamic moisture sorption (DVS) patterns are collected by an intrinsic dynamic moisture sorption device manufactured by SMS (Surface Measurement Systems Ltd.). The device control software is DVS-Intrinsic Control Software. The method parameters of the dynamic moisture sorption device are as follows:

[0096] Temperature: 25℃ Carrier gas and flow rate: N2 and 200 ml / min Mass change per unit time: 0.002% / min Relative humidity range: 0%RH~95%RH

[0097] The test methods for the relevant substances in the present invention are shown in Table 1.

[0098] [Table 1]

[0099] In the present invention, "drying" is carried out by a conventional method in the art, such as vacuum drying, blow drying, or air drying. The drying temperature may be room temperature or higher, preferably room temperature to about 60°C, or room temperature to 50°C, or room temperature to 40°C. The drying time may be 2 to 48 hours, or may be overnight. Drying is carried out in a draft device, forced air oven, or vacuum oven.

[0100] "Volatilization" is carried out by conventional methods in the art, such as slow evaporation or fast evaporation. Slow evaporation refers to evaporation in a container that is sealed with a sealing film that is punctured for evaporation and left to stand. Fast evaporation refers to evaporation in a container that is open for evaporation.

[0101] "Room temperature" does not refer to a specific temperature value, but rather to a temperature range of 10 to 30°C.

[0102] "Stirring" is carried out by a conventional method in the art, for example, by magnetic stirring or mechanical stirring at a stirring speed of 50 to 1800 rpm, with the magnetic stirring speed being preferably 300 to 900 rpm and the mechanical stirring speed being preferably 100 to 300 rpm.

[0103] "Separation" is carried out by conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation includes placing a sample in a centrifuge tube to be separated and centrifuging at 10,000 rpm until all solids settle to the bottom of the centrifuge tube.

[0104] "Characteristic peak" means a typical diffraction peak used to identify a crystal, and the peak position may typically have an error of ±0.2° when Cu-Kα radiation is used.

[0105] In the present invention, "amorphous" refers to a non-crystalline substance that lacks long-range regularity, and its X-ray powder diffractogram typically shows a relatively broad "bun-shaped peak."

[0106] In the present invention, "crystals" or "crystalline forms" can be characterized by powder X-ray diffraction. Those skilled in the art will appreciate that powder X-ray diffraction patterns can vary depending on instrument conditions and sample preparation and purity. The relative intensities of diffraction peaks in a powder X-ray diffraction pattern can also vary depending on test conditions. As a result, diffraction peak intensities are a determining factor for determining a crystalline form, but are not the only determining factor. In practice, the relative intensities of diffraction peaks in a powder X-ray diffraction pattern are related to the preferred orientation of the crystal, and the intensities of diffraction peaks shown in the present invention are illustrative and not for absolute comparison. As a result, those skilled in the art will understand that the powder X-ray diffraction pattern of the claimed crystalline form of the present invention need not be exactly the same as the powder X-ray diffraction pattern in the embodiments herein, and that any crystalline form having a powder X-ray diffraction pattern with the same or similar characteristic peaks in these patterns is within the scope of the invention. One skilled in the art can compare the powder X-ray diffraction pattern generated in this invention with the powder X-ray diffraction pattern of an unknown crystalline form to determine whether the two patterns reflect the same or different crystalline forms.

[0107] In some embodiments, the crystalline forms CSI, CSII, CSIII, CSIV, and CSV in the present invention are single and substantially free of any other crystalline forms. As used herein, "substantially free" when used in reference to a novel crystalline form means that the crystalline form is less than 20% by weight of other crystalline forms, particularly less than 10% by weight, more particularly less than 5% by weight, and even more particularly less than 1% by weight.

[0108] As used herein, the term "about" when used to refer to a measurable numerical value, such as mass, time, temperature, etc., refers to a range of some variation around the particular numerical value, which may be in the range of ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0109] The following examples are carried out at room temperature unless otherwise specified.

[0110] The starting compound I according to the present invention may be in the form of, but not limited to, a solid (crystalline or amorphous), an oil, a liquid, or a solution. Preferably, the starting compound I is in the form of a solid.

[0111] Compound I used in the following examples can be prepared according to the methods described in the prior art, for example, WO2018002760A1, in combination with conventional salt decomposition methods in the art. [Example]

[0112] Example 1 Preparation of Crystalline Form CSI 9.5 mg of Compound I was weighed into a vial, and 0.4 mL of acetone was added to obtain a clear solution. The solution was filtered, and the filtrate was evaporated at room temperature to obtain a solid. The solid was dried under vacuum at 25°C for about 20 hours to obtain a crystalline solid.

[0113] In the test, the resulting dry solid was crystalline form CSI of the present invention, the powder X-ray diffraction pattern of which is shown in FIG. 1, and the powder X-ray diffraction data of which is shown in Table 2.

[0114] [Table 2]

[0115] Example 2: Preparation of crystalline form CSII 9.1 mg of Compound I was weighed and placed in a vial, and 0.2 mL of a mixed solvent of methanol / methyl tert-butyl ether (1:9 v / v) was added thereto. The mixture was then stirred at room temperature for approximately 68 hours, and the solid was separated by centrifugation and then vacuum-dried at 25°C for approximately 20 hours to obtain a crystalline solid.

[0116] In the test, the obtained dry solid was crystalline form CSII of the present invention, the powder X-ray diffraction pattern of which is shown in FIG. 2, and the powder X-ray diffraction data of which is shown in Table 3.

[0117] The TGA is shown in Figure 3 and shows virtually no weight loss upon heating from room temperature to 180°C.

[0118] The DSC is shown in Figure 4, with an endothermic peak beginning at about 183°C, which is the melting endothermic peak.

[0119] [Table 3] TIFF2025530462000006.tif32168

[0120] Example 3 Preparation of Crystalline Form CSIII 14.6 mg of Compound I was weighed and placed in a vial, and 2 mL of a tetrahydrofuran / n-heptane (1:1 v / v) mixed solvent was added to obtain a clear solution. The solution was filtered, and half of the filtrate was evaporated at 50°C to obtain a solid. This solid was dried under vacuum at room temperature for about 24 hours to obtain a crystalline solid. In testing, the obtained crystalline solid was identified as crystalline form CSIII of the present invention. Its powder X-ray diffraction pattern is shown in Figure 5, and its powder X-ray diffraction data is shown in Table 4.

[0121] The TGA is shown in Figure 6 and shows virtually no weight loss upon heating from room temperature to 170°C.

[0122] [Table 4]

[0123] Example 4 Preparation of Crystalline Form CSIV Compound I was heated to 190°C at 10°C / min in a nitrogen atmosphere, followed by a 1 minute hold, to obtain a crystalline solid. In testing, the resulting crystalline solid was identified as crystalline form CSIV of the present invention, and its powder X-ray diffraction pattern is shown in Figure 7, and its powder X-ray diffraction data is shown in Table 5.

[0124] The TGA is shown in Figure 8 and shows virtually no weight loss upon heating from room temperature to 180°C.

[0125] [Table 5]

[0126] [Example 5] Preparation of crystalline form CSV 3.8 mg of Compound I was weighed and placed in a vial, and 0.1 mL of a mixed solvent of dimethyl sulfoxide / water (1:1 v / v) was added. The mixture was stirred at 50°C for 4 days to obtain a crystalline solid. In the test, the obtained crystalline solid was CSV crystal form of the present invention, and its powder X-ray diffraction pattern is shown in Figure 9, and its powder X-ray diffraction data is shown in Table 6.

[0127] [Table 6] TIFF2025530462000010.tif46168

[0128] Example 6 TGA of CSV Crystal Form The TGA of the crystalline form CSV is shown in Figure 10, which shows a weight loss of 3.8% upon heating from 35 to 150°C.

[0129] Example 7: Stability of crystalline form CSI An appropriate amount of crystalline form CSI sample was packaged under corresponding packaging conditions and allowed to stand at 40°C / 75%RH for a certain period of time, and the purity and crystalline form were measured by HPLC and XRPD, the results of which are shown in Table 7. The XRPD patterns of crystalline form CSI before and after standing are shown in Figure 11.

[0130] [Table 7]

[0131] Open: The sample was placed in an open glass vial and the glass vial was left open in a corresponding environment.

[0132] The results show that the crystalline form CSI is stable for at least 6 months at 40°C / 75%RH and has good physicochemical stability.

[0133] Example 8: Stability of crystalline form CSI under mechanical force The crystalline form CSI sample was ball milled at a vibration speed of 500 rpm for 5 minutes, and the sample was measured by XRPD before and after ball milling, and the measurement results are shown in Figure 12. The crystalline form CSI does not change after ball milling.

[0134] An appropriate amount of crystalline form CSI sample was taken and pressed into tablets using a manual tablet press with a 6 mm diameter circular flat die under a pressure of 15 kN. XRPD was performed before and after tableting. The measurement results show that the crystalline form CSI remains unchanged after tableting.

[0135] The results show that the crystalline form CSI has good stability under mechanical force.

[0136] Example 9: Hygroscopicity of crystalline form CSI Approximately 10 mg of a sample of crystalline form CSI was tested for hygroscopicity using a dynamic moisture sorption (DVS) apparatus in a relative humidity cycle of 30%, 90%, 0%, and 90% RH, and the mass change at each humidity level was recorded. The sample was analyzed by XRPD before and after the DVS measurement. The experimental results show that crystalline form CSI does not change after the DVS measurement. The DVS pattern of crystalline form CSI is shown in Figure 13. The weight gain due to hygroscopicity of crystalline form CSI at 30% to 80% RH is 0.36%.

[0137] Example 10: Preparation of crystalline CSI formulation Crystalline form CSI formulations were prepared using the formulation formulation shown in Table 8 and the formulation process shown in Table 10, with the excipient mixture formulation shown in Table 9. The excipient mixture and samples before and after formulation were measured by XRPD, and the results are shown in Figure 14. The results show that crystalline form CSI remains unchanged after the formulation formulation process.

[0138] [Table 8]

[0139] [Table 9]

[0140] [Table 10]

[0141] Example 11: Stability of crystalline CSI formulations A sample of the crystalline CSI formulation was packaged under the packaging conditions and stored at 25°C / 60%RH, and its purity and crystalline form were measured by HPLC and XRPD. The results are shown in Table 11, and the XRPD patterns before and after storage are shown in Figure 15. The results show that the crystalline CSI formulation sample is stable at 25°C / 60%RH for at least one month with little change in purity.

[0142] [Table 11]

[0143] Example 12: Stability of crystalline form CSII An appropriate amount of crystalline form CSII sample was packaged under the corresponding packaging conditions and allowed to stand at 25°C / 60%RH, 40°C / 75%RH, and 60°C / 75%RH for a certain period of time, and the purity and crystalline form were measured by HPLC and XRPD, and the results are shown in Table 12. The XRPD patterns of crystalline form CSII before and after standing are shown in Figure 16.

[0144] [Table 12]

[0145] Sealing: The sample was placed in a glass vial, which was then capped and sealed in a two-layer PE bag, followed by an aluminum foil bag.

[0146] The results show that crystalline form CSII is stable for at least 6 months at 25°C / 60%RH and 40°C / 75%RH, and for at least 1 month at 60°C / 75%RH, and has good physicochemical stability.

[0147] Example 13: Stability of CSII morphology under mechanical force A sample of crystalline form CSII was ball milled at a vibration speed of 500 rpm for 5 minutes, and the sample was analyzed by XRPD before and after ball milling, and the results are shown in Figure 17. Crystalline form CSII remains unchanged after ball milling.

[0148] An appropriate amount of crystalline form CSII sample was taken and pressed into tablets using a manual tablet press with a 6 mm diameter circular flat die under a pressure of 15 kN, and XRPD was performed before and after tableting. The measurement results show that crystalline form CSII remains unchanged after tableting.

[0149] The results show that crystalline form CSII has good stability under mechanical force.

[0150] Example 14: Hygroscopicity of crystalline form CSI Approximately 10 mg of a sample of crystalline form CSII was tested for hygroscopicity using a dynamic moisture sorption (DVS) apparatus in a relative humidity cycle of 0%-90%-0% RH, and the mass change at each humidity level was recorded. The sample was analyzed by XRPD before and after the DVS measurement. The experimental results show that crystalline form CSII remains unchanged after the DVS measurement. The DVS pattern of crystalline form CSII is shown in Figure 18. The weight gain due to hygroscopicity of crystalline form CSII from 0% to 80% RH is 0.28%.

[0151] Example 15: Preparation of crystalline form CSII formulation Crystalline Form CSII formulations were prepared using the formulation blend shown in Table 8 and the formulation process shown in Table 10, with the excipient blend shown in Table 9. The excipient mixture and samples before and after formulation blending were measured by XRPD, and the results are shown in Figure 19. The results indicate that crystalline Form CSII remains unchanged after the formulation blending process.

[0152] Example 16: Stability of crystalline form CSII formulation A sample of crystalline form CSII formulation was packaged under packaging conditions and stored at 25°C / 60% RH and 40°C / 75% RH, and its purity and crystalline form were measured by HPLC and XRPD, the results of which are shown in Table 13. The XRPD patterns before and after storage are shown in Figure 20. The results show that the crystalline form CSII formulation sample is stable at 25°C / 60% RH and 40°C / 75% RH for at least one month with little change in purity.

[0153] [Table 13]

[0154] Example 17: Stability of crystalline form CSIII An appropriate amount of crystalline form CSIII sample was packaged under corresponding packaging conditions and allowed to stand at 40°C / 75% RH for a certain period of time, and the crystalline form was measured by XRPD, the results of which are shown in Table 14. The XRPD patterns of crystalline form CSIII before and after standing are shown in Figure 21.

[0155] [Table 14]

[0156] Sealing: The sample was placed in a glass vial, which was then capped and sealed in a two-layer PE bag, followed by an aluminum foil bag.

[0157] The results show that crystalline form CSIII is stable for at least 2 months at 40°C / 75% RH and has good physical stability.

[0158] Example 18: Stability of crystalline form CSIII under mechanical force A sample of crystalline form CSIII was ball milled for 5 minutes at a vibration speed of 500 rpm, and the sample was analyzed by XRPD before and after ball milling, and the results are shown in Figure 22. Crystalline form CSIII remains unchanged after ball milling.

[0159] The results show that crystalline form CSIII has good stability under mechanical force.

[0160] Example 19: Hygroscopicity of Crystalline Form CSIII Approximately 10 mg of a sample of crystalline form CSIII was tested for hygroscopicity using a dynamic moisture sorption (DVS) apparatus in a relative humidity cycle of 0%-90%-0% RH, and the mass change at each humidity level was recorded. The sample was analyzed by XRPD before and after the DVS measurement. The experimental results show that crystalline form CSIII remains unchanged after the DVS measurement. The DVS pattern of crystalline form CSIII is shown in Figure 23. The weight gain due to hygroscopicity of crystalline form CSIII from 0% to 80% RH is 0.21%.

[0161] Example 20: Stability of crystalline form CSIV An appropriate amount of crystalline form CSIV sample was packaged under corresponding packaging conditions and allowed to stand at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH for a certain period of time, and the crystalline form was measured by XRPD, the results of which are shown in Table 15. The XRPD patterns of crystalline form CSIV before and after standing are shown in Figure 24.

[0162] [Table 15]

[0163] Sealing: The sample was placed in a glass vial, which was then capped and sealed in a two-layer PE bag, followed by an aluminum foil bag.

[0164] The results show that crystalline form CSIV is stable for at least 6 months at 25°C / 60%RH and 40°C / 75%RH, and for at least 1 month at 60°C / 75%RH, and has good physicochemical stability.

[0165] Example 21: Stability of crystalline form CSIV under mechanical force A sample of crystalline form CSIV was ball milled for 5 minutes at a vibration speed of 500 rpm, and the sample was analyzed by XRPD before and after ball milling, and the results are shown in Figure 25. Crystalline form CSIV remains unchanged after ball milling.

[0166] The results show that crystalline form CSIV has good stability under mechanical force.

[0167] Example 22: Hygroscopicity of Crystalline Form CSIV Approximately 10 mg of a sample of crystalline form CSIV was tested for hygroscopicity using a dynamic moisture sorption (DVS) apparatus in a relative humidity cycle of 0%-90%-0% RH, and the mass change at each humidity was recorded. The sample was analyzed by XRPD before and after the DVS measurement. The experimental results show that crystalline form CSIV remains unchanged after the DVS measurement. The DVS pattern of crystalline form CSIV is shown in Figure 26. The weight gain due to hygroscopicity of crystalline form CSIV from 0% to 80% RH is 0.11%.

[0168] [Example 23] Stability of CSV crystal form An appropriate amount of crystal-forming CSV sample was packaged under the corresponding packaging conditions and allowed to stand at 25°C / 60%RH, 40°C / 75%RH, and 60°C / 75%RH for a certain period of time, and the purity and crystalline form were measured by HPLC and XRPD, and the results are shown in Table 16. The XRPD patterns of the crystalline form CSV before and after standing are shown in Figure 27.

[0169] [Table 16]

[0170] Sealing: The sample was placed in a glass vial, which was then capped and sealed in a two-layer PE bag, followed by an aluminum foil bag.

[0171] The results show that the crystalline form CSV is stable for at least 6 months at 25°C / 60%RH and 40°C / 75%RH, and for at least 2 months at 60°C / 75%RH, and has good physicochemical stability.

[0172] [Example 24] Stability of CSV crystal form under mechanical force The CSV crystal form sample was ball milled at a vibration speed of 500 rpm for 5 minutes, and the sample was measured by XRPD before and after ball milling, and the measurement results are shown in Figure 28. The CSV crystal form does not change after ball milling.

[0173] An appropriate amount of the crystalline form CSV sample was taken and pressed into tablets using a manual tablet press with a φ6 mm circular flat punch under a pressure of 15 kN, and XRPD was performed before and after tableting. The measurement results show that the crystalline form CSV remains unchanged after tableting.

[0174] The results show that the crystalline form CSV has good stability under mechanical force.

[0175] [Example 25] Hygroscopicity of CSV crystal form Approximately 10 mg of a sample of crystalline form CSV was taken and subjected to a hygroscopicity test using a dynamic moisture sorption (DVS) apparatus, cycling from 30% to 90% to 0% to 90% RH, and the mass change at each humidity level was recorded. The sample was measured by XRPD before and after the DVS measurement. The experimental results show that crystalline form CSV does not change after the DVS measurement. The DVS pattern of crystalline form CSV is shown in Figure 29. The weight gain due to hygroscopicity of crystalline form CSV at 30% to 80% RH is 0.29%.

[0176] [Example 26] Preparation of crystalline CSV formulation The crystalline form CSV formulation was prepared using the formulation blend shown in Table 8 and the formulation process shown in Table 10, with the excipient blend shown in Table 9. The excipient mixture and samples before and after formulation blending were measured by XRPD, and the results are shown in Figure 30. The results show that the crystalline form CSV remains unchanged after the formulation blending process.

[0177] [Example 27] Stability of crystalline CSV formulation Samples of the crystalline CSV formulation were packaged under packaging conditions and stored at 25°C / 60% RH and 40°C / 75% RH, and their purity and crystalline form were measured by HPLC and XRPD. The results are shown in Table 17, and the XRPD patterns before and after storage are shown in Figure 31. The results show that the crystalline CSV formulation samples are stable at 25°C / 60% RH and 40°C / 75% RH for at least one month with little change in purity.

[0178] [Table 17]

[0179] The above embodiments are merely illustrative of the technical concepts and features of the present invention, intended to enable those skilled in the art to understand and implement the present invention, and do not limit the protection scope of the present invention. Any equivalent changes or modifications made within the spirit of the present invention shall be included within the protection scope of the present invention.

Claims

1. Crystalline form CSI of Compound I, characterized in that its powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at 2θ values ​​of 11.9°±0.2°, 5.9°±0.2°, and 9.5°±0.2°. 【Chemical 1】

2. 2. The crystalline form CSI of compound I of claim 1, wherein a powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 10.7°±0.2°, 14.1°±0.2°, and 22.2°±0.2°.

3. 2. The crystalline form CSI of compound I of claim 1, wherein a powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 10.4°±0.2°, 16.3°±0.2°, and 19.1°±0.2°.

4. 3. The crystalline form CSI of compound I of claim 2, wherein a powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 10.4°±0.2°, 16.3°±0.2°, and 19.1°±0.2°.

5. 2. The crystalline form CSI of compound I of claim 1, having a powder X-ray diffraction pattern using Cu-Kα radiation substantially as shown in FIG.

6. Crystalline form CSII of Compound I, characterized in that its powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at 2θ values ​​of 12.8°±0.2°, 19.8°±0.2°, and 24.4°±0.2°. 【Chemistry 2】

7. 7. The crystalline form CSII of compound I of claim 6, wherein a powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 21.5°±0.2°, 22.5°±0.2°, and 23.3°±0.2°.

8. 7. The crystalline form CSII of compound I of claim 6, wherein a powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 19.2°±0.2°, 20.8°±0.2°, and 25.8°±0.2°.

9. 8. The crystalline form CSII of compound I of claim 7, wherein a powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 19.2°±0.2°, 20.8°±0.2°, and 25.8°±0.2°.

10. 7. The crystalline form CSII of Compound I of claim 6, having a powder X-ray diffraction pattern using Cu-Kα radiation substantially as shown in FIG.

11. Crystalline form CSIII of Compound I, characterized in that its powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at 2θ values ​​of 12.5°±0.2°, 6.2°±0.2°, 18.8°±0.2° and 17.5°±0.2°. 【Chemistry 3】

12. 12. The crystalline form CSIII of compound I of claim 11, wherein a powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 18.1°±0.2° and 21.7°±0.2°.

13. 12. The crystalline form CSIII of Compound I of claim 11, having a powder X-ray diffraction pattern using Cu-Kα radiation substantially as shown in FIG.

14. Crystalline form CSIV of Compound I, characterized in that its powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at 2θ values ​​of 13.0°±0.2°, 16.4°±0.2°, 23.1°±0.2° and 22.0°±0.2°. 【Chemistry 4】

15. 15. The crystalline form CSIV of compound I of claim 14, wherein a powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 24.0°±0.2°, 14.2°±0.2°, and 17.2°±0.2°.

16. 15. The crystalline form CSIV of compound I of claim 14, wherein the powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 18.1°±0.2°, 20.8°±0.2°, and 27.2°±0.2°.

17. 16. The crystalline form CSIV of compound I of claim 15, wherein the powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 18.1°±0.2°, 20.8°±0.2°, and 27.2°±0.2°.

18. 15. The crystalline form CSIV of Compound I of claim 14, having a powder X-ray diffraction pattern using Cu-Kα radiation substantially as shown in FIG.

19. Crystalline form CSV of Compound I, characterized in that its powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at 2θ values ​​of 10.3°±0.2°, 19.2°±0.2°, 13.5°±0.2° and 14.5°±0.2°. 【Chemistry 5】

20. 20. The CSV crystalline form of Compound I according to claim 19, wherein the powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 18.1°±0.2° and 20.0°±0.2°.

21. 20. The CSV of crystalline form I of compound I according to claim 19, wherein the powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 20.6°±0.2° and 12.5°±0.2°.

22. 21. The crystalline form CSV of compound I according to claim 20, wherein a powder X-ray diffraction pattern using Cu-Kα radiation contains characteristic peaks at at least one 2θ value of 20.6°±0.2° and 12.5°±0.2°.

23. 20. The crystalline form CSV of Compound I of claim 19, having a powder X-ray diffraction pattern using Cu-Kα radiation substantially as shown in FIG.

9.

24. A crystalline form of Compound I characterized as being an anhydrate.

25. 20. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound I according to claim 1, 6, 11, 14 and / or 19 and a pharmaceutically acceptable excipient.

26. 20. Use of a crystalline form of Compound I according to claims 1, 6, 11, 14 and / or 19 in the preparation of an M4 receptor modulator drug.

27. 20. Use of a crystalline form of Compound I according to claims 1, 6, 11, 14 and / or 19 in the preparation of a medicament for the treatment of schizophrenia.

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