Crystal form of Emraclidine as well as preparation method and application thereof

Abstract

Relates to a crystal form of Emraclidine (hereinafter referred to as' Compound I ') and a preparation method thereof, a pharmaceutical composition containing the crystal form, and application of the crystal form in preparation of M4 receptor modulator drugs and drugs for treating schizophrenia.

Description

Crystal form of Emraclidine, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of crystal chemistry, and in particular to a crystal form of Emraclidine, a preparation method thereof, and uses thereof. Background Art

[0002] Schizophrenia is a severe, complex and debilitating mental health disorder characterized by a constellation of symptoms including delusions, hallucinations, disorganized speech or behavior, slowed speech and blunted emotions.

[0003] Emraclidine (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. Phase Ib clinical results showed that emraclidine exhibited clinically significant antipsychotic activity compared to placebo.

[0004] The chemical name of emraclidine is 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"), which is disclosed in WO2018002760A1. The structural formula of Compound I is as follows:

[0005] It is well known in the art that drug polymorphism is a common phenomenon in small molecule drug development and a significant factor affecting drug quality. A crystal is a solid in which compound molecules are arranged in a three-dimensional, ordered microstructure to form a crystalline lattice. Polymorphism refers to the phenomenon of a single compound existing in multiple crystalline forms. A compound may exist in one or more crystalline forms, but their existence and properties cannot be specifically predicted. APIs with different crystalline forms have different physicochemical properties, including chemical stability, thermal stability, solubility, hygroscopicity, and / or particle size, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the drug's clinical efficacy to a certain extent. In addition, APIs with different crystalline forms have different manufacturability, including yield, purification properties, filtration properties, drying properties, and milling properties. Stability to pressure during tableting may also affect the processing of the API during production. Therefore, polymorphism is a key aspect of pharmaceutical research and drug quality control. For at least these reasons, there is a need to identify a solid form of Compound I.

[0006] The inventors of the present application unexpectedly discovered that the crystals of Compound I provided by the present invention have good physicochemical stability, good stability under mechanical forces, and low hygroscopicity, which is of great significance for the development of drugs containing Compound I.

[0007] Summary of the Invention

[0008] The present invention provides a crystal of Compound I and a preparation method thereof, including a pharmaceutical composition and use of the crystal.

[0009] According to the purpose of the present invention, the present invention provides a crystalline form CSI of Compound I (hereinafter referred to as "crystalline form CSI").

[0010] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 11.9°±0.2°, 5.9°±0.2°, and 9.5°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 11.9°±0.2°, 5.9°±0.2°, and 9.5°±0.2°.

[0011] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 10.7°±0.2°, 14.1°±0.2°, and 22.2°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 10.7°±0.2°, 14.1°±0.2°, and 22.2°±0.2°.

[0012] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, or two, or three of the diffraction angles 2θ of 10.4°±0.2°, 16.3°±0.2°, and 19.1°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 10.4°±0.2°, 16.3°±0.2°, and 19.1°±0.2°.

[0013] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at any one of the diffraction angles 2θ values ​​of 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°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13.

[0014] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSI is substantially as shown in FIG1 .

[0015] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSI, which comprises: dissolving Compound I in a ketone solvent and volatilizing to obtain the crystalline form CSI.

[0016] Furthermore, the volatilization temperature is preferably -20°C to 50°C.

[0017] According to the purpose of the present invention, the present invention provides a crystalline form of Compound I, which is, without limitation, crystalline form CSII (hereinafter referred to as "crystalline form CSII").

[0018] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 12.8°±0.2°, 19.8°±0.2°, and 24.4°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2θ of 12.8°±0.2°, 19.8°±0.2°, and 24.4°±0.2°.

[0019] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 21.5°±0.2°, 22.5°±0.2°, and 23.3°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2θ of 21.5°±0.2°, 22.5°±0.2°, and 23.3°±0.2°.

[0020] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 19.2°±0.2°, 20.8°±0.2°, and 25.8°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2θ of 19.2°±0.2°, 20.8°±0.2°, and 25.8°±0.2°.

[0021] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has 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 diffraction angles 2θ of 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°.

[0022] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSII is substantially as shown in FIG2 .

[0023] Without limitation, the thermogravimetric analysis diagram of Form CSII is substantially as shown in FIG3 , and there is substantially no weight loss when heated from room temperature to 180° C.

[0024] Without limitation, the differential scanning calorimetry analysis diagram of the crystalline form CSII is substantially as shown in FIG4 , which has an endothermic peak that begins to appear around 183° C., and is a melting endothermic peak.

[0025] Without limitation, Form CSII is an anhydrate.

[0026] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSII, which comprises: placing compound I in a mixed system of methyl tert-butyl ether and alcohol and stirring to obtain the crystalline form CSII.

[0027] Furthermore, the alcohol is preferably methanol; the stirring temperature is preferably 0° C.-50° C.; and the stirring time is preferably 1-10 days.

[0028] According to the purpose of the present invention, the present invention provides a crystalline form of Compound I, which is, without limitation, crystalline form CSIII (hereinafter referred to as "crystalline form CSIII").

[0029] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at 1, 2, 3, or 4 of the diffraction angles 2θ of 12.5°±0.2°, 6.2°±0.2°, 18.8°±0.2°, and 17.5°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 12.5°±0.2°, 6.2°±0.2°, 18.8°±0.2°, and 17.5°±0.2°.

[0030] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at one or two of the diffraction angles 2θ of 18.1°±0.2° and 21.7°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 18.1°±0.2° and 21.7°±0.2°.

[0031] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8 of the 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°.

[0032] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSIII is substantially as shown in FIG5 .

[0033] Without limitation, the thermogravimetric analysis diagram of Form CSIII is substantially as shown in FIG6 , and there is substantially no weight loss when heated from room temperature to 170° C.

[0034] Without limitation, Form CSIII is an anhydrate.

[0035] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSIII, which comprises: dissolving compound I in a mixed solvent of ether and alkane, and volatilizing to obtain the crystalline form CSIII.

[0036] Furthermore, the ether is preferably tetrahydrofuran; the alkane is preferably n-heptane; and the volatilization temperature is preferably 40-60°C.

[0037] According to the purpose of the present invention, the present invention provides a crystalline form of Compound I, and without limitation, the crystalline form is crystalline form CSIV (hereinafter referred to as "crystalline form CSIV").

[0038] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at one, or two, or three, or four of the diffraction angles 2θ of 13.0°±0.2°, 16.4°±0.2°, 23.1°±0.2°, and 22.0°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angles 2θ of 13.0°±0.2°, 16.4°±0.2°, 23.1°±0.2°, and 22.0°±0.2°.

[0039] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at one, two, or three of the diffraction angles 2θ of 24.0°±0.2°, 14.2°±0.2°, and 17.2°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angles 2θ of 24.0°±0.2°, 14.2°±0.2°, and 17.2°±0.2°.

[0040] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at one, two, or three of the diffraction angles 2θ of 18.1°±0.2°, 20.8°±0.2°, and 27.2°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angles 2θ of 18.1°±0.2°, 20.8°±0.2°, and 27.2°±0.2°.

[0041] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or ten of the 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°±0.2°, 20.0°±0.2°, 20.4°±0.2°, and 26.4°±0.2°.

[0042] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSIV is substantially as shown in FIG. 7 .

[0043] Without limitation, the thermogravimetric analysis diagram of Form CSIV is substantially as shown in FIG8 , and there is substantially no weight loss when heated from room temperature to 180° C.

[0044] Without limitation, Form CSIV is an anhydrate.

[0045] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSIV, which comprises: heating compound I to 185° C.-190° C. to obtain the crystalline form CSIV.

[0046] According to the purpose of the present invention, the present invention provides a crystalline form of Compound I, and without limitation, the crystalline form is crystalline form CSV (hereinafter referred to as "crystalline form CSV").

[0047] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at one, or two, or three, or four of the diffraction angles 2θ of 10.3°±0.2°, 19.2°±0.2°, 13.5°±0.2°, and 14.5°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at diffraction angles 2θ of 10.3°±0.2°, 19.2°±0.2°, 13.5°±0.2°, and 14.5°±0.2°.

[0048] Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at one or two of the diffraction angles 2θ values ​​of 18.1°±0.2° and 20.0°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at diffraction angles 2θ values ​​of 18.1°±0.2° and 20.0°±0.2°.

[0049] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at one or two of the diffraction angles 2θ of 20.6°±0.2° and 12.5°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at diffraction angles 2θ of 20.6°±0.2° and 12.5°±0.2°.

[0050] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has a characteristic peak at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the 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°.

[0051] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSV is substantially as shown in FIG9 .

[0052] Without limitation, the thermogravimetric analysis chart of the crystalline form CSV is substantially as shown in FIG10 , and the weight loss upon heating from 35° C. to 150° C. is approximately 3.8%.

[0053] According to the purpose of the present invention, the present invention also provides a method for preparing crystalline CSV, which comprises: placing compound I in a mixed system of dimethyl sulfoxide and water and stirring to obtain crystalline CSV.

[0054] Furthermore, the stirring temperature is preferably 0° C.-50° C., more preferably 25° C.-50° C. The stirring time is preferably 1-10 days, more preferably 4-6 days.

[0055] According to the purpose of the present invention, the present invention provides the use of crystal form CSI, crystal form CSII, crystal form CSIII, crystal form CSIV and / or crystal form CSV for preparing other crystal forms or co-crystals of compound I and its salts.

[0056] Furthermore, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline form CSI, crystalline form CSII, crystalline form CSIII, crystalline form CSIV and / or crystalline form CSV and pharmaceutically acceptable excipients.

[0057] Furthermore, according to the purpose of the present invention, the present invention provides the use of crystal form CSI, crystal form CSII, crystal form CSIII, crystal form CSIV and / or crystal form CSV in the preparation of M4 receptor modulator drugs.

[0058] Furthermore, according to the purpose of the present invention, the present invention provides the use of crystal form CSI, crystal form CSII, crystal form CSIII, crystal form CSIV and / or crystal form CSV in the preparation of a drug for treating schizophrenia.

[0059] The present invention provides excellent properties of the crystal form

[0060] The crystalline CSI provided by the present invention has the following excellent properties:

[0061] (1) The crystalline CSI API and preparation provided by the present invention have good physicochemical stability. The crystalline CSI API of the present invention is stable for at least 6 months at 40°C / 75% RH, and its purity remains substantially unchanged during storage. After the crystalline CSI of the present invention is mixed with excipients to form a pharmaceutical preparation, it is stable for at least 1 month at 25°C / 60% RH and 40°C / 75% RH, and its purity remains substantially unchanged during storage. After the crystalline CSI API undergoes a humidity cycle of 30%-90%-0%-90% RH, the sample properties do not change significantly, and the crystal form does not change.

[0062] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs and drug products. Crystalline CSI APIs and drug products exhibit excellent physicochemical stability, helping to prevent degradation of the drug's quality due to crystal transformation or purity loss during storage.

[0063] (2) The crystalline form CSI provided by the present invention has a low moisture gain. The moisture gain of the crystalline form CSI at 30%-80% RH is 0.36%. High hygroscopicity can easily cause chemical degradation and crystal transformation of the API, thereby affecting the physicochemical stability of the API. At the same time, highly hygroscopic drugs place higher demands on production. The low hygroscopic crystalline form is less demanding on the environment, reduces material production, storage, and quality control costs, and has strong economic value.

[0064] (3) The crystalline CSI provided by the present invention has good physical stability under mechanical forces. The crystalline CSI API maintains its crystal form after grinding and after the formulation process. During the formulation process, APIs often need to be ground or pulverized. Good physical stability can reduce the risk of API crystallinity reduction and crystal transformation during the formulation process. In addition, the crystalline CSI API also has good physical stability under pressure, which is beneficial for maintaining crystal stability during the tableting process.

[0065] The crystal form CSII provided by the present invention has the following excellent properties:

[0066] (1) The crystalline CSII API and preparation provided by the present invention have good physicochemical stability. The crystalline CSII API of the present invention 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 its purity remains substantially unchanged during storage. After the crystalline CSII of the present invention is mixed with excipients to form a pharmaceutical preparation, it is stable for at least 1 month at 25°C / 60% RH and 40°C / 75% RH, and its purity remains substantially unchanged during storage. After the crystalline CSII API undergoes a humidity cycle from 0% to 90% to 0% RH, the sample properties do not change significantly, and the crystal form does not change.

[0067] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs and drug products. Crystalline CSII APIs and drug products exhibit excellent physicochemical stability, helping to prevent degradation of drug quality due to crystal transformation or purity loss during storage.

[0068] (2) The crystalline form CSII provided by the present invention has a low weight gain upon moisture absorption. The weight gain upon moisture absorption of the crystalline form CSII under conditions of 0%-80% RH is 0.28%. High hygroscopicity can easily cause chemical degradation and crystal transformation of the API, thereby affecting the physicochemical stability of the API. Furthermore, highly hygroscopic drugs place higher demands on production. The low hygroscopic crystalline form is less demanding on the environment, reduces material production, storage, and quality control costs, and has strong economic value.

[0069] (3) The crystalline form CSII provided by the present invention has good physical stability under mechanical forces. The crystalline form CSII API maintains its crystal form after grinding and after the formulation process. Grinding or crushing the API is often required during the formulation process. Good physical stability can reduce the risk of API crystallinity reduction and crystal transformation during the formulation process. In addition, the crystalline form CSII API also has good physical stability under pressure, which is beneficial for maintaining the crystal form stable during the formulation tableting process.

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

[0071] (1) The crystalline CSIII API provided by the present invention exhibits excellent physicochemical stability. The crystalline CSIII API is stable for at least two months at 40°C / 75% RH. The crystalline CSIII API exhibits no significant changes in properties or crystal form after cycling through a humidity range of 0%-90%-0% RH.

[0072] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs and drug products. The excellent physical and chemical stability of the crystalline CSIII API helps prevent the effects of crystal transformation or purity loss during storage that could affect drug quality.

[0073] (2) The crystalline form CSIII provided by the present invention exhibits low moisture gain. The moisture gain of the crystalline form CSIII at 0%-80% RH is 0.21%. High hygroscopicity can easily cause chemical degradation and crystal transformation of the API, thereby affecting the API's physicochemical stability. Furthermore, highly hygroscopic drugs place higher demands on production. Low hygroscopicity crystalline forms are less demanding on the environment, reduce material production, storage, and quality control costs, and possess significant economic value.

[0074] (3) The crystalline form CSIII provided by the present invention has good physical stability under mechanical forces. The crystalline form CSIII API maintains its crystalline form after grinding. Grinding or pulverizing APIs is often required during formulation processing. Good physical stability can reduce the risk of API crystallinity loss and crystal transformation during formulation processing.

[0075] The crystalline form CSIV provided by the present invention has the following excellent properties:

[0076] (1) The crystalline CSIV API provided by the present invention exhibits excellent physicochemical stability. The crystalline CSIV API is stable for at least six months at 25°C / 60% RH and 40°C / 75% RH, and for at least one month at 60°C / 75% RH. The crystalline CSIV API exhibits no significant changes in sample properties and crystal form after undergoing humidity cycling from 0% to 90% to 0% RH.

[0077] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs and drug products. The excellent physical and chemical stability of the crystalline CSIV API helps prevent the effects of crystal transformation or purity loss during storage that could affect drug quality.

[0078] (2) The crystalline form CSIV provided by the present invention exhibits low moisture gain. The moisture gain of the crystalline form CSIV at 0%-80% RH is 0.11%. High hygroscopicity can easily cause chemical degradation and crystal transformation of the API, thereby affecting the API's physicochemical stability. Furthermore, highly hygroscopic drugs place higher demands on production. Low hygroscopicity crystalline forms are less demanding on the environment, reduce material production, storage, and quality control costs, and possess significant economic value.

[0079] (3) The crystalline CSIV provided by the present invention exhibits excellent physical stability under mechanical forces. The crystalline CSIV API maintains its crystalline form after grinding. Grinding or pulverizing APIs is often required during pharmaceutical preparation processing. Good physical stability can reduce the risk of API crystallinity loss and crystal transformation during preparation processing.

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

[0081] (1) The crystalline CSV API and preparation provided by the present invention have good physicochemical stability. The crystalline CSV API of the present invention 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. After the crystalline CSV of the present invention is mixed with excipients to form a pharmaceutical preparation, it is stable for at least 1 month at 25°C / 60% RH and 40°C / 75% RH, and its purity remains substantially unchanged during storage. The crystalline CSV API exhibits no significant changes in sample properties and crystal form after undergoing a humidity cycle of 30%-90%-0%-90% RH.

[0082] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs and drug products. The excellent physical and chemical stability of crystalline CSV APIs helps prevent the effects of crystal transformation or purity loss during storage, which can affect drug quality.

[0083] (2) The crystalline CSV provided by the present invention exhibits low moisture gain. The moisture gain of the crystalline CSV at 30%-80% RH is 0.29%. High hygroscopicity can easily cause chemical degradation and crystal transformation of the API, thereby affecting the API's physicochemical stability. Furthermore, highly hygroscopic drugs place higher demands on production. Low hygroscopicity crystalline forms are less demanding on the environment, reduce material production, storage, and quality control costs, and possess significant economic value.

[0084] (3) The crystalline CSV provided by the present invention has good physical stability under mechanical forces. The crystalline CSV API maintains its crystal form after grinding and after the formulation process. Grinding or crushing APIs are often required during the formulation process. Good physical stability can reduce the risk of API crystallinity reduction and crystal transformation during the formulation process. In addition, the crystalline CSV API also has good physical stability under pressure, which is beneficial for maintaining crystal stability during the tableting process. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] Figure 1 is the XRPD pattern of crystal form CSI

[0086] Figure 2 is the XRPD pattern of crystal form CSII

[0087] Figure 3 is the TGA diagram of crystal form CSII

[0088] Figure 4 is the DSC graph of crystal form CSII

[0089] Figure 5 is the XRPD pattern of Form CSIII

[0090] Figure 6 is a TGA diagram of Form CSIII

[0091] Figure 7 is the XRPD pattern of Form CSIV

[0092] Figure 8 is the TGA diagram of crystal form CSIV

[0093] Figure 9 is the XRPD pattern of crystalline form CSV

[0094] Figure 10 is the TGA graph of crystal form CSV

[0095] Figure 11 is a comparison of XRPD patterns of Form CSI before and after exposure to 40°C / 75% RH for a period of time (from bottom to top: before exposure, after exposure to 40°C / 75% RH for 6 months).

[0096] Figure 12 is a comparison of XRPD images of the crystal form CSI before and after ball milling (from bottom to top: before ball milling, after ball milling)

[0097] Figure 13 is the DVS diagram of crystal form CSI

[0098] Figure 14 XRPD patterns of crystalline CSI and its preparations (from bottom to top: crystalline CSI API, crystalline CSI preparation after process, blank mixed powder preparation after process)

[0099] Figure 15 XRPD comparison of crystalline CSI preparations stored under different conditions (from bottom to top: before storage, after storage at 25°C / 60% RH for 1 month, and after storage at 40°C / 75% RH for 1 month)

[0100] Figure 16 is a comparison of XRPD patterns of Form CSII before and after storage under different conditions (from bottom to top: before storage, after 6 months at 25°C / 60% RH, after 6 months at 40°C / 75% RH, and after 1 month at 60°C / 75% RH).

[0101] Figure 17 is a comparison of XRPD images of Form CSII before and after ball milling (from bottom to top: before ball milling, after ball milling)

[0102] Figure 18 is a DVS diagram of crystal form CSII

[0103] Figure 19 XRPD patterns of crystal form CSII and its preparation (from bottom to top: crystal form CSII API, crystal form CSI preparation after process, blank powder mixture preparation after process)

[0104] Figure 20 XRPD comparison of crystalline form CSII preparations placed under different conditions (from bottom to top: before placement, after 1 month at 25°C / 60% RH, and after 1 month at 40°C / 75% RH)

[0105] FIG21 is a comparison of XRPD patterns of Form CSIII before and after storage at 40°C / 75% RH for a period of time (from bottom to top: before storage, after sealed storage at 40°C / 75% RH for 2 months)

[0106] Figure 22 is a comparison of XRPD images of Form CSIII before and after ball milling (from bottom to top: before ball milling, after ball milling)

[0107] Figure 23 is a DVS diagram of Form CSIII

[0108] FIG24 is a comparison of XRPD patterns of Form CSIV before and after storage under different conditions (from bottom to top: before storage, after 6 months at 25°C / 60% RH, after 6 months at 40°C / 75% RH, and after 1 month at 60°C / 75% RH).

[0109] Figure 25 is a comparison of XRPD images of Form CSIV before and after ball milling (from bottom to top: before ball milling, after ball milling)

[0110] Figure 26 is a DVS diagram of crystal form CSIV

[0111] FIG27 is a comparison of XRPD patterns of Form CSV before and after storage under different conditions (from bottom to top: before storage, after 6 months at 25°C / 60% RH, after 6 months at 40°C / 75% RH, and after 2 months of sealed storage at 60°C / 75% RH).

[0112] Figure 28 is a comparison of XRPD images of the CSV crystal before and after ball milling (from bottom to top: before ball milling, after ball milling)

[0113] Figure 29 is a DVS diagram of crystal form CSV

[0114] Figure 30 XRPD patterns of crystalline CSV and its preparations (from bottom to top: crystalline CSV API, crystalline CSI preparation after process, blank mixed powder preparation after process)

[0115] Figure 31. XRPD comparison of crystalline CSV preparations placed under different conditions (from bottom to top: before placement, after 1 month at 25°C / 60% RH, and after 1 month at 40°C / 75% RH) DETAILED DESCRIPTION

[0116] The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many variations in both materials and methods may be made without departing from the scope of the present invention.

[0117] The abbreviations used in the present invention are explained as follows:

[0118] XRPD: X-ray powder diffraction

[0119] TGA: Thermogravimetric analysis

[0120] DSC: Differential Scanning Calorimetry

[0121] DVS: Dynamic Water Sorption

[0122] HPLC: High Performance Liquid Chromatography

[0123] RH: relative humidity

[0124] Instruments and methods used to collect data:

[0125] The X-ray powder diffraction pattern of the present invention was collected on a Bruker X-ray powder diffractometer. The method parameters of the X-ray powder diffraction of the present invention are as follows:

[0126] X-ray source: Cu, Kα

[0127] Kα1 1.54060; Kα2 1.54439

[0128] Kα2 / Kα1 intensity ratio: 0.50

[0129] The thermogravimetric analysis (TGA) graphs of the present invention were collected on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

[0130] Scan rate: 10℃ / min

[0131] Shielding gas: N2

[0132] The differential scanning calorimetry (DSC) graphs of the present invention were collected on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

[0133] Scan rate: 10℃ / min

[0134] Shielding gas: N2

[0135] The dynamic moisture sorption (DVS) graphs used in this experiment were collected using an Intrinsic dynamic moisture sorption instrument manufactured by SMS (Surface Measurement Systems Ltd.). The instrument was controlled using the DVS-Intrinsic control software. The instrument parameters were as follows:

[0136] Temperature: 25℃

[0137] Carrier gas, flow rate: N2, 200 ml / min

[0138] Mass change per unit time: 0.002% / minute

[0139] Relative humidity range: 0%RH-95%RH

[0140] The testing methods for related substances of the present invention are shown in Table 1:

[0141] Table 1

[0142] In the present invention, the "drying" is accomplished using conventional methods in the art, such as vacuum drying, forced air drying, or air drying. The drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 2-48 hours, or overnight. Drying is performed in a fume hood, forced air oven, or vacuum oven.

[0143] The "evaporation" is accomplished by conventional methods in the art, such as slow evaporation or fast evaporation. Slow evaporation involves sealing the container with a sealing film, puncturing a hole, and allowing the container to evaporate; fast evaporation involves leaving the container open for evaporation.

[0144] The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.

[0145] The "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is preferably 100-300 rpm.

[0146] The separation is accomplished by conventional methods in the art, such as centrifugation or filtration. The centrifugation operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all solids settle to the bottom of the centrifuge tube.

[0147] The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Kα radiation, the peak position can usually have an error of ±0.2°.

[0148] In the present invention, the amorphous material refers to a non-crystalline material without long-range order, and its X-ray powder diffraction pattern usually shows a broad "steamed bun peak".

[0149] In the present invention, "crystals" or "crystal forms" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that X-ray powder diffraction patterns can vary depending on instrument conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in an X-ray powder diffraction pattern may also vary with experimental conditions, so the diffraction peak intensities cannot be the sole or decisive factor in determining a crystal form. In fact, the relative intensities of diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown herein are illustrative and not intended for absolute comparison. Therefore, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed by the present invention do not necessarily have to be identical to those in the Examples described herein; any crystal form having an X-ray powder diffraction pattern with characteristic peaks identical or similar to those in these patterns falls within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction patterns listed herein with those of an unknown crystal form to determine whether the two patterns reflect the same or different crystal forms.

[0150] In some embodiments, the crystalline Form CSI, Form CSII, Form CSIII, Form CSIV, and Form CSV of the present invention are pure and substantially free of any other crystalline forms. As used herein, "substantially free" when referring to a new crystalline form means that the crystalline form contains less than 20% (by weight) of any other crystalline form, particularly less than 10% (by weight) of any other crystalline form, more particularly less than 5% (by weight) of any other crystalline form, and even more particularly less than 1% (by weight) of any other crystalline form.

[0151] The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0152] Unless otherwise specified, the following examples were all performed at room temperature.

[0153] According to the present invention, the compound I as a raw material includes but is not limited to solid form (crystalline or amorphous), oily form, liquid form and solution. Preferably, the compound I as a raw material is in solid form.

[0154] Compound I used in the following examples can be prepared according to existing technologies, for example, according to the method described in WO2018002760A1, combined with conventional salt breaking methods in the art.

[0155] Example 1 Preparation method of crystal form CSI

[0156] 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 allowed to evaporate at room temperature to obtain a solid. The solid was then dried under vacuum at 25°C for approximately 20 hours to obtain a crystalline solid.

[0157] After testing, the obtained dry solid was found to be the crystalline form CSI of the present invention. Its X-ray powder diffraction pattern is shown in FIG1 , and the X-ray powder diffraction data are shown in Table 2.

[0158] Table 2

[0159] Example 2 Preparation Method of Crystal Form CSII

[0160] 9.1 mg of Compound I was weighed into a vial, followed by the addition of 0.2 mL of a methanol / methyl tert-butyl ether (1:9, v / v) mixed solvent. The mixture was stirred at room temperature for approximately 68 hours, the solid was separated by centrifugation, and vacuum dried at 25°C for approximately 20 hours to obtain a crystalline solid.

[0161] After testing, the obtained crystalline solid was found to be the crystalline form CSII of the present invention. Its X-ray powder diffraction pattern is shown in FIG2 , and the X-ray powder diffraction data are shown in Table 3.

[0162] As shown in Figure 3, TGA shows that there is almost no weight loss when heated from room temperature to 180°C.

[0163] As shown in FIG4 , DSC has an endothermic peak which begins to appear around 183° C. and is a melting endothermic peak.

[0164] Table 3

[0165] Example 3 Preparation Method of Crystalline Form CSIII

[0166] 14.6 mg of Compound I was weighed into a vial and 2 mL of a tetrahydrofuran / n-heptane (1:1, v / v) solvent mixture 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 then vacuum-dried at room temperature for approximately 24 hours to obtain a crystalline solid. Testing confirmed that the resulting crystalline solid was Form CSIII of the present invention. Its X-ray powder diffraction pattern is shown in Figure 5, and the X-ray powder diffraction data are shown in Table 4.

[0167] As shown in Figure 6, TGA shows that there is almost no weight loss when heated from room temperature to 170°C.

[0168] Table 4

[0169] Example 4 Preparation Method of Crystalline Form CSIV

[0170] Compound I was heated to 190°C at 10°C / min under nitrogen and held for 1 minute to obtain a crystalline solid. Testing confirmed that the resulting crystalline solid was Form CSIV of the present invention, as shown in Figure 7 and in Table 5, by its X-ray powder diffraction pattern.

[0171] As shown in Figure 8, TGA shows that there is almost no weight loss when heated from room temperature to 180°C. Table 5

[0172] Example 5 Preparation Method of Crystalline Form CSV

[0173] 3.8 mg of Compound I was weighed into a vial, and 0.1 mL of a 1:1, v / v, dimethyl sulfoxide / water mixture was added. The mixture was stirred at 50°C for 4 days to obtain a crystalline solid. Testing confirmed that the resulting crystalline solid was Form CSV, as described herein. Its X-ray powder diffraction pattern is shown in Figure 9, and the X-ray powder diffraction data are shown in Table 6.

[0174] Table 6

[0175] Example 6 TGA of Crystalline Form CSV

[0176] The TGA of the crystal form CSV is shown in Figure 10. The weight loss when heated from 35°C to 150°C is about 3.8%. Example 7 Stability of the crystal form CSI

[0177] An appropriate amount of crystalline CSI was packaged using the corresponding packaging conditions and then placed at 40°C / 75% RH for a period of time. The purity and crystalline form were determined by HPLC and XRPD. The results are shown in Table 7. The XRPD patterns of crystalline CSI before and after placement are shown in Figure 11.

[0178] Table 7

[0179] Open: Place the sample in a glass vial without covering it and leave it open in the corresponding environment.

[0180] The results showed that the crystalline CSI was stable for at least 6 months at 40°C / 75% RH and had good physicochemical stability.

[0181] Example 8 Stability of Crystalline Form CSI under Mechanical Force

[0182] The crystal form CSI was ball milled at a vibration speed of 500 rpm for 5 minutes using a ball mill. The samples were subjected to XRPD detection before and after ball milling. The test results are shown in FIG12 . The crystal form CSI did not change after ball milling.

[0183] Take an appropriate amount of crystal form CSI, select a Φ6mm round flat punch, and press it into tablets using a manual tablet press with a pressure of 15KN. XRPD tests are performed before and after tableting. The test results show that the crystal form of crystal form CSI does not change after tableting.

[0184] The results show that the crystal form CSI has good stability under mechanical force.

[0185] Example 9 Hygroscopicity of Crystalline Form CSI

[0186] Approximately 10 mg of crystalline CSI was tested for hygroscopicity using a dynamic moisture sorption (DVS) instrument. The sample was cycled through relative humidity levels of 30%-90% and then 0%-90% RH, with the mass change recorded at each humidity level. XRPD was also performed on the sample before and after the DVS test. The experimental results showed that the crystalline form of CSI remained unchanged after the DVS test. The DVS graph of crystalline CSI is shown in Figure 13. The hygroscopic weight gain of crystalline CSI under 30%-80% RH conditions was 0.36%.

[0187] Example 10 Preparation of Crystalline Form CSI

[0188] Crystalline CSI preparations were prepared using the formulation formula in Table 8 and the formulation process in Table 10. A blank formulation is shown in Table 9. XRPD results of blank mixed powders and samples before and after the formulation formula were tested, as shown in Figure 14. The results indicate that the crystalline form of CSI remained unchanged after the formulation formula process.

[0189] Table 8

[0190] Table 9

[0191] Table 10

[0192] Example 11 Formulation Stability of Crystalline Form CSI

[0193] Crystalline CSI formulation samples were packaged according to the corresponding conditions and then stored at 25°C / 60% RH. The purity and crystal form were determined using HPLC and XRPD. The results are shown in Table 11, and the XRPD patterns before and after storage are shown in Figure 15. These results demonstrate that the crystalline CSI formulation samples are stable at 25°C / 60% RH for at least one month with little change in purity.

[0194] Table 11

[0195] Example 12 Stability of Crystal Form CSII

[0196] An appropriate amount of Form CSII was packaged using the corresponding packaging conditions and then stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH for a period of time. The purity and crystal form were determined by HPLC and XRPD. The results are shown in Table 12. The XRPD patterns of Form CSII before and after storage are shown in Figure 16.

[0197] Table 12

[0198] Sealing: Place the sample in a glass vial, cover it with a lid, seal it in a double-layer PE bag, and then seal it in an aluminum foil bag.

[0199] The results showed that the crystalline form CSII was 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, showing good physicochemical stability.

[0200] Example 13 Stability of Form CSII under Mechanical Force

[0201] The crystal form CSII was ball milled at a vibration speed of 500 rpm for 5 minutes using a ball mill. The samples were subjected to XRPD detection before and after ball milling. The test results are shown in FIG17 . The crystal form CSII did not change after ball milling.

[0202] Take an appropriate amount of crystal form CSII, select a Φ6mm round flat punch, and press it into tablets using a pressure of 15KN on a manual tablet press. XRPD tests are performed before and after tableting. The test results show that the crystal form CSII does not change after tableting.

[0203] The results show that the crystal form CSII has good stability under mechanical force.

[0204] Example 14 Hygroscopicity of Form CSII

[0205] Approximately 10 mg of Form CSII was tested for hygroscopicity using a dynamic moisture sorption (DVS) instrument. The sample was cycled through a relative humidity range of 0%-90%-0% RH, and the mass change at each humidity level was recorded. XRPD was also performed on the sample before and after the DVS test. The experimental results showed that Form CSII exhibited no change in crystalline form after the DVS test. The DVS plot of Form CSII is shown in Figure 18. The hygroscopic weight gain of Form CSII under 0%-80% RH conditions was 0.28%.

[0206] Example 15 Preparation of Form CSII

[0207] The crystalline Form CSII preparation was prepared using the formulation described in Table 8 and the formulation process described in Table 10. A blank formulation is shown in Table 9. XRPD results of the blank powder mix and samples before and after the formulation were tested are shown in Figure 19. The results indicate that the crystalline form of Form CSII remained unchanged after the formulation process.

[0208] Example 16 Formulation Stability of Crystalline Form CSII

[0209] Samples of the crystalline Form CSII formulation were packaged under the corresponding conditions and then stored at 25°C / 60% RH and 40°C / 75% RH. The purity and crystal form were determined using HPLC and XRPD. The results are shown in Table 13, and the XRPD patterns before and after storage are shown in Figure 20. These results demonstrate that the crystalline Form CSII formulation samples were stable at 25°C / 60% RH and 40°C / 75% RH for at least one month with little change in purity.

[0210] Table 13

[0211] Example 17 Stability of Form CSIII

[0212] An appropriate amount of Form CSIII was packaged using the corresponding packaging conditions and then placed at 40°C / 75% RH for a period of time. The crystal form was determined by XRPD, and the results are shown in Table 14. The XRPD patterns of Form CSIII before and after placement are shown in Figure 21.

[0213] Table 14

[0214] Sealing: Place the sample in a glass vial, cover it with a lid, seal it in a double-layer PE bag, and then seal it in an aluminum foil bag.

[0215] The results showed that the crystalline form CSIII was stable for at least 2 months at 40°C / 75% RH and had good physical stability.

[0216] Example 18 Stability of Form CSIII under Mechanical Force

[0217] The crystal form CSIII was ball milled at a vibration speed of 500 rpm for 5 minutes using a ball mill. The samples were subjected to XRPD detection before and after ball milling. The test results are shown in Figure 22. The crystal form CSIII did not change after ball milling.

[0218] The results show that the crystal form CSIII has good stability under mechanical force.

[0219] Example 19 Hygroscopicity of Form CSIII

[0220] Approximately 10 mg of Form CSIII was tested for hygroscopicity using a dynamic moisture sorption (DVS) instrument. The sample was cycled through a relative humidity range of 0%-90%-0% RH, and the mass change at each humidity level was recorded. XRPD was also performed on the sample before and after the DVS test. The results showed no change in the crystalline form of Form CSIII after the DVS test. As shown in Figure 23 of the DVS diagram for Form CSIII, the hygroscopic weight gain of Form CSIII under 0%-80% RH conditions was 0.21%.

[0221] Example 20 Stability of Form CSIV

[0222] An appropriate amount of Form CSIV was packaged using the corresponding packaging conditions and then stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH for a period of time. The crystal form was determined by XRPD, and the results are shown in Table 15. The XRPD patterns of Form CSIV before and after storage are shown in Figure 24.

[0223] Table 15

[0224] Sealing: Place the sample in a glass vial, cover it with a lid, seal it in a double-layer PE bag, and then seal it in an aluminum foil bag.

[0225] The results show that crystalline 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, showing good physicochemical stability.

[0226] Example 21 Stability of Form CSIV under Mechanical Force

[0227] The crystalline form CSIV was ball milled at a vibration speed of 500 rpm for 5 minutes using a ball mill. The samples were subjected to XRPD detection before and after ball milling. The test results are shown in FIG25 . The crystalline form CSIV did not change after ball milling.

[0228] The results show that the crystalline CSIV has good stability under mechanical force.

[0229] Example 22 Hygroscopicity of Form CSIV

[0230] Approximately 10 mg of crystalline Form CSIV was tested for hygroscopicity using a dynamic moisture sorption (DVS) instrument. The sample was cycled through a relative humidity range of 0%-90%-0% RH, and the mass change at each humidity level was recorded. XRPD was also performed on the sample before and after the DVS test. The experimental results showed that the crystalline form of Form CSIV remained unchanged after the DVS test. The DVS of Form CSIV is shown in Figure 26. The hygroscopic weight gain of Form CSIV under 0%-80% RH conditions was 0.11%.

[0231] Example 23 Stability of Crystalline Form CSV

[0232] An appropriate amount of crystalline Form CSV was packaged using the corresponding packaging conditions and then stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH for a period of time. The purity and crystal form were determined by HPLC and XRPD. The results are shown in Table 16. The XRPD patterns of crystalline Form CSV before and after storage are shown in Figure 27.

[0233] Table 16

[0234] Sealing: Place the sample in a glass vial, cover it with a lid, seal it in a double-layer PE bag, and then seal it in an aluminum foil bag.

[0235] The results showed that the crystalline CSV was 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, demonstrating good physicochemical stability.

[0236] Example 24 Stability of Crystalline Form CSV under Mechanical Force

[0237] The crystalline form CSV was ball milled at a vibration speed of 500 rpm for 5 minutes using a ball mill. The samples were subjected to XRPD detection before and after ball milling. The test results are shown in FIG28 . The crystalline form CSV did not change after ball milling.

[0238] Take an appropriate amount of crystal form CSV, select a Φ6mm round flat punch, and press it into tablets using a manual tablet press with a pressure of 15KN. XRPD tests are performed before and after tableting. The test results show that the crystal form of crystal form CSV does not change after tableting.

[0239] The results show that the crystal form CSV has good stability under mechanical force.

[0240] Example 25 Hygroscopicity of Crystalline Form CSV

[0241] Approximately 10 mg of crystalline Form CSV was tested for hygroscopicity using a dynamic moisture sorption (DVS) instrument. The sample was cycled through 30%-90% and then 0%-90% relative humidity (RH), with the mass change recorded at each humidity level. XRPD analysis was also performed before and after the DVS test. The results showed no change in the crystalline form of Form CSV after the DVS test. The DVS graph of Form CSV is shown in Figure 29. The hygroscopic weight gain of Form CSV under 30%-80% RH conditions was 0.29%.

[0242] Example 26 Preparation of Crystalline Form CSV

[0243] A crystalline CSV preparation was prepared using the formulation described in Table 8 and the formulation process described in Table 10. A blank formulation is shown in Table 9. XRPD results of the blank mixed powder and samples before and after the formulation were tested, as shown in Figure 30. The results indicate that the crystalline form of CSV remained unchanged after the formulation process.

[0244] Example 27 Formulation Stability of Crystalline Form CSV

[0245] Crystalline CSV samples were packaged and stored at 25°C / 60% RH and 40°C / 75% RH, and their purity and crystal form were determined using HPLC and XRPD. The results are shown in Table 17, and the XRPD patterns before and after storage are shown in Figure 31. These results demonstrate that the crystalline CSV samples are stable at 25°C / 60% RH and 40°C / 75% RH for at least one month, with little change in purity.

[0246] Table 17

[0247] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the present invention and implement it accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be encompassed within the scope of protection of the present invention.

Claims

1. A crystalline form CSI of Compound I, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 11.9°±0.2°, 5.9°±0.2°, and 9.5°±0.2°.

2. The crystalline form CSI of Compound 1 according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 10.7°±0.2°, 14.1°±0.2°, and 22.2°±0.2°.

3. The crystalline form CSI of Compound 1 according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 10.4°±0.2°, 16.3°±0.2°, and 19.1°±0.2°.

4. The crystalline form CSI of Compound 1 according to claim 2, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 10.4°±0.2°, 16.3°±0.2°, and 19.1°±0.2°.

5. The crystalline form CSI of Compound 1 according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 1.

6. A crystalline form CSII of compound I, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 12.8°±0.2°, 19.8°±0.2°, and 24.4°±0.2°.

7. The crystalline form CSII of compound 1 according to claim 6, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 21.5°±0.2°, 22.5°±0.2°, and 23.3°±0.2°.

8. The crystalline form CSII of compound 1 according to claim 6, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 19.2°±0.2°, 20.8°±0.2°, and 25.8°±0.2°.

9. The crystalline form CSII of Compound 1 according to claim 7, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 19.2°±0.2°, 20.8°±0.2°, and 25.8°±0.2°.

10. The crystalline form CSII of Compound 1 according to claim 6, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 2.

11. A crystalline form CSIII of compound I, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 12.5°±0.2°, 6.2°±0.2°, 18.8°±0.2°, and 17.5°±0.2°.

12. The crystalline form CSIII of Compound 1 according to claim 11, characterized in that The X-ray powder diffraction pattern thereof, using Cu-Kα radiation, has characteristic peaks at at least one of 2θ values ​​of 18.1°±0.2° and 21.7°±0.2°.

13. The crystalline form CSIII of Compound 1 according to claim 11, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 5.

14. A crystalline form CSIV of Compound I, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 13.0°±0.2°, 16.4°±0.2°, 23.1°±0.2°, and 22.0°±0.2°.

15. The crystalline form CSIV of Compound 1 according to claim 14, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 24.0°±0.2°, 14.2°±0.2°, and 17.2°±0.2°.

16. The crystalline form CSIV of Compound 1 according to claim 14, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 18.1°±0.2°, 20.8°±0.2°, and 27.2°±0.2°.

17. The crystalline form CSIV of Compound 1 according to claim 15, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 18.1°±0.2°, 20.8°±0.2°, and 27.2°±0.2°.

18. The crystalline form CSIV of Compound 1 according to claim 14, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 7.

19. A crystalline form CSV of Compound I, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.3°±0.2°, 19.2°±0.2°, 13.5°±0.2°, and 14.5°±0.2°.

20. The crystalline form CSV of Compound 1 according to claim 19, characterized in that The X-ray powder diffraction pattern thereof using Cu-Kα radiation has a characteristic peak at at least one of 2θ values ​​of 18.1°±0.2° and 20.0°±0.2°.

21. The crystalline form CSV of Compound 1 according to claim 19, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 20.6°±0.2° and 12.5°±0.2°.

22. The crystalline form CSV of Compound 1 according to claim 20, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least one of 2θ values ​​of 20.6°±0.2° and 12.5°±0.2°.

23. The crystalline form CSV of Compound 1 according to claim 19, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 9.

24. A crystalline form of Compound I, characterized in that: It is anhydrous.

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

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

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

Images