Crystal form of iclepertin, preparation method therefor, and use thereof

Abstract

The present invention relates to a novel crystal form of iclepertin, a preparation method therefor, a pharmaceutical composition containing the crystal form, and a use of the crystal form in the preparation of a GlyT1 inhibitor drug and a drug for a cognitive disorder related to schizophrenia.

Description

Iclepertin crystal form, preparation method and use thereof Technical Field

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

[0002] Schizophrenia is a progressive and devastating psychiatric disorder characterized by the onset of sudden positive symptoms (such as delusions, hallucinations, thought disorder, and psychosis) and persistent negative symptoms (such as flattened mood, impaired attention, social withdrawal, and cognitive impairment).

[0003] Iclepertin is a glycine transporter 1 (GlyT1) inhibitor used to treat cognitive impairment associated with schizophrenia (CIAS), and has achieved positive results in clinical trials. Iclepertin's chemical name is [5-(methylsulfonyl)-2-{[(2R)-1,1,1-trifluoropropyl-2-yl]oxy}phenyl]{(1R,5R)-1-[5-(trifluoromethyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexan-3-yl}methanone (hereinafter referred to as "Compound I"), and its structural formula is as follows:

[0004] A crystal is a solid formed by the orderly three-dimensional arrangement of compound molecules within a microscopic structure, forming a lattice. Polymorphism refers to the phenomenon of a single compound existing in multiple crystal forms. A compound may exist in one or more crystal forms, but their existence and properties cannot be precisely predicted. APIs in different crystal forms have varying physicochemical properties, which can lead to varying dissolution and absorption in the body, thereby impacting the drug's clinical efficacy to a certain extent. Crystal form is particularly crucial to product performance for poorly soluble oral solid or semisolid dosage forms. Furthermore, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is a crucial aspect of pharmaceutical research and quality control.

[0005] Amorphous solids are non-crystalline materials lacking long-range order, typically exhibiting a broad "steamed bun" peak in their XRPD patterns. The disordered molecular arrangement within amorphous solids leads to poor stability, making amorphous drugs susceptible to crystallization transitions during production and storage. This poor stability can lead to changes in drug bioavailability, dissolution, and other parameters, ultimately altering the drug's clinical efficacy.

[0006] WO2013017657A1 discloses the structure and preparation method of Compound I, but does not disclose any crystalline forms. WO2020223419A1 discloses that the preparation method in WO2013017657A1 produces an amorphous form. Furthermore, WO2020223419A1 discloses three crystalline forms: Form I, Form II, and Form III. The inventors of this application have discovered that Form II is a mixed crystal, and Form III is unstable and easily converts to Form I.

[0007] To overcome the shortcomings of the prior art, a new crystalline form that meets pharmaceutical requirements is still needed for the development of pharmaceuticals containing Compound I. The inventors of the present application unexpectedly discovered that the crystalline form of Compound I provided by the present invention exhibits advantages in at least one of solubility, hygroscopicity, purification efficiency, stability, adhesion, compressibility, flowability, in vitro and in vivo dissolution, and bioavailability. In particular, it exhibits excellent stability, solubility, and compressibility, which overcomes the problems of the prior art and is of great significance to the development of pharmaceuticals containing Compound I. Summary of the Invention

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

[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 diffraction angles 2θ of 5.4°±0.2°, 9.3°±0.2°, and 18.7°±0.2°.

[0011] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one or two of the diffraction angles 2θ of 16.4°±0.2° and 22.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 16.4°±0.2° and 22.9°±0.2°.

[0012] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form CSI has characteristic peaks at 3, or 4, or 5, or 6, or 7, or 8 of the diffraction angle 2θ values ​​of 5.4°±0.2°, 9.3°±0.2°, 18.7°±0.2°, 16.4°±0.2°, 22.9°±0.2°, 6.8°±0.2°, 10.9°±0.2°, and 13.7°±0.2°.

[0013] Without limitation, using Cu-Ka radiation, the XRPD pattern of Form CSI is substantially as shown in FIG1 .

[0014] Without limitation, the TGA of Form CSI is substantially as shown in FIG. 2 , and when heated to 150° C., it has a mass loss of about 0.1%.

[0015] Without limitation, the crystalline form CSI is an anhydrate.

[0016] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSI, which comprises: placing the solid compound I in isopropanol, heating until it becomes clear, transferring it to -20°C and letting it stand, filtering and centrifuging the precipitated solid, and vacuum drying it to obtain the crystalline form CSI.

[0017] Furthermore, the drying time is at least 12 hours; the drying temperature is preferably 25°C.

[0018] The crystalline form CSI provided by the present invention has the following advantages:

[0019] (1) Compared with the prior art, the crystalline form CSI provided by the present invention has higher solubility. In particular, in FaSSGF, the solubility is more than twice that of the prior art form I.

[0020] Compound I is a poorly water-soluble drug. The crystalline form CSI provided by the present invention has higher solubility, which helps improve drug absorption in the human body and enhances bioavailability. Furthermore, higher solubility can reduce drug dosage while maintaining drug efficacy, thereby reducing drug side effects and improving drug safety.

[0021] (2) Compared with the prior art, the crystalline CSI provided by the present invention has superior compressibility. The good compressibility of the crystalline CSI can effectively improve problems such as substandard hardness / friability and tablet cracking during the tableting process, making the formulation process more reliable, improving product appearance, and enhancing product quality and production efficiency.

[0022] (3) The crystal form of CSI did not change under long-term and accelerated conditions for at least 6 months, and the purity remained basically unchanged during storage, both above 99.9%.

[0023] Crystalline CSI APIs exhibit excellent long-term stability, facilitating drug storage. High temperatures and humidity, caused by seasonal variations, regional climate differences, and environmental factors, can impact the storage, transportation, and production of APIs and drug products. Therefore, APIs exhibiting excellent stability under accelerated conditions can help prevent drug quality degradation due to crystal transformation or purity loss during storage. Crystalline CSI exhibits excellent physicochemical stability, ensuring consistent and controllable quality of the API and drug product, minimizing variations in drug quality, bioavailability, and toxic side effects caused by changes in crystal form or the formation of impurities.

[0024] According to the purpose of the present invention, the present invention provides a crystalline form CSII of Compound I (hereinafter referred to as "crystalline form CSII").

[0025] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at 3, or 4, or 5, or 6, or 7 of the diffraction angle 2θ values ​​of 8.9°±0.2°, 11.6°±0.2°, 15.5°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 19.6°±0.2°, and 22.3°±0.2°.

[0026] Without limitation, using Cu-Ka radiation, the XRPD pattern of Form CSII is substantially as shown in FIG3 .

[0027] Without limitation, the TGA of Form CSII is substantially as shown in FIG4 , and when heated to about 100° C., there is substantially no mass loss.

[0028] Without limitation, Form CSII is an anhydrate.

[0029] According to the purpose of the present invention, the present invention also provides a preparation method of the crystalline form CSII, which comprises: dissolving the solid compound I in 2-methyltetrahydrofuran, cooling and crystallizing, filtering and centrifuging the precipitated solid, and vacuum drying to obtain the crystalline form CSII.

[0030] The crystal form CSII provided by the present invention has the following advantages:

[0031] (1) Compared with the prior art, the crystalline form CSII provided by the present invention has higher solubility. In particular, in FaSSGF, the solubility is more than twice that of the prior art form I.

[0032] Compound I is a poorly water-soluble drug. The crystalline form CSII provided by the present invention has higher solubility, which helps improve drug absorption in the human body and enhances bioavailability. Furthermore, higher solubility can reduce drug dosage while maintaining drug efficacy, thereby reducing drug side effects and improving drug safety.

[0033] (2) The crystal form of CSII did not change under long-term and accelerated conditions for at least 6 months, and the purity remained basically unchanged during storage, both above 99.8%.

[0034] Crystalline CSII APIs exhibit excellent long-term stability, facilitating drug storage. High temperatures and humidity, often caused by seasonal variations, regional climate differences, and environmental factors, can impact the storage, transportation, and production of APIs and formulations. Therefore, the API's excellent stability under accelerated conditions helps prevent drug quality degradation due to crystal transformation or purity loss during storage. Crystalline CSII exhibits excellent physicochemical stability, ensuring consistent and controllable quality of the API and formulation, while minimizing variations in drug quality, bioavailability, and toxic side effects caused by changes in crystal form or impurities.

[0035] According to the purpose of the present invention, the present invention provides a crystalline form CSIII of Compound I (hereinafter referred to as "crystalline form CSIII").

[0036] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 10.6°±0.2°, 20.4°±0.2°, 23.2°±0.2°, or 1, 2, or 3; preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 10.6°±0.2°, 20.4°±0.2°, and 23.2°±0.2°.

[0037] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 8.3°±0.2°, 15.9°±0.2°, 16.6°±0.2°, or 1, 2, or 3; preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 8.3°±0.2°, 15.9°±0.2°, and 16.6°±0.2°.

[0038] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 15.3°±0.2°, 19.6°±0.2°, 22.5°±0.2°, or 1, or 2, or 3; preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 15.3°±0.2°, 19.6°±0.2°, and 22.5°±0.2°.

[0039] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at 3, or 4, or 5, or 6, or 7, or 8, or 9 of the diffraction angle 2θ values ​​of 10.6°±0.2°, 20.4°±0.2°, 23.2°±0.2°, 8.3°±0.2°, 15.9°±0.2°, 16.6°±0.2°, 15.3°±0.2°, 19.6°±0.2°, and 22.5°±0.2°.

[0040] Without limitation, using Cu-Ka radiation, the XRPD pattern of Form CSIII is substantially as shown in FIG6 .

[0041] Without limitation, the TGA graph of Form CSIII is substantially as shown in FIG7 , and when heated to about 100° C., there is substantially no mass loss.

[0042] Without limitation, the DSC graph of Form CSIII is shown in FIG8 , which has an endothermic peak at around 131° C.

[0043] Without limitation, Form CSIII is an anhydrate.

[0044] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSIII, which comprises: dissolving the solid compound I in diethyl carbonate, cooling and crystallizing, and placing the precipitated solid in an ethylene glycol monomethyl ether atmosphere for gas-solid diffusion to obtain the crystalline form CSIII.

[0045] The crystalline form CSIII provided by the present invention has the following advantages:

[0046] (1) Compared with the prior art, the crystalline form CSIII provided by the present invention has higher solubility.

[0047] Compound I is a poorly water-soluble drug. The crystalline form CSIII provided by the present invention has higher solubility, which helps improve drug absorption in the human body and enhances bioavailability. Furthermore, higher solubility can reduce drug dosage while maintaining drug efficacy, thereby reducing drug side effects and improving drug safety.

[0048] (2) Compared with the prior art, the crystalline form CSIII provided by the present invention has superior compressibility. The good compressibility of the crystalline form CSIII can effectively improve problems such as substandard hardness / friability and tablet cracking during the tableting process, making the formulation process more reliable, improving product appearance, and enhancing product quality and production efficiency.

[0049] (3) Form CSIII maintained its crystalline form for at least six months under both long-term and accelerated conditions, and its purity remained essentially unchanged during storage, exceeding 99.9%. Furthermore, Form CSIII remained unchanged before and after the formulation process.

[0050] Crystalline Form CSIII API exhibits excellent long-term stability, facilitating drug storage. High temperatures and humidity, caused by seasonal variations, regional climate differences, and environmental factors, can affect the storage, transportation, and production of APIs and formulations. Therefore, the API exhibits excellent stability under accelerated conditions, helping to prevent drug quality from being affected by crystal transformation or purity loss during storage. Crystalline Form CSIII exhibits excellent physicochemical stability, ensuring consistent and controllable quality of the API and formulation, and minimizing changes in drug quality, bioavailability, and toxic side effects caused by changes in crystal form or impurities. Furthermore, excellent physical stability reduces the risk of API crystallinity loss and crystal transformation during formulation processing.

[0051] According to the purpose of the present invention, the present invention provides the crystalline form CSIV of Compound I (hereinafter referred to as "crystalline form CSIV").

[0052] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angles 2θ of 10.8°±0.2°, 12.4°±0.2°, and 19.3°±0.2°.

[0053] 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 14.1°±0.2°, 16.0°±0.2°, and 23.3°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angles 2θ of 14.1°±0.2°, 16.0°±0.2°, and 23.3°±0.2°.

[0054] 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 4.5°±0.2°, 9.0°±0.2°, and 20.0°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angles 2θ of 4.5°±0.2°, 9.0°±0.2°, and 20.0°±0.2°.

[0055] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at 3, or 4, or 5, or 6, or 7, or 8, or 9 of the diffraction angle 2θ values ​​of 10.8°±0.2°, 12.4°±0.2°, 19.3°±0.2°, 14.1°±0.2°, 16.0°±0.2°, 23.3°±0.2°, 4.5°±0.2°, 9.0°±0.2°, 20.0°±0.2°, 9.6°±0.2°, 24.9°±0.2°, and 30.3°±0.2°.

[0056] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSIV is substantially as shown in FIG. 9 .

[0057] Without limitation, the TGA of Form CSIV is substantially as shown in FIG. 10 , and when heated to 150° C., it has a mass loss of about 0.2%.

[0058] Without limitation, the DSC of the crystalline form CSIV is substantially as shown in FIG11 , where an endothermic peak begins to appear around 137° C.

[0059] Without limitation, Form CSIV is an anhydrate.

[0060] According to the purpose of the present invention, the present invention also provides a preparation method of the crystalline form CSIV, which comprises: dissolving the compound in a mixed solvent of alcohol and methyl tert-butyl ether, cooling, separating the solid and placing it under a certain temperature and humidity to remove the solvent.

[0061] Furthermore, the alcohol is preferably methanol; the volume ratio of the alcohol to methyl tert-butyl ether is preferably 1:9; the temperature is preferably 30-60° C.; and the humidity is preferably 60-80% RH.

[0062] The crystalline form CSIV provided by the present invention has the following advantages: compared with the prior art, the crystalline form CSIV provided by the present invention has higher solubility.

[0063] Compound I is a poorly water-soluble drug. The crystalline form CSIV provided by the present invention has higher solubility, which helps improve drug absorption in the human body and enhances bioavailability. Furthermore, higher solubility can reduce drug dosage while maintaining drug efficacy, thereby reducing drug side effects and improving drug safety.

[0064] According to the purpose of the present invention, the crystal form CSI, crystal form CSII, crystal form CSIII, and crystal form CSIV of the present invention are used to prepare other crystal forms or salts or co-crystals of compound I.

[0065] According to the purpose of the present invention, the present invention provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystal form CSI, crystal form CSII, crystal form CSIII, crystal form CSIV and pharmaceutically acceptable excipients.

[0066] According to the purpose of the present invention, the present invention provides uses of crystal form CSI, crystal form CSII, crystal form CSIII, and crystal form CSIV in the preparation of GlyT1 inhibitor drugs.

[0067] According to the purpose of the present invention, the present invention provides the use of crystal form CSI, crystal form CSII, crystal form CSIII, and crystal form CSIV in the preparation of drugs for treating cognitive impairment associated with schizophrenia. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 is the XRPD pattern of crystal form CSI

[0069] Figure 2 is the TGA diagram of crystal form CSI

[0070] Figure 3 is the XRPD pattern of crystal form CSII

[0071] Figure 4 is the TGA diagram of crystal form CSII

[0072] Figure 5 is the DSC graph of crystal form CSII

[0073] Figure 6 is the XRPD pattern of Form CSIII

[0074] Figure 7 is a TGA diagram of Form CSIII

[0075] Figure 8 is the DSC diagram of Form CSIII

[0076] Figure 9 is the XRPD pattern of Form CSIV

[0077] Figure 10 is the TGA diagram of crystal form CSIV

[0078] Figure 11 is the DSC diagram of crystal form CSIV

[0079] Figure 12 is the XRPD pattern of Form K14

[0080] Figure 13 is the TGA diagram of Form K14

[0081] FIG14 is a comparison of XRPD patterns of Form CSI before and after storage under different conditions (from bottom to top: before storage, after 6 months of storage at 25°C / 60% RH sealed with desiccant, and after 6 months of storage at 40°C / 75% RH sealed with desiccant)

[0082] FIG15 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 of storage at 25°C / 60% RH sealed with desiccant, and after 6 months of storage at 40°C / 75% RH sealed with desiccant)

[0083] FIG16 is a comparison of XRPD patterns of Form CSIII before and after storage under different conditions (from bottom to top: before storage, after storage at 25°C / 60% RH sealed with desiccant for 6 months, and after storage at 40°C / 75% RH sealed with desiccant for 6 months).

[0084] Figure 17 XRPD comparison of Form CSIII before and after the preparation process (from top to bottom: blank formulation, Form CSIII after the preparation process, Form CSIII) DETAILED DESCRIPTION

[0085] 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.

[0086] The abbreviations used in the present invention are explained as follows:

[0087] XRPD: X-ray powder diffraction

[0088] TGA: Thermogravimetric analysis

[0089] DVS: Dynamic Water Sorption

[0090] HPLC: High Performance Liquid Chromatography

[0091] 1 H NMR: hydrogen nuclear magnetic resonance

[0092] RH: relative humidity

[0093] Instruments and methods used to collect data:

[0094] The XRPD patterns described in the present invention were collected on a Bruker D8 ADVANCE X-ray powder diffractometer. The X-ray powder diffraction method parameters described in the present invention are as follows:

[0095] X-ray source: Cu, Kα

[0096] 1.54060; 1.54439

[0097] Kα2 / Kα1 intensity ratio: 0.50

[0098] Voltage: 40kV

[0099] Current: 40mA

[0100] Scanning range: from 4.0 to 40.0 degrees

[0101] The TGA graphs described in the present invention were collected on a TA Q500 or TA Q5000. The method parameters for the thermogravimetric analysis described in the present invention are as follows:

[0102] Scan rate: 10℃ / min

[0103] Shielding gas: N2

[0104] The DSC graphs described in the present invention were collected on a METTLER TOLEDO DSC 3. The method parameters for differential scanning calorimetry analysis described in the present invention are as follows:

[0105] Scan rate: 10℃ / min

[0106] Shielding gas: N2

[0107] 1 H NMR data were collected on a Bruker Avance II DMX 400M HZ NMR spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated chloroform to prepare a 2-10 mg / mL solution.

[0108] The solubility detection method of the present invention is shown in Table 1; the related substance detection method is shown in Table 2.

[0109] Table 1

[0110] Table 2

[0111] 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.

[0112] 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 0.5-48 hours, or overnight. Drying is performed in a fume hood, forced air oven, or vacuum oven. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

[0113] The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.

[0114] The "gas-solid diffusion" is accomplished by conventional methods in the art, such as placing the solid in a solvent atmosphere for induction.

[0115] The "anhydrous substance" refers to a solid substance that does not contain crystal water or crystallization solvent.

[0116] 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°, or ±0.15°, or ±0.1°.

[0117] 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.

[0118] In some embodiments, the crystalline forms CSI, CSII, CSIII, and CSIV 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 other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more particularly less than 5% (by weight) of other crystalline forms, and even more particularly less than 1% (by weight) of other crystalline forms.

[0119] 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%.

[0120] Unless otherwise specified, the following examples were all performed at room temperature.

[0121] 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.

[0122] Compound I used in the following examples can be prepared according to existing technology, for example, according to the method described in WO2020223419A1.

[0123] Example 1 Preparation method of crystal form CSI

[0124] 52.9 mg of Compound I solid was added to 0.7 mL of isopropanol solvent, heated until dissolved, transferred to -20°C and allowed to stand for 3 days, after which the solid was separated and dried in vacuo at 25°C for about 65 hours to obtain a dry solid.

[0125] After testing, the obtained dry solid was the crystalline form CSI of the present invention. Its XRPD data is shown in Table 3, and the XRPD pattern is shown in Figure 1.

[0126] As shown in FIG2 , TGA analysis showed that when the crystal was heated to 150° C., the crystal had a mass loss of about 0.1%, indicating that the crystal form CSI was anhydrous.

[0127] Table 3

[0128] Example 2 Stability of Crystalline Form CSI

[0129] Appropriate amounts of the crystalline form CSI prepared according to the present invention were stored for a period of time at 25°C / 60% RH and 40°C / 75% RH, respectively. At each sampling time, the purity and crystalline form were determined using HPLC and XRPD, respectively. The results are shown in Table 4, and a comparative XRPD diagram is shown in Figure 14. These results demonstrate that crystalline form CSI is stable for at least six months at both 25°C / 60% RH and 40°C / 75% RH, demonstrating its excellent stability under both long-term and accelerated conditions.

[0130] Table 4

[0131] Example 3 Solubility of Crystalline Form CSI

[0132] Appropriate amounts of the crystalline Form CSI of the present invention and the prior art Form I were dispersed in FaSSGF and FaSSIF, respectively, to prepare suspensions. The suspensions were equilibrated at 37°C for 1 hour and then filtered to obtain corresponding saturated solutions. The concentrations of Compound I in each saturated solution were measured by HPLC, and the results are shown in Table 5. The results demonstrate that compared to the prior art Form I, the crystalline Form CSI has higher solubility in FaSSGF and FaSSIF.

[0133] Table 5

[0134] Example 4 Compressibility of Crystalline Form CSI

[0135] The tablets were compressed using an ENERPAC manual tablet press. A Φ6mm round flat punch was selected, and about 80mg of the crystalline form CSI or the prior art form I was added. The tablets were pressed into round tablets using a pressure of 5kN. The tablets were placed at room temperature for 24 hours. After complete elastic recovery, the diameter (D) and thickness (L) of the tablets were measured using a vernier caliper, and the radial crushing force (hardness, H) was tested using a tablet hardness tester. The tensile strength of the powder was calculated using the formula T=2H / πDL, and the results are shown in Table 6. Under a certain pressure, the greater the tensile strength, the better the compressibility. The results show that the crystalline form CSI of the present invention has better compressibility than the prior art form I.

[0136] Table 6

[0137] Example 5 Preparation Method of Crystal Form CSII

[0138] 50.3 mg of Compound I solid was added to 0.14 mL of 2-methyltetrahydrofuran solvent and heated at 50°C for 3.5 hours to obtain a clear solution. The solution was then transferred to -20°C and allowed to stand for 6 days, after which the solid was isolated and dried under vacuum at 25°C for approximately 2.5 hours to obtain Form CSII of the present invention. An appropriate amount of Form CSII solid was sealed and packaged with a desiccant, then stored at 40°C / 75% RH for 6 days. The crystalline form was then analyzed by XRPD.

[0139] After testing, the solid was still the crystalline form CSII of the present invention after being placed under the conditions of 40°C / 75%RH for 6 days. The X-ray powder diffraction data thereof are shown in Table 7, and the X-ray powder diffraction pattern is shown in FIG3 .

[0140] The TGA graph is shown in Figure 4. When heated to approximately 100°C, there is essentially no mass loss. Form CSII is an anhydrate.

[0141] Table 7

[0142] Example 6 DSC of Form CSII

[0143] The crystal form CSII of the present invention was subjected to DSC testing. The DSC graph is shown in FIG5 , which shows two endothermic peaks at around 114° C. and 149° C., and one exothermic peak at around 126° C.

[0144] Example 7 Stability of Crystal Form CSII

[0145] Appropriate amounts of Form CSII of the present invention were stored at 25°C / 60% RH and 40°C / 75% RH for a period of time. Purity and crystal form were determined by HPLC and XRPD at each sampling time. The results are shown in Table 8, and a comparative XRPD plot is shown in Figure 15. These results demonstrate that Form CSII is stable for at least six months at both 25°C / 60% RH and 40°C / 75% RH, demonstrating its excellent stability under both long-term and accelerated conditions.

[0146] Table 8

[0147] Example 8 Solubility of Form CSII

[0148] Appropriate amounts of the crystalline Form CSII of the present invention and the prior art Form I were dispersed in FaSSGF and FaSSIF, respectively, to prepare suspensions. The suspensions were equilibrated at 37°C for 1 hour and then filtered to obtain corresponding saturated solutions. The concentration of Compound I in each saturated solution was measured by HPLC, and the results are shown in Table 9. The results demonstrate that compared to the prior art Form I, the crystalline Form CSII has higher solubility in FaSSGF and FaSSIF.

[0149] Table 9

[0150] Example 9 Preparation Method of Crystalline Form CSIII

[0151] Approximately 1 g of Compound I solid was dissolved in 2 mL of diethyl carbonate by heating to obtain a clear solution. 0.5 mL of the clear solution was allowed to stand at -20°C overnight, then brought to room temperature and 1 mL of dibutyl ether was added. After stirring at room temperature for approximately 5 minutes, the solid was separated by filtration. The resulting wet product was vacuum dried at room temperature to obtain a dry sample. Approximately 10 mg of the dry sample was weighed into a single crystal tube. The tube was placed open in a glass bottle containing ethylene glycol monomethyl ether. The glass bottle was sealed and placed in a gas-solid diffusion reaction at -20°C for 2 days. The sample in the single crystal tube was then vacuum dried at room temperature overnight to obtain a crystalline solid.

[0152] After testing, the obtained crystalline solid was found to be the crystalline form CSIII of the present invention. Its X-ray powder diffraction data are shown in Table 10, and its X-ray powder diffraction pattern is shown in FIG6 .

[0153] As shown in the TGA graph in Figure 7, there is essentially no mass loss when heated to approximately 100° C. Form CSIII is an anhydrate.

[0154] The DSC graph is shown in FIG8 , which has an endothermic peak near 131°C.

[0155] Table 10

[0156] Example 10 Stability of Form CSIII

[0157] Appropriate amounts of Form CSIII of the present invention were stored at 25°C / 60% RH and 40°C / 75% RH for a period of time. Purity and crystal form were determined by HPLC and XRPD at each sampling time. The results are shown in Table 11, and a comparative XRPD plot is shown in Figure 16. These results demonstrate that Form CSIII is stable for at least six months at both 25°C / 60% RH and 40°C / 75% RH, demonstrating its excellent stability under both long-term and accelerated conditions.

[0158] Table 11

[0159] Example 11 Solubility of Form CSIII

[0160] Appropriate amounts of the crystalline Form CSIII of the present invention and the prior art Form I were dispersed in FaSSGF and FaSSIF, respectively, to prepare suspensions. The suspensions were equilibrated at 37°C for 4 hours and then filtered to obtain corresponding saturated solutions. The concentrations of Compound I in each saturated solution were measured by HPLC, and the results are shown in Table 12. The results demonstrate that compared to the prior art Form I, the crystalline Form CSIII has higher solubility in FaSSGF and FaSSIF.

[0161] Table 12

[0162] Example 12 Compressibility of Form CSIII

[0163] The tablets were compressed using an ENERPAC manual tablet press. A Φ6mm round flat punch was selected, and about 80mg of the crystalline form CSIII or the prior art form I was added. The tablets were pressed into round tablets using a pressure of 5kN. The tablets were placed at room temperature for 24 hours. After complete elastic recovery, the diameter (D) and thickness (L) of the tablets were measured using a vernier caliper, and the radial crushing force (hardness, H) was tested using a tablet hardness tester. The tensile strength of the powder was calculated using the formula T=2H / πDL, and the results are shown in Table 13. Under a certain pressure, the greater the tensile strength, the better the compressibility. The results show that the crystalline form CSIII of the present invention has better compressibility than the prior art form I.

[0164] Table 13

[0165] Example 13 Preparation of Form CSIII

[0166] Form CSIII was prepared using the formulation described in Table 14 and the formulation process described in Table 15. A blank formulation is shown in Table 16. XRPD results of the blank powder mix and samples before and after the formulation are shown in Figure 17. The results demonstrate that Form CSIII remains stable before and after the formulation process.

[0167] Table 14 Preparation prescription

[0168] Table 15 Preparation process

[0169] Table 16 Blank prescription

[0170] Example 14 Preparation Method of Crystalline Form CSIV

[0171] 473.0 mg of Compound I was weighed into a glass vial, and 2 mL of methanol / methyl tert-butyl ether (v:v, 1:9) was added to obtain a clear solution. The solution was then transferred to -20°C and allowed to stand for 5 days. The solid was filtered and vacuum dried at 40°C for approximately 23 hours, then at 50°C for approximately 4.5 hours, and then transferred to 40°C / 75% RH and left open for approximately 3 days to obtain a crystalline solid.

[0172] After testing, the obtained crystalline solid was found to be the crystalline form CSIV of the present invention. Its XRPD pattern is shown in FIG9 , and the X-ray powder diffraction data are shown in Table 17.

[0173] As shown in the TGA graph of FIG10 , when heated to 150° C., the mass loss was about 0.2%.

[0174] The DSC graph is shown in FIG11 , which shows that an endothermic peak begins to appear around 137° C.

[0175] Table 17

[0176] Example 15 NMR of Form CSIV

[0177] The data of crystalline form CSIV are: 1H NMR (400 MHz, Chloroform-d) δ 8.02-7.94 (m, 1H), 7.89 (t, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.49 (s, 0.5H), 6.37 (s, 0.5H), 4.98-4.72 (m, 1H), 4.36 (dd, J = 89.1, 12.1 Hz, 1H), 4.0 8-3.82 (m, 1H), 3.74-3.48 (m, 1.5H), 3.34 (d, J = 10.7 Hz, 0.5H), 3.06 (s, 3H), 2.14-1.96 (m, 1H), 1.61-1.51 (m, 3H), 1.41 (q, J = 7.6 Hz, 1H), 1.14 (t, J = 5.4 Hz, 1H), consistent with compound I.

[0178] Example 16 Solubility of Form CSIV

[0179] Appropriate amounts of the crystalline Form CSIV of the present invention and the prior art Form I were dispersed in FaSSGF and FaSSIF, respectively, to prepare suspensions. The suspensions were equilibrated at 37°C for 1 hour and then filtered to obtain corresponding saturated solutions. The concentration of Compound I in each saturated solution was measured by HPLC, and the results are shown in Table 18. The results demonstrate that compared to the prior art Form I, the crystalline Form CSIV has higher solubility in FaSSGF and FaSSIF.

[0180] Table 18

[0181] Example 17 Preparation Method of Crystal Form K14

[0182] 15.0 mg of Compound I was weighed into a glass bottle, and 0.05 mL of formic acid / methyl tert-butyl ether (v:v, 1:9) was added at -20°C, followed by standing at -20°C for 28 days to obtain a crystalline solid.

[0183] After testing, the obtained crystalline solid was found to be Form K14, and its XRPD pattern is shown in FIG12 , and the XRPD data are shown in Table 19.

[0184] As shown in the TGA graph of FIG13 , when heated to 150° C., the mass loss was about 7.1%.

[0185] Table 19

[0186] 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 contents of the present invention and implement them 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 covered by the scope of protection of the present invention.

Claims

1. A crystalline form of Compound I , characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 10.6° ± 0.2°, 20.4° ± 0.2°, and 23.2° ± 0.2°.

2. The crystal form of Compound I according to claim 1, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 8.3° ± 0.2°, 15.9° ± 0.2°, and 16.6° ± 0.2°.

3. The crystal form of Compound I according to claim 2, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 15.3° ± 0.2°, 19.6° ± 0.2°, and 22.5° ± 0.2°.

4. The crystal form of Compound I according to claim 1, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in Figure 6.

5. A compound I in a crystalline form, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 5.4° ± 0.2°, 9.3° ± 0.2°, and 18.7° ± 0.2°.

6. The crystal form of Compound I according to claim 5, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 16.4° ± 0.2° and 22.9° ± 0.2°.

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

8. A crystalline form of Compound I , characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at at least 3 of the 2θ values of 8.9° ± 0.2°, 11.6° ± 0.2°, 15.5° ± 0.2°, 17.0° ± 0.2°, 18.7° ± 0.2°, 19.6° ± 0.2°, and 22.3° ± 0.2°.

9. The crystal form of Compound I according to claim 8, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in Figure 3.

10. A crystal form of Compound I , characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 10.8° ± 0.2°, 12.4° ± 0.2°, and 19.3° ± 0.2°.

11. The crystal form of Compound I according to claim 10, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 14.1° ± 0.2°, 16.0° ± 0.2°, and 23.3° ± 0.2°.

12. The crystal form of compound I according to claim 11, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 4.5° ± 0.2°, 9.0° ± 0.2°, and 20.0° ± 0.2°.

13. The crystal form of compound I according to claim 10, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in Figure 9.

14. The crystal form of compound I according to claim 1, claim 5, claim 8 or claim 10, characterized in that It is the anhydrous form.

15. A pharmaceutical composition, which comprises a pharmaceutically acceptable excipient and a crystalline form of Compound I according to claim 1, claim 5, claim 8 or claim 10 in an effective therapeutically amount.

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