Crystalline forms of trebrutinib and methods for producing and using same

Abstract

The present invention relates to a novel crystalline form of tolebrutinib (hereinafter referred to as "Compound I"), its preparation method, pharmaceutical compositions containing the crystalline form, and its use in BTK inhibitors and drugs for treating multiple sclerosis. The provided crystalline forms of trebrutinib have one or more improved properties compared to the prior art and are of high value for future drug optimization and development. [Formula 1] TIFF2024521412000027.tif7189

Description

[Technical field]

[0001] Technical Field The present disclosure relates to the field of chemical crystallography, and in particular to crystalline forms of Tolebrutinib, methods for their preparation and uses. [Background technology]

[0002] background Multiple sclerosis (MS) is a neurological disease that affects more than one million people worldwide. It is the most common cause of neurological disability in young and middle-aged adults and has severe physical, psychological, social and economic impacts on subjects and their families. MS involves an immune-mediated process in which an abnormal response of the body's immune system is directed at the central nervous system (CNS). During the course of the disease, sclerosis, i.e., lesions or scars, appear in the myelin sheath of nerve cells, interfering with the transmission of electrical signals. The sclerosis accumulates over time and results in the debilitating symptoms experienced by MS patients.

[0003] Immunomodulatory drugs have been the mainstay of MS treatment. Results from a 2017 clinical trial (Non-Patent Document 1) demonstrated the efficacy of drugs targeting B lymphocytes.

[0004] The Bruton's tyrosine kinase (BTK) pathway is essential for signaling in myeloid cells, including B lymphocytes and CNS microglia. Each of these cell types has been implicated in the pathophysiology of MS. Furthermore, because BTK signaling is crucial for the maturation of B cells into antibody-secreting plasma cells, BTK inhibition may regulate both cellular and humoral immunity. Thus, inhibitors of BTK signaling represent a dual mechanism to target both aspects of the immune system.

[0005] Therefore, compounds that inhibit BTK, which can inhibit antigen-induced B cell activation responsible for neuroinflammation and regulate maladaptive microglia associated with neuroinflammation in the brain and spinal cord, may be useful in the treatment of relapsing multiple sclerosis (RMS) with superior benefits when compared to currently available therapies.

[0006] Trebrutinib, an oral selective BTK inhibitor, has been shown to be safe and effective in patients with RMS.

[0007] The chemical name of trebrutinib is (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (hereinafter referred to as Compound I) and the structure is: [ka] It is shown as follows.

[0008] A crystalline form is a solid substance whose components are arranged in a highly ordered microstructure, forming a crystal lattice that extends in all directions. Polymorphism refers to the phenomenon that a compound exists in more than one crystalline form. A compound may exist in one or more crystalline forms, but their existence and characteristics cannot be predicted with certainty. Different crystalline forms of a drug substance have different physicochemical properties, which may affect the drug's dissolution and absorption in vivo, and further affect the drug's clinical efficacy to some extent. Especially for some poorly soluble oral solid or semi-solid dosage forms, the crystalline form may be crucial to the performance of the formulation. Moreover, the physicochemical properties of the crystalline form are very important to the manufacturing process. Polymorphism is therefore an important part of drug research and drug quality control.

[0009] The white solid of compound I is disclosed in Patent Document 1. The inventors of the present disclosure have repeated the preparation process and obtained an amorphous substance of compound I. Furthermore, the inventors of the present disclosure have investigated the obtained amorphous substance, and the results show that the amorphous substance of compound I has disadvantages such as poor stability, strong hygroscopicity and easy decomposition, and is not suitable for pharmaceutical use. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] WO2016196840A1 [Non-patent literature]

[0011] [Non-Patent Document 1] Hauser et al., N Engl JMed. 2017;376 (3):221-34 Summary of the Invention [Problem to be solved by the invention]

[0012] In order to overcome the disadvantages of the prior art, there is still a need for a new crystalline form that meets pharmaceutical standards for the development of drugs containing compound I. The inventors of the present disclosure have surprisingly obtained a crystalline form of compound I that has advantages in aspects such as solubility, hygroscopicity, purification ability, stability, adhesion, compressibility, flowability, in vitro and in vivo dissolution, bioavailability, etc. In particular, the crystalline form of compound I of the present disclosure has advantages such as good stability, lower hygroscopicity and almost no decomposition, which solves the problems existing in the prior art and is very important for the development of drugs containing compound I. [Means for solving the problem]

[0013] Abstract The present disclosure provides novel crystalline forms of Compound I, methods for their preparation and use, and pharmaceutical compositions containing the novel crystalline forms.

[0014] For purposes of this disclosure, there is provided crystalline form CSII of Compound I (hereinafter referred to as Form CSII).

[0015] In one embodiment provided herein, Form CSII has an X-ray powder diffraction pattern using CuKα radiation that includes characteristic peaks at 2θ values ​​of 4.1°±0.2°, 10.2°±0.2°, and 22.6°±0.2°.

[0016] Additionally, Form CSII has an X-ray powder diffraction pattern using CuKα radiation that includes one, two, or three characteristic peaks at 2θ values ​​of 11.3°±0.2°, 16.5°±0.2°, and 17.8°±0.2°. Preferably, Form CSII has an X-ray powder diffraction pattern using CuKα radiation that includes characteristic peaks at 2θ values ​​of 11.3°±0.2°, 16.5°±0.2°, and 17.8°±0.2°.

[0017] Additionally, Form CSII has an X-ray powder diffraction pattern using CuKα radiation that includes one, two, or three characteristic peaks at 2θ values ​​of 8.2°±0.2°, 10.8°±0.2°, and 24.7°±0.2°. Preferably, Form CSII has an X-ray powder diffraction pattern using CuKα radiation that includes characteristic peaks at 2θ values ​​of 8.2°±0.2°, 10.8°±0.2°, and 24.7°±0.2°.

[0018] In another embodiment provided herein, Form CSII has an X-ray powder diffraction pattern using CuKα radiation that contains 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 characteristic peaks at 2θ values ​​of 4.1°±0.2°, 10.2°±0.2°, 22.6°±0.2°, 11.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 8.2°±0.2°, 10.8°±0.2°, 24.7°±0.2°, and 20.5°±0.2°.

[0019] Without implying any limitation, the powder X-ray diffraction pattern of Form CSII using CuKα radiation is substantially as shown in FIG.

[0020] Without implying any limitation, the TGA curve for Form CSII is substantially as shown in Figure 2, which shows a weight loss of about 0.1% when heated from 26°C to 100°C.

[0021] Without implying any limitation, the DSC curve for Form CSII is substantially as shown in Figure 3, which shows an endothermic peak at approximately 131°C (onset temperature). This peak is the melting endothermic peak.

[0022] Without implying any limitation, Form CSII is anhydrous.

[0023] In accordance with the objectives of the present disclosure, there is also provided a method for producing Form CSII, the method comprising: adding Compound I solid into an alcohol solvent to form a suspension, stirring at a specific temperature, and isolating to obtain a solid, which is dried by high temperature vacuum drying for a specific time to obtain Form CSII; Includes.

[0024] Furthermore, the alcohol solvent is preferably a C1-C4 alcohol, more preferably ethanol; the temperature is preferably 0-50°C, more preferably 50°C; the stirring time is preferably longer than 1 day; the temperature of the high-temperature vacuum drying is preferably 50-75°C; and the drying time is longer than 3 hours.

[0025] For purposes of this disclosure, the present disclosure provides Form CSIII of Compound I (hereinafter referred to as Form CSIII).

[0026] In one embodiment provided herein, Form CSIII has a powder X-ray diffraction pattern using CuKα radiation that includes characteristic peaks at 2θ values ​​of 4.2°±0.2°, 11.1°±0.2°, and 21.7°±0.2°.

[0027] Additionally, Form CSIII has an X-ray powder diffraction pattern using CuKα radiation that includes one, two, or three characteristic peaks at 2θ values ​​of 20.6°±0.2°, 21.0°±0.2°, and 22.2°±0.2°. Preferably, Form CSIII has an X-ray powder diffraction pattern using CuKα radiation that includes characteristic peaks at 2θ values ​​of 20.6°±0.2°, 21.0°±0.2°, and 22.2°±0.2°.

[0028] Additionally, Form CSIII has an X-ray powder diffraction pattern using CuKα radiation that includes one, two, or three characteristic peaks at 2θ values ​​of 10.4°±0.2°, 17.7°±0.2°, and 23.1°±0.2°. Preferably, Form CSIII has an X-ray powder diffraction pattern using CuKα radiation that includes characteristic peaks at 2θ values ​​of 10.4°±0.2°, 17.7°±0.2°, and 23.1°±0.2°.

[0029] In another embodiment provided herein, the powder X-ray diffraction pattern using CuKα radiation of Form CSIII contains 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 characteristic peaks at 2θ values ​​of 4.2°±0.2°, 11.1°±0.2°, 21.7°±0.2°, 20.6°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 10.4°±0.2°, 17.7°±0.2°, 23.1°±0.2°, 8.4°±0.2°, 13.3°±0.2°, 16.3°±0.2°, 24.2°±0.2°, and 25.4°±0.2°.

[0030] Without implying any limitation, the powder X-ray diffraction pattern of Form CSIII using CuKα radiation is substantially as shown in FIG.

[0031] Without implying any limitation, the TGA curve for Form CSIII is substantially as shown in Figure 7, which shows a weight loss of about 0.5% when heated from 26°C to 100°C.

[0032] Without implying any limitation, the DSC curve for Form CSIII is substantially as shown in Figure 8, which shows an endothermic peak at approximately 133°C (onset temperature). This peak is the melting endothermic peak.

[0033] Without implying any limitation, Form CSIII is anhydrous.

[0034] In accordance with the objectives of the present disclosure, there is also provided a method for producing Form CSIII, the method comprising: adding Compound I solid to acetone to form a suspension and stirring to obtain Form CSIII; Includes.

[0035] Furthermore, the stirring temperature is preferably 0 to 50°C, and more preferably 5°C.

[0036] For purposes of this disclosure, the present disclosure provides Form CSIV of Compound I (hereinafter referred to as Form CSIV).

[0037] In one embodiment provided herein, Form CSIV has a powder X-ray diffraction pattern using CuKα radiation that includes characteristic peaks at 2θ values ​​of 8.5°±0.2°, 18.6°±0.2°, and 22.0°±0.2°.

[0038] Additionally, Form CSIV has an X-ray powder diffraction pattern using CuKα radiation that includes one, two, or three characteristic peaks at 2θ values ​​of 12.9°±0.2°, 19.1°±0.2°, and 23.3°±0.2°. Preferably, Form CSIV has an X-ray powder diffraction pattern using CuKα radiation that includes characteristic peaks at 2θ values ​​of 12.9°±0.2°, 19.1°±0.2°, and 23.3°±0.2°.

[0039] Additionally, Form CSIV has an X-ray powder diffraction pattern using CuKα radiation that includes one, two, or three characteristic peaks at 2θ values ​​of 13.2°±0.2°, 13.8°±0.2°, and 21.1°±0.2°. Preferably, Form CSIV has an X-ray powder diffraction pattern using CuKα radiation that includes characteristic peaks at 2θ values ​​of 13.2°±0.2°, 13.8°±0.2°, and 21.1°±0.2°.

[0040] In another embodiment provided herein, the powder X-ray diffraction pattern using CuKα radiation of Form CSIV contains 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 characteristic peaks at 2θ values ​​of 8.5°±0.2°, 18.6°±0.2°, 22.0°±0.2°, 12.9°±0.2°, 19.1°±0.2°, 23.3°±0.2°, 13.2°±0.2°, 13.8°±0.2°, 21.1°±0.2°, 7.7°±0.2°, 17.2°±0.2°, and 26.7°±0.2°.

[0041] Without implying any limitation, the powder X-ray diffraction pattern of Form CSIV using CuKα radiation is substantially as shown in FIG.

[0042] Without implying any limitation, the DSC curve for Form CSIV is substantially as shown in Figure 13, which shows an endothermic peak at approximately 144°C (onset temperature). This peak is the melting endothermic peak.

[0043] Without implying any limitation, the TGA curve for Form CSIV is substantially as shown in Figure 14, which shows a weight loss of about 0.2% when heated from 29°C to 120°C.

[0044] Without implying any limitation, Form CSIV is anhydrous.

[0045] In accordance with the objectives of the present disclosure, there is also provided a method for producing Form CSIV, the method comprising: Adding a solid of Compound I to an ether solvent or an aromatic hydrocarbon solvent to form a suspension, and stirring at -20°C to 5°C to obtain Form CSIV of the present invention; Includes.

[0046] Furthermore, the ether solvent is preferably a C5 ether, more preferably methyl tert-butyl ether; the aromatic hydrocarbon solvent is preferably a C9 aromatic hydrocarbon solvent, more preferably isopropylbenzene; and the stirring temperature is preferably -20°C.

[0047] In accordance with the purposes of this disclosure, the disclosure provides the use of Form CSII, Form CSIII, Form CSIV, or any mixture of any two of said crystalline forms, or any mixture of the three crystalline forms, to prepare other crystalline forms or salts of Compound I.

[0048] In accordance with the objectives of the present disclosure, there is provided a pharmaceutical composition comprising a therapeutically effective amount of Form CSII, Form CSIII, Form CSIV, or a mixture of any of the three said crystalline forms, and a pharma- ceutically acceptable excipient.

[0049] Further provided by the present disclosure is the use of Form CSII, Form CSIII, Form CSIV, or any mixture of any two of said crystalline forms, or any mixture of the three crystalline forms, for the manufacture of a BTK inhibitor.

[0050] Further provided by the present disclosure is the use of Form CSII, Form CSIII, Form CSIV, or any mixture of any two of said crystalline forms, or any mixture of the three crystalline forms, for the manufacture of a medicament for the treatment of multiple sclerosis.

[0051] Technical effects The Form CSII drug substance of the present disclosure has the following unexpected advantages: (1) The Form CSII drug substance of the present disclosure has better stability than the prior art.

[0052] The chemical purity of the prior art solid decreases significantly when stored under conditions of 25° C. / 60% RH, 40° C. / 75% RH, 60° C. / 75% RH, and 80° C. in the presence of light. In particular, after six months of storage at 40° C. / 75% RH, the purity decreases by 3.46% and the number of impurities exceeding the certified limit increases to 4. After only one month of storage at 60° C. / 75% RH, the purity decreases by more than 6.3% and the number of impurities exceeding the certified limit increases to 4. The chemical stability of the prior art solid is well below pharmaceutical standards.

[0053] The crystalline state of Form CSII drug substance of the present disclosure remains unchanged for at least 6 months when stored under conditions of 25° C. / 60% RH. The chemical purity is greater than 99.8%, and the crystalline form remains substantially unchanged during storage. These results indicate that Form CSII drug substance of the present disclosure has good stability under long-term conditions suitable for drug storage.

[0054] On the other hand, the crystalline state of Form CSII drug substance remains unchanged for at least 6 months when stored under 40°C / 75% RH. The crystalline state of Form CSII drug substance remains unchanged for at least 1 month when stored under 60°C / 75% RH. The chemical purity is greater than 99.8% and remains substantially unchanged during storage. The chemical purity of Form CSII drug substance remains substantially unchanged for at least 2 days when stored under 80°C.

[0055] The total illuminance of the light source is 1.2×10 6 lux-hr or more, and the energy of the near-ultraviolet lamp is 200W-hr / m 2 There is no change in purity for at least one week under conditions of greater than or equal to the energy. These results indicate that Form CSII drug substance has better stability under accelerated, high temperature and lighting conditions.

[0056] High temperature and humidity conditions caused by different seasons, local climates, environments, etc., affect the storage, transportation and manufacturing process of drug substances and drug products. During the storage, transportation and manufacturing process of drug substances, there is inevitably an influence of light conditions, so good stability under accelerated high temperature and lighting conditions is very important for drug development. Form CSII drug substance has good stability under accelerated high temperature and lighting conditions, which is beneficial to avoid the influence on drug quality caused by crystal transition or the decrease in purity during drug storage.

[0057] In addition, the impurity content of Form CSII drug substance did not exceed the certified limit throughout the stability study process, meeting the requirements for drug development.

[0058] Good physical and chemical stability of the drug substance ensures that no crystal transformation occurs during manufacturing and storage and that virtually no impurities are formed. Form CSII has good physical and chemical stability, ensuring consistent and controllable quality of the drug substance and drug product, and minimizing quality changes, bioavailability changes, toxicity and side effects caused by crystal transformation or impurity formation.

[0059] Furthermore, the crystalline form of Form CSII does not change after being mixed with excipients to form a formulation, indicating that Form CSII formulations are stable during the manufacturing process, which is advantageous for the manufacture of a drug.

[0060] In addition, Form CSII has good physical stability under mechanical forces. Form CSII remains unchanged after milling of the drug substance. It is often necessary to mill or pulverize the drug substance during the manufacturing process, and good physical stability can reduce the risk of reduced crystallinity and crystal transition of the drug substance during the manufacturing process.

[0061] (2) Compared with the prior art, the foam CSII of the present disclosure has lower hygroscopicity. The test results show that the weight gain of the foam CSII is only 1 / 6 of that of the prior art. The weight gain of the foam CSII at 80% RH is 0.60%, indicating that the foam CSII is slightly hygroscopic. The weight gain of the prior art solid at 80% RH is 3.69%, indicating that the prior art is hygroscopic.

[0062] In one aspect, high hygroscopicity tends to cause chemical degradation and polymorphic transformation, which directly affects the physical and chemical stability of the drug substance. Moreover, high hygroscopicity reduces the flowability of the drug substance, thereby affecting the processing of the drug substance.

[0063] In another aspect, highly hygroscopic drug substances require a low humidity environment during manufacturing and storage, which imposes stringent manufacturing requirements and higher costs.More importantly, high hygroscopicity affects the quality of the formulation, as it can cause variations in the content of active pharmaceutical ingredients in the formulation.

[0064] Form CSII provided by the present disclosure, having lower moisture absorption, is less demanding on manufacturing and storage conditions, thereby reducing manufacturing, storage and quality control costs and has strong economic value.

[0065] The Form CSIII drug substance of the present disclosure has the following unexpected advantages: (1) The Form CSIII drug substance of the present disclosure has better stability than the prior art. When stored under light conditions of 25° C. / 60% RH, 40° C. / 75% RH, 60° C. / 75% RH, and 80° C., the chemical purity of the prior art solid decreases significantly. In particular, after storage at 40° C. / 75% RH for 6 months, the purity decreases by 3.46% and the number of impurities exceeding the certified limit increases to 4. After storage at 60° C. / 75% RH for only 1 month, the purity decreases by more than 6.3% and the number of impurities exceeding the certified limit increases to 4. The chemical stability of the prior art solid is well below pharmaceutical standards.

[0066] The crystalline state of the Form CSIII drug substance of the present disclosure remains unchanged for at least 6 months when stored under conditions of 25°C / 60%RH. The chemical purity is greater than 99.9%, and the crystalline form remains substantially unchanged during storage. These results indicate that the Form CSIII drug substance of the present disclosure has good stability under long-term conditions suitable for drug storage.

[0067] Meanwhile, the crystalline state of Form CSIII drug substance remains unchanged for at least 6 months when stored under 40°C / 75%RH conditions. The crystalline state of Form CSIII drug substance remains unchanged for at least 1 month when stored under 60°C / 75%RH conditions. The chemical purity is greater than 99.8% and remains substantially unchanged during storage. The chemical purity of Form CSIII drug substance remains substantially unchanged for at least 2 days when stored under 80°C conditions.

[0068] The total illuminance of the light source is 1.2×10 6 lux-hr or more, and the energy of the near-ultraviolet lamp is 200W-hr / m 2 Under conditions where the energy is equal to or greater than 1000 MPa, there is no change in purity for at least one week. These results indicate that Form CSIII drug substance has better stability under accelerated high temperature and lighting conditions. High temperature and high humidity conditions caused by various seasons, local climates, environments, etc. affect the storage, transportation and manufacturing process of drug substances and formulations. During the storage, transportation and manufacturing process of drug substances, there is inevitably an influence of light conditions, so good stability under accelerated high temperature and lighting conditions is very important for drug development. Form CSIII drug substance has good stability under accelerated high temperature and lighting conditions, which is beneficial to avoid the influence on drug quality caused by crystal transition or the decrease in purity during drug storage.

[0069] In addition, the impurity content of Form CSIII drug substance did not exceed the certified limit throughout the stability study process, meeting the requirements of drug development.

[0070] Good physical and chemical stability of the drug substance ensures that no crystal transformation occurs during manufacturing and storage and that virtually no impurities are formed. Form CSIII has good physical and chemical stability, ensuring consistent and controllable quality of the drug substance and drug product, and minimizing quality changes, bioavailability changes, toxicity and side effects caused by crystal transformation or impurity formation.

[0071] Furthermore, the crystalline form of Form CSIII does not change after being mixed with excipients to form a formulation, indicating that Form CSIII formulations are stable during the manufacturing process, which is advantageous for the manufacture of a drug.

[0072] In addition, Form CSIII has good physical stability under mechanical forces. Form CSIII remains unchanged after milling of the drug substance. It is often necessary to mill or pulverize the drug substance during the manufacturing process, and good physical stability can reduce the risk of reduced crystallinity and crystal transition of the drug substance during the manufacturing process.

[0073] (2) Compared with the prior art, the present disclosure's Form CSIII has lower hygroscopicity. Test results show that the weight gain of Form CSIII is only 1 / 6 of that of the prior art. The weight gain of Form CSIII at 80% RH is 0.66%, indicating that Form CSIII is slightly hygroscopic. The weight gain of the prior art solid at 80% RH is 3.69%, indicating that the prior art is hygroscopic.

[0074] In one aspect, high hygroscopicity tends to cause chemical degradation and polymorphic transformation, which directly affects the physical and chemical stability of the drug substance. Moreover, high hygroscopicity reduces the flowability of the drug substance, thereby affecting the processing of the drug substance.

[0075] In another aspect, highly hygroscopic drug substances require a low humidity environment during manufacturing and storage, which imposes stringent manufacturing requirements and higher costs.More importantly, high hygroscopicity affects the quality of the formulation, as it can cause variations in the content of active pharmaceutical ingredients in the formulation.

[0076] Form CSIII provided by the present disclosure, which has lower moisture absorption, is less demanding on manufacturing and storage conditions, thereby reducing the costs of manufacturing, storage and quality control, and has strong economic value.

[0077] The Form CSIV drug substance of the present disclosure has the following unexpected advantages: (1) The Form CSIV drug substance of the present disclosure has better stability than the prior art. The chemical purity of the prior art solid decreases significantly when stored for 2 months under 40° C. / 75% RH conditions, with a purity decrease of 2.18%.

[0078] The crystalline state of the Form CSIV drug substance of the present disclosure does not change for at least 2 months when stored under conditions of 25° C. / 60% RH. The chemical purity is greater than 99.7%, and the crystalline form remains substantially unchanged during storage. These results indicate that the Form CSIV drug substance of the present disclosure has good stability under long-term conditions suitable for drug storage.

[0079] Meanwhile, the crystalline state of Form CSIV drug substance remains unchanged for at least 2 months when stored under 40°C / 75%RH conditions. These results indicate that Form CSIV drug substance has better stability under accelerated conditions. High temperature and high humidity conditions caused by various seasons, local climates, environments, etc. affect the storage, transportation and manufacturing process of drug substances and formulations. Therefore, good stability under accelerated conditions is very important for drug development. Form CSIV drug substance has good stability under accelerated conditions, which is beneficial to avoid the impact on drug quality caused by crystal transition or the decrease in purity during drug storage.

[0080] Good physical and chemical stability of the drug substance ensures that no crystal transformations occur during manufacturing and storage and that virtually no impurities are formed. Form CSIV has good physical and chemical stability, ensuring consistent and controllable quality of the drug substance and drug product, and minimizing quality changes, bioavailability changes, toxicity and side effects caused by crystal transformations or impurity formation.

[0081] Furthermore, the crystalline form of Form CSIV does not change after being mixed with excipients to form a formulation, indicating that Form CSIV formulations are stable during the manufacturing process, which is advantageous for the manufacture of the drug.

[0082] In addition, Form CSIV has good physical stability under mechanical forces. Form CSIV remains unchanged after milling of the drug substance. It is often necessary to mill or pulverize the drug substance during the manufacturing process, and good physical stability can reduce the risk of reduced crystallinity and crystal transition of the drug substance during the manufacturing process.

[0083] (2) Compared with the prior art, the Foam CSIV of the present disclosure has lower hygroscopicity. Test results show that the weight gain of Foam CSIV is only 1 / 15 of that of the prior art. The weight gain of Foam CSIV at 80% RH is 0.24%, indicating that Foam CSIV is slightly hygroscopic. The weight gain of the prior art solid at 80% RH is 3.69%, indicating that the prior art is hygroscopic.

[0084] In one aspect, high hygroscopicity tends to cause chemical degradation and polymorphic transformation, which directly affects the physical and chemical stability of the drug substance. Moreover, high hygroscopicity reduces the flowability of the drug substance, thereby affecting the processing of the drug substance.

[0085] In another aspect, highly hygroscopic drug substances require a low humidity environment during manufacturing and storage, which imposes stringent manufacturing requirements and higher costs.More importantly, high hygroscopicity affects the quality of the formulation, as it can cause variations in the content of active pharmaceutical ingredients in the formulation.

[0086] Form CSIV provided by the present disclosure, having lower moisture absorption, is less demanding on manufacturing and storage conditions, thereby reducing manufacturing, storage and quality control costs and has strong economic value. [Brief description of the drawings]

[0087] [Figure 1] FIG. 1 shows the XRPD pattern of Form CSII. [Diagram 2] FIG. 2 shows the TGA curve of Form CSII. [Diagram 3] FIG. 3 shows the DSC curve of Form CSII. [Figure 4] FIG. 4 shows an overlay of XRPD patterns of Form CSII before and after storage (top to bottom: initial, storage for 6 months at 25° C. / 60% RH (open packaging), storage for 6 months at 40° C. / 75% RH (open packaging), storage for 1 month at 60° C. / 75% RH (open packaging)). [Diagram 5] FIG. 5 shows an overlay of XRPD patterns of Form CSII before and after DVS testing (from top to bottom: initial, final). [Figure 6] FIG. 6 shows the XRPD pattern of Form CSIII. [Figure 7] FIG. 7 shows the TGA curve of Form CSIII. [Figure 8] FIG. 8 shows the DSC curve of Form CSIII. [Figure 9]FIG. 9 shows an overlay of XRPD patterns of Form CSIII before and after storage (top to bottom: initial, storage for 6 months at 25° C. / 60% RH (open packaging), storage for 6 months at 40° C. / 75% RH (open packaging), storage for 1 month at 60° C. / 75% RH (open packaging)). [Figure 10] FIG. 10 shows an overlay of XRPD patterns of Form CSIII before and after DVS testing (top to bottom: initial, final). [Figure 11] FIG. 11 shows the XRPD pattern of Form CSIV. [Figure 12] FIG. 12 shows the XRPD pattern of Form CSIV. [Figure 13] FIG. 13 shows the DSC curve of Form CSIV. [Figure 14] FIG. 14 shows the TGA curve of Form CSIV. [Figure 15] FIG. 15 shows an overlay of XRPD patterns of Form CSIV before and after storage (top to bottom: initial, stored at 25° C. / 60% RH (open packaging) for 2 months, stored at 40° C. / 75% RH (open packaging) for 2 months). [Figure 16] FIG. 16 shows an overlay of XRPD patterns of Form CSIV before and after DVS testing (from top to bottom: initial, final). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] Detailed Description The present disclosure is further illustrated by the following examples which detail the preparation and use of the crystalline forms of the present disclosure. It will be apparent to those skilled in the art that variations in materials and methods can be accomplished without departing from the scope of the disclosure.

[0089] Abbreviations used in this disclosure are explained below: XRPD: X-ray powder diffraction DSC: Differential scanning calorimetry TGA: Thermogravimetric analysis DVS: Dynamic Vapor Sorption Measurement 1 H NMR: proton nuclear magnetic resonance RH: Relative humidity UPLC: Ultra-high performance liquid chromatography LC: Liquid chromatography TEA: Triethylamine

[0090] Equipment and methods used to collect data: The X-ray powder diffraction patterns in this disclosure were obtained on a Bruker X-ray powder diffractometer. The X-ray powder diffraction parameters in this disclosure are as follows: X-ray: Cu, Kα Kα1(Å):1.54060;Kα2(Å):1.54439 Kα2 / Kα1 intensity ratio: 0.50

[0091] The TGA data in this disclosure was obtained on a TA Q500. The parameters of the TGA method in this disclosure are as follows: Heating rate: 10℃ / min Purge gas: Nitrogen

[0092] The DSC data in this disclosure was obtained on a TA Q2000. The DSC method parameters for this disclosure are as follows: Heating rate: 10℃ / min Purge gas: Nitrogen

[0093] DVS was measured with an SMS (Surface Measurement Systems Ltd.) Instrinsic DVS instrument. The instrument control software was the DVS-Instrinsic control software. The parameters for the DVS method were as follows: Temperature: 25℃ Gas and flow rate: Nitrogen, 200mL / min RH range: 0%RH~95%RH 1H NMR was collected on a Bruker Avance II DMX 400M HZ NMR spectrometer. Samples were weighed out to 1–5 mg and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to give solutions with concentrations ranging from 2–10 mg / mL.

[0094] The relevant substances in this disclosure were detected by UPLC and the parameters are given below.

[0095] [Table 1]

[0096] In the present disclosure, the above "stirring" is achieved by using conventional methods in this field, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 r / min. Preferably, the magnetic stirring speed is 300-900 r / min, and the mechanical stirring speed is 100-300 r / min.

[0097] The above "separation" is achieved by using conventional methods in this field, such as centrifugation or filtration. The operation of "centrifugation" is as follows: the sample to be separated is placed in a centrifuge tube, and then centrifuged at a speed of 10000r / min until all solids sink to the bottom of the tube.

[0098] The "drying" is accomplished using methods conventional in the art, such as vacuum drying, blast drying, or air drying. The drying temperature can be room temperature or higher. Preferably, the drying temperature is from room temperature to about 60°C, or 50°C, or 40°C. The drying time can be 2 to 48 hours, or overnight. Drying is accomplished in a fume hood, a forced air convection oven, or a vacuum oven.

[0099] The above "room temperature" is not a specific temperature, but is in the range of 10 to 30° C. The above "open packaging" is to place the sample in a glass vial, cover the vial with aluminum foil, and punch 5 to 10 holes in the foil.

[0100] The above "characteristic peaks" refer to typical diffraction peaks used to identify crystals, which may typically have a deviation of ±0.2° using CuKα radiation.

[0101] In this disclosure, "crystal" or "crystalline form" refers to a crystalline form or morphology identified by the X-ray diffraction pattern shown herein. Those skilled in the art can understand that experimental error depends on the instrument conditions, sample preparation, and purity of the sample. The relative intensity of the diffraction peaks in the X-ray diffraction pattern may also vary depending on the experimental conditions; therefore, the rank order of the diffraction peak intensities cannot be considered as the only or decisive factor. In fact, the relative intensity of the diffraction peaks in the powder X-ray diffraction pattern is related to the preferred orientation of the crystal, and the diffraction peak intensities shown herein are illustrative, and identical diffraction peak intensities are not necessary. Thus, it will be understood by those skilled in the art that the crystalline forms of this disclosure do not necessarily have exactly the same X-ray diffraction patterns as the X-ray diffraction patterns of the examples shown herein. Any crystalline form whose X-ray diffraction pattern has the same or similar characteristic peaks should be within the scope of this disclosure. Those skilled in the art can compare the patterns shown in this disclosure with unknown crystalline forms to identify whether the two groups of patterns reflect the same crystalline form or different crystalline forms.

[0102] In some embodiments, Forms CSII, CSIII, and CSIV of the present disclosure are pure and substantially free of any other crystalline forms. In this disclosure, the term "substantially free" when used to describe a novel crystalline form means that the novel crystalline form contains less than 20% (w / w) of other crystalline forms, specifically less than 10% (w / w), more specifically less than 5% (w / w), and even more specifically less than 1% (w / w).

[0103] In this disclosure, the term "about" when referring to a measurable value such as weight, time, temperature, etc., is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or ±0.1% of the specified amount.

[0104] Unless otherwise specified, the following examples were carried out at room temperature.

[0105] According to the present disclosure, the compound I and / or its salt used as raw material is in solid (crystalline or amorphous), oil, liquid form or solution. Preferably, the compound I used as raw material is solid.

[0106] The starting materials for compound I and / or its salts used in the following examples were prepared by methods known in the prior art, for example, the methods disclosed in WO2016196840A1.

[0107] Example 1: Preparation of Form CSII 1000.0 mg of Compound I solid was weighed into a 20 mL glass vial, followed by the addition of 10.0 mL of ethanol. After magnetic stirring at 500 rpm at 50° C. for about 7 days, the resulting suspension was allowed to stand at room temperature for 10 days. The solid was then isolated by suction filtration. After vacuum drying at 50° C. for about 3 hours, at 60° C. for about 17 hours, and at 75° C. for about 5 hours, the resulting solid was confirmed to be Form CSII of the present disclosure as determined by XPRD, the XRPD pattern of which is shown in FIG. 1, and the XRPD data are set forth in Table 2.

[0108] The TGA curve is shown in Figure 2, which shows a weight loss of about 0.1% when heated from 26°C to 100°C.

[0109] The DSC curve is shown in Figure 3. It shows one endothermic peak at approximately 131°C (onset temperature), which is the melting endothermic peak of Form CSII.

[0110] [Table 2-1] [Table 2-2]

[0111] Example 2: NMR Characterization of Form CSII Form CSII 1 The H NMR data is as follows: 1 H NMR (400MHz, DMSO) δ 7.76(d, J=5.6Hz, 1H), 7.53-7.37(m, 4H), 7.22(t, J=10.6, 4.2Hz, 1H), 7.14(t, 4H), 6.97(d , J=5.5Hz, 1H), 6.91-6.71(m, 1H), 6.14(dd, J=16.8Hz, 1H), 5.69(dd, 1H), 4.81(s, 2H), 4.5 1 (t, J = 13.4 Hz, 1H), 4.15 (dd, J = 34.1, 12.7 Hz, 2H), 3.76 (t, J = 12.1 Hz, 0.5H), 3.16 (t, J = 12.8 Hz, 0.5H), 2.83-2.61 (m, 0.5H), 2.46-2.30 (m, 1H), 2.03-1.77 (m, 2H), 1.66-1.45 (m, 1H). (According to the structure of compound I, the peak of one hydrogen on the piperidine ring appears at δ 3.33-3.76 ppm. The 0.5H split from this hydrogen is covered by the water signal because it is close to the water peak.)

[0112] Example 3: Physical and Chemical Stability of Form CSII Form CSII of the present disclosure and the prior art amorphous form were weighed and stored in open packages under conditions of 25° C. / 60% RH, 40° C. / 75% RH, and 60° C. / 75% RH, respectively. Purity and solid form were determined by UPLC and XRPD. The results are listed in Table 3, and the overlaid XRPD patterns of Form CSII before and after storage for stability evaluation are shown in FIG. 4.

[0113] [Table 3]

[0114] These results show that Form CSII was stable for at least 6 months under conditions of 25°C / 60% RH and 40°C / 75% RH, and the solid form and purity remained essentially unchanged, indicating that Form CSII has good stability under both long-term and accelerated conditions. After one month of storage under 60°C / 75% RH conditions, the solid form and purity remained essentially unchanged, indicating that Form CSII has good stability under stress conditions as well. The impurity content of Form CSII did not exceed the certification limit throughout the stability testing process, meeting the requirements for drug development. After storage at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH, the purity of the prior art amorphous form decreased significantly, which is far below the requirements for drug development. In particular, after storage for 6 months at 40°C / 75% RH, the purity decreased by 3.46%, and the number of impurities exceeding the certification limit increased to 4. After only one month of storage at 60° C. / 75% RH, the purity decreased by more than 6.3% and the number of impurities exceeding the certification limit increased to 4. These results indicate that Form CSII of the present disclosure has superior chemical stability when compared to the prior art amorphous form.

[0115] Example 4: Stability of Foam CSII at High Temperatures Specific amounts of Form CSII of the present disclosure and the prior art amorphous form were weighed and stored at 80° C. for 2 days, and the purity of the solids before and after storage was determined by UPLC, the results are shown in Table 4.

[0116] [Table 4]

[0117] These results show that the chemical purity of Form CSII remained essentially unchanged at 80° C. for 2 days, while significant decomposition of the amorphous form was observed under the same conditions. Form CSII of the present disclosure has superior stability at high temperatures compared to the prior art amorphous forms.

[0118] Example 5: Photostability of Form CSII Specific amounts of Form CSII of the present disclosure and the prior art amorphous form are weighed out, and then measured according to the method of the Chinese Pharmacopoeia, with the total illuminance of the light source being 1.2×10 lux-hr or more and the energy of the near-ultraviolet lamp being 200 W-hr / m 2 After storage under the above conditions for about one week, the purity of the solid before and after storage was measured by UPLC, and the results are shown in Table 5.

[0119] [Table 5]

[0120] These results indicate that the chemical purity of Form CSII remained essentially unchanged under the above light conditions, while significant degradation of the amorphous form was observed under the same conditions. Form CSII of the present disclosure has superior light stability compared to the prior art amorphous forms.

[0121] Example 6: Moisture absorption of foam CSII Specific amounts of Form CSII of the present disclosure and the prior art amorphous form were sampled for moisture absorption testing using a DVS instrument. The weight change at each relative humidity was recorded during a cycle of 0% RH-95% RH-0% RH at 25° C.

[0122] The results are set forth in Table 6, and the overlaid XRPD patterns of Form CSII before and after DVS testing are shown in FIG.

[0123] [Table 6]

[0124] These results show that Form CSII was slightly hygroscopic with a weight gain of 0.60% at 80% RH, while the prior art solid was hygroscopic with a weight gain of 3.69% at 80% RH. The hygroscopicity of Form CSII is superior to that of the prior art solid. Furthermore, the crystalline state of Form CSII remained unchanged after the DVS test, indicating that Form CSII has good stability.

[0125] Description and definition of hygroscopicity (General Rule 9103 Drug Hygroscopicity Test Guideline in the 2020 Edition of the Chinese Pharmacopoeia, Experimental conditions: 25±1℃, 80±2%RH): Deliquescent: Sufficient water is absorbed to form a solution. Very hygroscopic: mass gain greater than or equal to 15.0 percent. Hygroscopicity: Mass increase of less than 15.0 percent but equal to or greater than 2.0 percent. Slightly hygroscopic: mass gain less than 2.0 percent but equal to or greater than 0.2 percent. Non-hygroscopic or nearly non-hygroscopic: less than 0.2 percent mass gain. (The definition of hygroscopicity in 5.11 of the 10th edition of the European Pharmacopoeia is the same as that in the Chinese Pharmacopoeia).

[0126] Example 7: Crush Stability of Foam CSII Form CSII was manually ground in a mortar for 5 minutes. XRPD was examined before and after grinding. The results showed that the crystalline state of Form CSII remained unchanged after grinding, indicating that Form CSII has good grinding stability.

[0127] Example 8: Preparation of Formulations Containing Form CSII Tablets were manufactured with an appropriate amount of Form CSII of the present disclosure according to the formulation and process in Tables 7 and 8. XRPD was tested before and after formulation. The results show that the crystalline state of Form CSII remains unchanged after the formulation process.

[0128] [Table 7]

[0129] [Table 8]

[0130] Example 9: Preparation of Form CSIII 491.9 mg of Compound I solid was weighed into a 20 mL glass vial, followed by the addition of 5 mL of acetone. The resulting suspension was stirred at room temperature for about 15 minutes, and then 3 mL of acetone was added. After stirring for about 4 days at 5° C., the solid was isolated. After drying under vacuum at 50° C. for about 20 hours, the resulting solid was confirmed as Form CSIII of the present disclosure as determined by XRPD, for which the XRPD pattern is shown in FIG. 6, and the XRPD data is set forth in Table 9.

[0131] The TGA curve is shown in FIG. 7, which shows a weight loss of about 0.5% when heated from 26° C. to 100° C.

[0132] The DSC curve is shown in Figure 8. It shows one endothermic peak at approximately 133°C (onset temperature), which is the melting endothermic peak of Form CSIII.

[0133] [Table 9-1] [Table 9-2]

[0134] Example 10: NMR Characterization of Form CSIII Form CSIII 1 The H NMR data is as follows: 1H NMR (400MHz, DMSO) δ 7.76(d, J=5.6Hz, 1H), 7.52-7.36(m, 4H), 7.21(t, 1H), 7.14(t, 4H), 6.97(d, J=5.5Hz, 1H) , 6.90-6.72(m, 1H), 6.14(dd, J=17.0Hz, 1H), 5.69(dd, J=13.6Hz, 1H), 4.81(s, 2H), 4.51( t, J = 13.5 Hz, 1H), 4.14 (dd, J = 33.1, 14.1 Hz, 2H), 3.76 (t, J = 12.1 Hz, 0.5H), 3.16 (t, J = 12.6 Hz, 0.5H), 2.82-2.59 (m, 0.5H), 2.44-2.28 (m, 1H), 2.11-1.75 (m, 2H), 1.68-1.37 (m, 1H). (According to the structure of compound I, the peak of one hydrogen on the piperidine ring appears at δ 3.33-3.76 ppm. The 0.5H split from this hydrogen is covered by the water signal because it is close to the water peak.)

[0135] Example 11: Physical and Chemical Stability of Form CSIII Form CSIII of the present disclosure and the prior art amorphous form were weighed and stored in open packages under conditions of 25° C. / 60% RH, 40° C. / 75% RH, and 60° C. / 75% RH, respectively. Purity and solid form were determined by UPLC and XRPD. The results are listed in Table 10, and the overlaid XRPD patterns of Form CSIII before and after storage for stability evaluation are shown in FIG. 9.

[0136] [Table 10]

[0137] These results show that Form CSIII is stable for at least 6 months under conditions of 25°C / 60% RH and 40°C / 75% RH, and the solid form and purity remained essentially unchanged, indicating that Form CSIII has good stability under both long-term and accelerated conditions. After storage under conditions of 60°C / 75% RH for one month, the solid form and purity remained essentially unchanged, indicating that Form CSIII has good stability under stress conditions as well. The impurity content of Form CSIII did not exceed the certification limit throughout the stability testing process, which meets the requirements for drug development. After storage at 25°C / 60% RH, 40°C / 75% RH and 60°C / 75% RH, the purity of the prior art amorphous form decreased significantly, falling far below the requirements for drug development. In particular, after storage at 40°C / 75% RH for six months, the purity decreased by 3.46%, and the number of impurities exceeding the certification limit increased to 4. After only one month of storage at 60° C. / 75% RH, the purity decreased by more than 6.3% and the number of impurities above the certification limit increased to 4. These results indicate that Form CSIII of the present disclosure has superior chemical stability when compared to the prior art amorphous form.

[0138] Example 12: Stability of Form CSIII at High Temperatures Specific amounts of Form CSIII of the present disclosure and the prior art amorphous form were weighed and stored at 80° C. for 2 days, and the purity of the solids before and after storage was determined by UPLC, with the results shown in Table 11.

[0139] [Table 11]

[0140] These results show that the chemical purity of Form CSIII remains essentially unchanged for 2 days at 80° C., while significant decomposition of the amorphous form was observed under the same conditions. Form CSIII of the present disclosure has superior stability at elevated temperatures compared to the prior art amorphous forms.

[0141] Example 13: Photostability of Form CSIII Specific amounts of Form CSIII of the present disclosure and the prior art amorphous form were weighed out and measured according to the method of the Chinese Pharmacopoeia with a total illuminance of a light source of 1.2×10 6 lux-hr or more, and the energy of the near-ultraviolet lamp is 200W-hr / m 2 After storage under the above conditions for about one week, the purity of the solids before and after storage was measured by UPLC, and the results are shown in Table 12.

[0142] [Table 12]

[0143] These results indicate that the chemical purity of Form CSIII remains essentially unchanged under the above light conditions, while significant degradation of the amorphous form was observed under the same conditions. Form CSIII of the present disclosure has superior light stability compared to the prior art amorphous forms.

[0144] Example 14: Hygroscopicity of Foam CSIII Specific amounts of Form CSIII of the present disclosure and the prior art amorphous form were sampled for hygroscopicity testing using a DVS instrument. The weight change at each relative humidity was recorded during cycling from 0% RH-95% RH-0% RH at 25° C. The results are listed in Table 13, and the overlaid XRPD patterns of Form CSIII before and after DVS testing are shown in FIG.

[0145] [Table 13]

[0146] These results show that Form CSIII was slightly hygroscopic with a weight gain of 0.66% at 80% RH, whereas the prior art solid was hygroscopic with a weight gain of 3.69% at 80% RH. The hygroscopicity of Form CSIII was superior to that of the prior art. Furthermore, the crystalline state of Form CSIII remained unchanged after the DVS test, indicating that Form CSIII has good stability.

[0147] Example 15: Milling stability of Foam CSIII formulations Form CSIII was manually ground in a mortar for 5 minutes. XRPD was performed before and after grinding. The results showed that the crystalline state of Form CSIII remained unchanged after grinding, indicating that Form CSIII has good grinding stability.

[0148] Example 16: Preparation of Formulations Containing Form CSIII Tablets were manufactured with an appropriate amount of Form CSIII of the present disclosure according to the formulation and process in Tables 7 and 8. XRPD was tested before and after formulation. The results show that the crystalline state of Form CSIII remains unchanged after the formulation process.

[0149] Example 17: Preparation of Form CSIV 11.0 mg of Compound I solid was weighed into a glass vial, followed by the addition of 0.08 mL of methyl tert-butyl ether to form a suspension. The suspension was stirred at -20°C for about 23 hours, and then a portion of the solid was isolated. The resulting solid was confirmed to be Form CSIV of the present disclosure as determined by XRPD. An additional 0.08 mL of methyl tert-butyl ether was then added into the vial. After stirring at room temperature for about 2 days, the solid was isolated. The resulting solid was confirmed to be Form CSIV of the present disclosure as determined by XRPD, the XRPD pattern for which is shown in Figure 11, and the XRPD data are set forth in Table 14.

[0150] [Table 14-1] [Table 14-2]

[0151] Example 18: Preparation of Form CSIV 300.0 mg of Compound I solid was weighed and placed in a glass vial, followed by the addition of 4.5 mL of isopropylbenzene. After stirring at -20°C for about 39 hours, the solid was isolated by filtration. After drying under vacuum at 50°C for 22 hours, the resulting solid was determined by XRPD to be Form CSIV of the present disclosure, the XRPD pattern for which is shown in Figure 12, and the XRPD data for which is set forth in Table 15.

[0152] The DSC curve is as shown in Figure 13. It shows one endothermic peak at approximately 144°C (onset temperature), which is the melting endothermic peak of Form CSIV.

[0153] Form CSIV 1 The H NMR data is as follows: 1 H NMR (400MHz, DMSO) δ 7.76(d, J=5.6Hz, 1H), 7.53-7.39(m, 4H), 7.22(t, J=7.4Hz, 1H), 7.14(t, J=7.7Hz, 4H), 6 .97(d, J=5.5Hz, 1H), 6.92-6.74(m, 1H), 6.14(dd, 1H), 5.69(dd, 1H), 4.82(s, 2H), 4.52(t , J=11.8Hz, 1H), 4.15 (dd, J=33.2, 12.0Hz, 2H), 3.78 (t, J=12.8Hz, 0.5H), 3.16 (t, J=12.6Hz, 0.5H), 2.79-2.63 (m, 0.5H), 2.40-2.25 (m, 1H), 2.07-1.76 (m, 2H), 1.68-1.40 (m, 1H). (According to the structure of compound I, the peak of one hydrogen on the piperidine ring appears at δ 3.33-3.76 ppm. The 0.5H split off from this hydrogen is covered by the water signal because it is close to the water peak.)

[0154] [Table 15-1] [Table 15-2]

[0155] Example 19: TGA Study of Form CSIV A certain amount of Foam CSIV was sampled for TGA testing, and the TGA results are shown in Figure 14, which shows a weight loss of about 0.2% when heated from 29°C to 120°C.

[0156] Example 20: Physical and Chemical Stability of Foam CSIV Form CSIV of the present disclosure and the prior art amorphous form were weighed and stored in open packages under conditions of 25° C. / 60% RH and 40° C. / 75% RH, respectively. Purity and solid form were determined by UPLC and XRPD. The results are listed in Table 16, and the overlaid XRPD patterns of Form CSIV before and after storage for stability evaluation are shown in FIG.

[0157] [Table 16]

[0158] The results show that Form CSIV was stable for at least two months under conditions of 25° C. / 60% RH and 40° C. / 75% RH, and the solid form and purity remained essentially unchanged, indicating that Form CSIV has good stability under both long-term and accelerated conditions. After storage at 40° C. / 75% RH, the purity of the prior art solid decreased significantly, with a purity decrease of 2.18%. These results indicate that Form CSIV of the present disclosure has superior chemical stability when compared to the prior art amorphous form.

[0159] Example 21: Stability of Foam CSIV at High Temperatures Specific amounts of Form CSIV of the present disclosure and the prior art amorphous form were stored at 80° C. for 2 days and the purity of the solids before and after storage was determined by UPLC with the results shown in Table 17.

[0160] [Table 17]

[0161] These results show that the chemical purity of Form CSIV remained essentially unchanged for 2 days at 80° C., while significant decomposition of the amorphous form was observed under the same conditions. Form CSIV of the present disclosure has superior stability at elevated temperatures compared to the prior art amorphous forms.

[0162] Example 22: Photostability of Form CSIV Specific amounts of Form CSIV of the present disclosure and the prior art amorphous form were weighed out and measured according to the method of the Chinese Pharmacopoeia, with the total illuminance of the light source being 1.2×10 6 lux-hr or more, and the energy of the near-ultraviolet lamp is 200W-hr / m 2 After storage under the above conditions for about one week, the purity of the solids before and after storage was determined by UPLC and the results are shown in Table 18.

[0163] [Table 18]

[0164] These results indicate that the chemical purity of Form CSIV remained essentially unchanged under the above light conditions, while significant degradation of the amorphous form was observed under the same conditions. Form CSIV of the present disclosure has superior light stability compared to the prior art amorphous forms.

[0165] Example 23: Hygroscopicity of Foam CSIV Specific amounts of Form CSIV of the present disclosure and the prior art amorphous form were sampled for hygroscopicity testing using a DVS instrument. The weight change at each relative humidity was recorded during cycles of 0% RH-95% RH-0% RH at 25° C. The results are set forth in Table 19, and the overlaid XRPD patterns of Form CSIV before and after DVS testing are shown in FIG.

[0166] [Table 19]

[0167] These results show that Form CSIV was slightly hygroscopic with a weight gain of 0.24% at 80% RH, whereas the prior art solid was hygroscopic with a weight gain of 3.69% at 80% RH. The hygroscopicity of Form CSIV is superior to the prior art. Furthermore, the crystalline state of Form CSIV remained unchanged after the DVS test, indicating that Form CSIV has good stability.

[0168] Example 24: Crush Stability of Foam CSIV Form CSIV was manually ground in a mortar for 5 minutes. XRPD was performed before and after grinding. The results showed that the crystalline state of Form CSIV remained unchanged after grinding, indicating that Form CSIV has good grinding stability.

[0169] Example 25: Preparation of a formulation containing Form CSIV Tablets were manufactured with an appropriate amount of Form CSIV of the present disclosure according to the formulation and process in Tables 7 and 8. XRPD was tested before and after formulation. The results show that the crystalline state of Form CSIV remains unchanged after the formulation process.

[0170] The above described embodiments are only intended to explain the technical concepts and features of the present disclosure, and are intended to enable those skilled in the art to understand and implement the present disclosure, and should not be concluded to limit the scope of protection of the present disclosure. Any equivalent variations or modifications according to the spirit of the present disclosure shall be encompassed within the scope of protection of the present disclosure.

Claims

1. A crystalline form of Compound I, wherein the powder X-ray diffraction pattern using CuKα radiation contains characteristic peaks at 2θ values of 4.1° ± 0.2°, 10.2° ± 0.2°, and 22.6° ± 0.2°. 【Chemical 1】

2. The crystalline form of Compound I according to Claim 1, wherein the powder X-ray diffraction pattern using CuKα radiation further contains a characteristic peak at at least one of 2θ values of 11.3° ± 0.2°, 16.5° ± 0.2°, and 17.8°.

3. The crystalline form of Compound I according to Claim 1, wherein the powder X-ray diffraction pattern using CuKα radiation further contains a characteristic peak at at least one of 2θ values of 8.2° ± 0.2°, 10.8° ± 0.2°, 20.5 ± 0.2°, and 24.7° ± 0.2°.

4. The crystalline form of Compound I according to Claim 2, wherein the powder X-ray diffraction pattern using CuKα radiation further contains a characteristic peak at at least one of 2θ values of 8.2° ± 0.2°, 10.8° ± 0.2°, 20.5 ± 0.2°, and 24.7°.

5. The crystalline form of Compound I according to Claim 1, wherein the powder X-ray diffraction pattern using CuKα radiation is substantially as shown in Figure 1.

6. The crystalline form of Compound I according to Claim 1, wherein the thermogravimetric analysis (TGA) curve shows a weight loss of about 0.1% when heated from 26°C to 100°C.

7. The crystalline form of Compound I according to Claim 1, wherein the thermogravimetric analysis (TGA) curve is substantially as shown in Figure 2.

8. The crystalline form of Compound I according to Claim 1, wherein the differential scanning calorimetry (DSC) curve shows an endothermic peak at approximately 131°C (starting temperature), which is the melting endothermic peak.

9. The crystalline form of Compound I according to Claim 1, wherein the differential scanning calorimetry (DSC) curve is substantially as shown in Figure 3.

10. The crystalline form of Compound I according to Claim 1, which is an anhydride.

11. A method for producing the crystalline form of Compound I according to Claim 1, comprising adding a solid of Compound I to an alcohol solvent to form a suspension, stirring the suspension, separating to obtain a solid, and drying the solid under high temperature vacuum to obtain the crystalline form of Compound I.

12. ​ The alcohol solvent is a C1-C4 alcohol, and the stirring temperature ranges from 0 to 50 °C, preferably 50 °C, the stirring time is longer than 1 day, the temperature of high-temperature vacuum drying ranges from 50 to 75 °C, and the drying time is longer than 3 hours, the method according to claim 11.

13. The crystalline form of Compound I, wherein the powder X-ray diffraction pattern using CuKα radiation contains characteristic peaks at 2θ values of 4.2° ± 0.2°, 11.1° ± 0.2°, and 21.7° ± 0.2°. 【Chemical 2】 of the crystalline form.

14. The crystalline form of Compound I according to claim 13, wherein the powder X-ray diffraction pattern using CuKα radiation contains characteristic peaks at at least one of 2θ values of 20.6° ± 0.2°, 21.0° ± 0.2°, and 22.2° ± 0.2°.

15. The crystalline form of Compound I according to claim 13, wherein the powder X-ray diffraction pattern using CuKα radiation contains characteristic peaks at at least one of 2θ values of 10.4° ± 0.2°, 17.7° ± 0.2°, and 23.1° ± 0.2°. of the crystalline form of Compound I according to claim 13.

16. The crystalline form of Compound I according to claim 13, wherein the powder X-ray diffraction pattern using CuKα radiation contains characteristic peaks at at least one of 2θ values of 8.4° ± 0.2°, 13.3° ± 0.2°, 16.3° ± 0.2°, 24.2° ± 0.2°, and 25.4° ± 0.2°.

17. The crystalline form of Compound I according to claim 13, wherein the powder X-ray diffraction pattern using CuKα radiation is substantially as shown in Figure 6.

18. The crystalline form of Compound I according to claim 13, wherein the thermogravimetric analysis (TGA) curve shows a weight loss of about 0.6% when heated from 26 °C to 100 °C.

19. The crystalline form of Compound I according to claim 13, wherein the thermogravimetric analysis (TGA) curve is substantially as shown in Figure 7.

20. The crystalline form of Compound I according to claim 13, wherein the differential scanning calorimetry (DSC) curve shows an endothermic peak at approximately 133 °C (starting temperature), which is the melting endothermic peak.

21. The crystalline form of Compound I according to claim 13, wherein the differential scanning calorimetry (DSC) curve is substantially as shown in Figure 8.

22. The crystalline form of Compound I according to claim 13, which is an anhydride.

23. A method for producing the crystalline form of Compound I according to claim 13, comprising adding a solid of Compound I into acetone to form a suspension, and stirring the suspension to obtain the crystalline form of Compound I.

24. The method according to claim 23, wherein the temperature of the stirring described is in the range of 0 to 50 °C, preferably 5 °C.

25. Compound I having a powder X-ray diffraction pattern using CuKα radiation containing characteristic peaks at 2θ values of 8.5° ± 0.2°, 18.6° ± 0.2°, and 22.0° ± 0.2°. [Chemical Formula 3] Crystal form.

26. The crystal form of Compound I according to claim 25, wherein the powder X-ray diffraction pattern using CuKα radiation contains characteristic peaks at at least one of 2θ values of 12.9° ± 0.2°, 19.1° ± 0.2°, and 23.3° ± 0.2°.

27. The crystal form of Compound I according to claim 25, wherein the powder X-ray diffraction pattern using CuKα radiation contains characteristic peaks at at least one of 2θ values of 13.2° ± 0.2°, 13.8° ± 0.2°, and 21.1° ± 0.2°.

28. The crystal form of Compound I according to claim 25, wherein the powder X-ray diffraction pattern using CuKα radiation contains characteristic peaks at at least one of 2θ values of 7.7° ± 0.2°, 17.2° ± 0.2°, and 26.7° ± 0.2°.

29. The crystal form of Compound I according to claim 25, wherein the powder X-ray diffraction pattern using CuKα radiation is substantially as shown in Figure 11.

30. The crystal form of Compound I according to claim 25, wherein the thermogravimetric analysis (TGA) curve shows a weight loss of about 0.2% when heated from 29 °C to 120 °C.

31. The crystal form of Compound I according to claim 25, wherein the thermogravimetric analysis (TGA) curve is substantially as shown in Figure 14.

32. The crystal form of Compound I according to claim 25, wherein the differential scanning calorimetry (DSC) curve shows one endothermic peak at approximately 144 °C (starting temperature), which is the melting endothermic peak.

33. The crystal form of Compound I according to claim 25, wherein the differential scanning calorimetry (DSC) curve is substantially as shown in Figure 13.

34. The crystal form of Compound I according to claim 25, which is an anhydride.

35. A method for producing the crystal form of Compound I according to claim 25, comprising adding a solid of Compound I to an ether or aromatic hydrocarbon solvent to form a suspension, and stirring the suspension at a temperature in the range of -20 °C to -5 °C to obtain the crystal form of Compound I.

36. The ether solvent is a C5 ether, preferably methyl tert-butyl ether, the aromatic hydrocarbon solvent is a C9 aromatic hydrocarbon solvent, preferably isopropylbenzene, and the stirring temperature is -20°C, the method according to claim 35.

37. A pharmaceutical composition comprising an effective amount of the crystalline form of compound I according to claim 1, or the crystalline form of compound I according to claim 13, or the crystalline form of compound I according to claim 25, or any arbitrary mixture of any two of the crystalline forms, or any arbitrary mixture of the three crystalline forms; and a pharmaceutically acceptable excipient.

38. Use of the crystalline form of compound I according to claim 1, or the crystalline form of compound I according to claim 13, or the crystalline form of compound I according to claim 25, or any arbitrary mixture of any two of the crystalline forms, or any arbitrary mixture of the three crystalline forms for the manufacture of a BTK inhibitor.

39. Use of the crystalline form of compound I according to claim 1, or the crystalline form of compound I according to claim 13, or the crystalline form of compound I according to claim 25, or any arbitrary mixture of any two of the crystalline forms, or any arbitrary mixture of the three crystalline forms for the manufacture of a drug for the treatment of multiple sclerosis.

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