Crystalline forms of trebrutinib, methods for preparing same, and uses thereof

Abstract

The present invention provides novel crystals of trebrutinib, a BTK inhibitor, with improved properties. SOLUTION: Trebrutinib (hereinafter referred to as Compound I) TIFF2026041905000020.tif70115 wherein the XRPD pattern contains characteristic peaks at 2θ values ​​of 7.7°±0.2°, 11.0°±0.2°, 22.8°±0.2°, 12.0°±0.2°, 16.1°±0.2°, and 18.5°±0.2° using CuKα radiation.

Description

[Technical Field]

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

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

[0003] Immunomodulatory drugs are the mainstay of MS treatment, and results from recent clinical trials have demonstrated the efficacy of agents that target B lymphocytes.

[0004] The Bruton's tyrosine kinase (BTK) pathway is important for signaling in myeloid cells, including B lymphocytes and CNS microglia. Each of these cell types is involved in the pathophysiology of MS. Furthermore, because BTK signaling is essential 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 for targeting both aspects of the immune system.

[0005] Therefore, compounds that inhibit BTK and can both inhibit antigen-induced B cell activation, which contributes to neuroinflammation, and modulate maladaptive microglial cells associated with neuroinflammation in the brain and spinal cord, may be useful in treating relapsing multiple sclerosis (RMS), offering significant advantages over currently available therapies.

[0006] Trebrutinib, an oral selective small molecule BTK inhibitor, has demonstrated safety and efficacy 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 shown as follows:

[0008] [ka]

[0009] A crystalline form is a solid material in which the components are arranged in a highly ordered microstructure, forming a crystal lattice that extends in all directions. Polymorphism refers to the phenomenon in which 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 reliably predicted. Different crystalline forms of a drug substance have different physicochemical properties, which can affect the drug's in vivo dissolution and absorption, and to some extent, its clinical efficacy. Especially for some poorly soluble oral solid or semisolid dosage forms, the crystalline form can be crucial to the drug product's performance. Furthermore, the physiochemical properties of the crystalline form are crucial for the production process. Therefore, polymorphism is an important part of drug research and drug quality control. Summary of the Invention [Problem to be solved by the invention]

[0010] The white solid of Compound I was disclosed in WO2016196840A1. The inventors of the present disclosure repeated the preparation process to obtain amorphous Compound I. Furthermore, the inventors of the present disclosure systematically evaluated the properties of the obtained amorphous compound, and the results showed that the amorphous compound I had drawbacks such as low stability, high hygroscopicity, and easy decomposition, making it unsuitable for pharmaceutical use. [Means for solving the problem]

[0011] To overcome the shortcomings of the prior art, the inventors of the present disclosure conducted systematic research on Compound I and found that Compound I is prone to forming amorphous forms and difficult to crystallize. Specifically, the inventors of the present disclosure designed numerous experiments, including different processing methods, solvent systems, and post-treatment processes, in an attempt to obtain a solid form of Compound I with good physicochemical stability, good hygroscopicity, and low decomposition. However, except for the amorphous form of Compound I, no crystalline form suitable for pharmaceutical use was obtained. The inventors of the present disclosure tried many more methods and surprisingly obtained a crystalline form of Compound I. This crystalline form has advantages in at least one aspect of solubility, hygroscopicity, purification ability, stability, viscosity, 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, good hygroscopicity, and low decomposition, which solves the problems existing in the prior art and is of great significance for the development of drugs containing Compound I.

[0012] The present disclosure provides novel crystalline forms of Compound I, methods for their preparation and uses.

[0013] For purposes of this disclosure, crystalline forms of Compound I are provided.

[0014] Additionally, crystalline form CSI of Compound I is provided (hereinafter referred to as Form CSI).

[0015] In one embodiment presented herein, the X-ray powder diffraction pattern of Form CSI contains one, two, or three characteristic peaks at 2-theta values ​​of 7.7°±0.2°, 11.0°±0.2°, and 22.8°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSI contains characteristic peaks at 2-theta values ​​of 7.7°±0.2°, 11.0°±0.2°, and 22.8°±0.2° using CuKα radiation.

[0016] In another embodiment provided herein, the X-ray powder diffraction pattern of Form CSI contains one, two, or three characteristic peaks at 2-theta values ​​of 12.0°±0.2°, 16.1°±0.2°, and 18.5°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSI contains characteristic peaks at 2-theta values ​​of 12.0°±0.2°, 16.1°±0.2°, and 18.5°±0.2° using CuKα radiation.

[0017] In another embodiment provided herein, the X-ray powder diffraction pattern of Form CSI contains one, two, or three characteristic peaks at 2-theta values ​​of 13.6°±0.2°, 20.1°±0.2°, and 24.8°±0.2° using CuKα radiation. Preferably, the X-ray powder diffraction pattern of Form CSI contains characteristic peaks at 2-theta values ​​of 13.6°±0.2°, 20.1°±0.2°, and 24.8°±0.2° using CuKα radiation.

[0018] In another embodiment provided herein, the X-ray powder diffraction pattern of Form CSI comprises one or two or three or four or five or six or seven or eight or nine characteristic peaks at 2-theta values ​​of 7.7°±0.2°, 11.0°±0.2°, 22.8°±0.2°, 12.0°±0.2°, 16.1°±0.2°, 18.5°±0.2°, 13.6°±0.2°, 20.1°±0.2°, 24.8°±0.2°, and 18.7°±0.2° using CuKα radiation.

[0019] Without implying any limitation, the X-ray powder diffraction pattern of Form CSI is substantially as depicted in FIG. 2 using CuKα radiation.

[0020] Without implying any limitation, the DSC curve for Form CSI is substantially as depicted in Figure 6 and exhibits an endothermic peak near 170°C (onset temperature). This peak is the melting endothermic peak.

[0021] Without implying any limitation, the TGA curve for Form CSI is substantially as depicted in Figure 5, showing a weight loss of about 0.4% when heated from 31°C to 160°C.

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

[0023] In accordance with the purposes of the present disclosure, there is also provided a method for fabricating a morphological CSI, the method comprising: This involves adding solid Compound I to a ketone or ether, stirring at a constant temperature, and isolating to obtain Form CSI.

[0024] Furthermore, the ketone is preferably a C3 to C6 ketone, and the ether is preferably a C5 ether.

[0025] Furthermore, the ketone is preferably 4-methyl-2-pentanone, and the ether is preferably methyl tertiary butyl ether.

[0026] Furthermore, the stirring temperature is preferably from room temperature to 55°C, and the stirring time is preferably more than 25 hours.

[0027] For purposes of this disclosure, the present disclosure provides the use of Form CSI to prepare other crystalline forms or salts of Compound I.

[0028] In accordance with the objects of the present disclosure, a pharmaceutical composition is provided, said pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound I and a pharmaceutically acceptable excipient.

[0029] Further provided is the use of a crystalline form of Compound I according to the present disclosure for the manufacture of a BTK inhibitor.

[0030] Further provided is the use of a crystalline form of Compound I according to the present disclosure for the manufacture of a medicament for the treatment of multiple sclerosis.

[0031] Furthermore, the crystalline form of Compound I is preferably Form CSI.

[0032] Technical Problem Solved by the Present Disclosure The inventors of the present disclosure have studied the prior art and found that the prior art is an amorphous form of Compound I. Through research, they have found that the amorphous form of Compound I has drawbacks such as poor chemical stability, poor hygroscopicity, and susceptibility to decomposition, making it unsuitable for pharmaceutical use and industrial production. To overcome the drawbacks of the prior art, the present disclosure provides a crystalline form of Compound I that has excellent physical and chemical stability, good hygroscopicity, and is suitable for the development of drugs containing Compound I.

[0033] As shown in Example 1, Compound I is difficult to crystallize. Only amorphous forms were obtained by various crystallization methods. Even when different crystallization methods were tried and processing conditions during the preparation process, such as solvents (alcohols, ketones, esters, ethers, acids, water, nitriles, amides, halogenated hydrocarbons, aromatic hydrocarbons, alkanes, sulfoxides, etc.), temperature, time, evaporation rate, additives, and other factors were controlled, only amorphous forms were obtained. To obtain Form CSI of the present disclosure, the inventors further tried various unconventional solvents and improved the preparation and post-processing conditions based on the previous preparation method. This indicates that Form CSI provided by the present disclosure would be unexpected for those skilled in the art.

[0034] Technical effects The disclosed form of CSI has the following unexpected advantages: (1) The chemical purity of the prior art solid significantly decreases when stored under conditions of 25°C / 60% RH, 40°C / 75% RH, 60°C / 75% RH, and 80°C. In particular, after storage in an open package at 40°C / 75% RH for six months, the purity decreases by 3.46%, and the number of impurities above the qualified threshold increases to four. After storage in a sealed package at 60°C / 75% RH for only one month, the purity decreases by 2.76%, and the number of impurities above the qualified threshold increases to two. After storage in an open package at 60°C / 75% RH for only one month, the purity decreases by more than 6.3%, and the number of impurities above the qualified threshold increases to four. The chemical stability of the prior art solid is far below pharmaceutical standards.

[0035] Compared to the prior art, the disclosed form of CSI drug substance has good properties both by itself and in drug products. It has stability. The crystalline state of Form CSI drug substance remains unchanged for at least six months when stored in open and sealed packages under conditions of 25°C / 60%RH. The chemical purity is greater than 99.8% and remains substantially unchanged during storage. After Form CSI is mixed with excipients to form a drug product and stored under conditions of 25°C / 60%RH, the crystalline state of Form CSI drug product remains unchanged for at least three months. These results indicate that Form CSI drug substance of the present disclosure, both by itself and in drug products, has good stability under long-term conditions and is suitable for drug storage.

[0036] On the other hand, the crystalline state of Form CSI drug substance remains unchanged for at least six months when stored in open or sealed packages at 40°C / 75% RH. The crystalline state of Form CSI drug substance remains unchanged for at least one month when stored in open or sealed packages at 60°C / 75% RH. The chemical purity is greater than 99.8% and remains substantially unchanged during storage. The chemical purity of Form CSI drug substance remains substantially unchanged for at least two days when stored at 80°C. After Form CSI is mixed with excipients to form a drug product and stored at 40°C / 75% RH, the crystalline state of Form CSI drug product remains unchanged for at least three months. These results indicate that Form CSI drug substance, both by itself and in drug products, has better stability under accelerated and stress conditions. During storage, transportation, and manufacturing, drug substances and drug products experience high temperature and humidity conditions caused by seasonal, regional climate, and environmental differences. Therefore, good stability under accelerated and stressed conditions is very important for drug development. Form CSI drug substance has good stability under stressed conditions, both in itself and in drug products, which is beneficial for avoiding the impact on drug quality due to crystal transformation or loss of purity during drug storage.

[0037] Furthermore, the impurity content of Form CSI drug substance did not exceed the qualification threshold throughout the stability investigation process, meeting the requirements for pharmaceutical development.

[0038] (2) Compared with the prior art, Form CSI of the present disclosure has good hygroscopicity. Test results show that the weight gain of Form CSI is only 1 / 7 of that of the prior art. The weight gain of Form CSI at 80% RH is 0.53%, indicating that Form CSI is slightly hygroscopic. The weight gain of the prior art solid at 80% RH is 3.69%, indicating that the prior art is hygroscopic.

[0039] In one aspect, low hygroscopicity increases susceptibility to chemical degradation and polymorphic transformation, which directly impacts the physical and chemical stability of the drug substance.

[0040] Furthermore, low hygroscopicity reduces the flowability of the drug substance, thereby affecting the processing of the drug substance.

[0041] In another aspect, a drug substance with low hygroscopicity requires a low humidity environment during production and storage, which imposes strict requirements on production and increases costs.More importantly, low hygroscopicity makes the content of active pharmaceutical ingredients in drug products more likely to vary, thereby affecting the quality of the drug products.

[0042] The form CSI provided by the present disclosure, which has good hygroscopicity, is less demanding on production and storage conditions, reduces production, storage, and quality control costs, and has strong economic value. [Brief explanation of the drawings]

[0043] [Figure 1] FIG. 1 shows the XRPD pattern of Sample 1 according to Example 1. [Figure 2] FIG. 1 shows the XRPD pattern of Form CSI according to Example 2. [Figure 3] FIG. 1 shows the XRPD pattern of Form CSI according to Example 3. [Figure 4] FIG. 1 shows the XRPD pattern of Form CSI according to Example 4. [Figure 5] FIG. 1 shows the TGA curve of form CSI. [Figure 6] FIG. 1 shows the DSC curve of form CSI. [Figure 7] Figure 1 shows XRPD pattern overlays of morphological CSI before and after storage (top to bottom: initial, 6 months storage at 25°C / 60% RH (open packaging), 6 months storage at 25°C / 60% RH (sealed packaging), 6 months storage at 40°C / 75% RH (open packaging), 6 months storage at 40°C / 75% RH (sealed packaging), 1 month storage at 60°C / 75% RH (open packaging), 1 month storage at 60°C / 75% RH (sealed packaging). [Figure 8] FIG. 10 shows a DVS plot of morphological CSI. [Figure 9]FIG. 1 shows a DVS plot of a prior art amorphous. [Figure 10] FIG. 1 shows an XRPD pattern overlay of Form CSI before and after compounding (top to bottom: excipients, after compounding, and Form CSI). [Figure 11] FIG. 1 shows XRPD pattern overlays of form CSI drug product stored under different conditions (top to bottom: pristine drug product, stored at 25° C. / 60% RH for 3 months, stored at 40° C. / 75% RH for 3 months). DETAILED DESCRIPTION OF THE INVENTION

[0044] 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.

[0045] The abbreviations used in this disclosure are explained below: XRPD: X-ray powder diffraction DSC: Differential scanning calorimetry TGA: Thermogravimetric analysis DVS: Dynamic Vapor Sorption 1 H NMR: proton nuclear magnetic resonance RH: Relative humidity UPLC: Ultra-high performance liquid chromatography LC: liquid chromatography PE: Polyethylene LDPE: Low-density polyethylene HDPE: High density polyethylene

[0046] 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

[0047] Thermogravimetric analysis (TGA) data in this disclosure was obtained on a TA Q500. The TGA method parameters for this disclosure are as follows: Heating rate: 10℃ / min Purge gas: Nitrogen

[0048] Differential scanning calorimetry (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

[0049] Dynamic vapor sorption (DVS) was measured by an SMS (Surface Measurement Systems Ltd.) proprietary DVS instrument. Typical parameters for a DVS test are as follows: Temperature: 25℃ Gas and flow rate: Nitrogen, 200 mL / min RH range: 0%RH~95%RH

[0050] Proton nuclear magnetic resonance spectrum data ( 1 H NMR) from Bruker Avance II DMX 400 MHz NMR spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to give a solution with a concentration of 2-10 mg / mL.

[0051] The related substances of the present disclosure were detected by UPLC, the parameters of which are shown below.

[0052] [Table 1]

[0053] In the present disclosure, the "stirring" is achieved using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50 to 1800 r / min.

[0054] Preferably, the magnetic stirring speed is 300 to 900 r / min, and the mechanical stirring speed is 100 to 150 r / min. It is 300 r / min.

[0055] The "separation" is achieved using 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 then centrifuged at a speed of 10,000 r / min until all solids settle to the bottom of the tube.

[0056] The "drying" is accomplished using conventional methods in the art, such as vacuum drying, blow drying, or free-air drying. The drying temperature can be room temperature or higher. Preferably, the drying temperature is room temperature to about 60°C, or room temperature to about 50°C, or room temperature to about 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.

[0057] The "room temperature" is not a specific temperature, but is a temperature in the range of 10 to 30°C.

[0058] The "open packaging" involves placing a sample in a glass vial, covering the vial with aluminum foil, and punching 5 to 10 holes in the foil.

[0059] The "sealed packaging" means placing the sample in a glass vial, tightly capping the vial, and sealing the vial in an aluminum foil bag.

[0060] The "characteristic peak" refers to a typical diffraction peak used to distinguish crystals, and may generally have a deviation of ±0.2° using CuKα radiation.

[0061] In this disclosure, "crystal" or "crystalline form" refers to a crystal or crystalline form identified by the X-ray diffraction pattern shown herein. Those skilled in the art will understand that experimental error depends on instrument conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in an X-ray diffraction pattern may also vary depending on experimental conditions; therefore, the order of diffraction peak intensities cannot be considered the sole or determinative factor. In fact, the relative intensities of diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal, and the diffraction peak intensities shown herein are illustrative and do not require identical diffraction peak intensities. Therefore, those skilled in the art will understand that the crystalline forms of the present disclosure do not necessarily have X-ray diffraction patterns identical to the examples shown herein. Any crystalline form whose X-ray diffraction pattern has the same or similar characteristic peaks should be included within the scope of this disclosure. Those skilled in the art can compare the patterns shown in this disclosure with those of an unknown crystalline form to determine whether the two patterns reflect the same or different crystalline forms.

[0062] In some embodiments, Form CSI of the present disclosure is pure and substantially free of any other crystalline forms. In the present 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).

[0063] 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 even ±0.1% of the stated amount.

[0064] Unless otherwise noted, the following examples were carried out at room temperature.

[0065] According to the present disclosure, Compound I and / or its salts used as raw materials are solid (crystalline) Preferably, the compound I used as starting material is a solid.

[0066] The starting materials for Compound I and / or its salts used in the following examples were prepared by known methods in the prior art, for example, the methods disclosed in WO2016196840A1. [Example]

[0067] Attempts to Prepare Compound I Solid Forms The inventors of this disclosure have tried various methods to produce solid forms, adjusting various processing conditions, such as solvents (alcohols, ketones, esters, ethers, acids, water, nitriles, amides, halogenated hydrocarbons, aromatic hydrocarbons, alkanes, sulfoxides, etc.), temperature, time, evaporation rate, additives, and other factors. Over 100 experiments were performed, but only amorphous forms were obtained. Some of the experimental methods and results are listed in Tables 2-6.

[0068] [Table 2]

[0069] Method 1: Stirring According to Table 3, a certain mass of Compound I solid was weighed into a glass vial, and then a certain volume of solvent was added. After stirring at a certain temperature for a certain period of time, the solid was separated. All the obtained solids were confirmed to be amorphous by XRPD. The XRPD pattern of Sample 1 was substantially as depicted in Figure 1.

[0070] [Table 3]

[0071] Method 2: Evaporation A certain mass of Compound I solid was weighed into a glass vial according to Table 4. After adding a certain volume of solvent and additives, the system was evaporated at room temperature. All the obtained solids were confirmed to be amorphous by XRPD.

[0072] [Table 4]

[0073] Method 3: Solid Vapor Diffusion A certain mass of Compound I solid was weighed into a glass vial according to Table 5. The vial was placed in a larger glass vial containing approximately 5 mL of the corresponding solvent. The larger glass vial was sealed with a lid and placed at a constant temperature to ensure sufficient contact between the solvent atmosphere and the solid in the vial. After one day, all solids were removed for XRPD testing and confirmed to be amorphous. Ta.

[0074] [Table 5]

[0075] Method 4: Liquid Vapor Diffusion A certain mass of Compound I solid was weighed into a glass vial and dissolved in a certain volume of solvent according to Table 6. The vial was placed in a larger glass vial containing approximately 5 mL of the corresponding antisolvent, which was then sealed with a cap and placed at a constant temperature to allow the antisolvent vapor to diffuse sufficiently into the inner vial. All solids were isolated and, after varying times of diffusion, were confirmed to be amorphous by XRPD.

[0076] [Table 6]

[0077] The above experimental results show that Compound I is difficult to crystallize and is easily obtained in an amorphous state. The disclosed inventors further tried various unconventional solvents and improved the preparation and work-up conditions, as described in Examples 2-4, and ultimately unexpectedly obtained a crystalline form of Compound I. [Example]

[0078] Manufacturing method of morphological CSI 300.8 mg of Compound I solid was weighed into a 3-mL glass vial, followed by addition of 2.0 mL of methyl isobutyl ketone. After stirring at 50° C. for approximately 39 hours, the solid was isolated. The resulting solid was confirmed to be Form CSI of the present disclosure. The XRPD pattern was substantially as depicted in FIG. 2, and the XRPD data are set forth in Table 7.

[0079] [Table 7-1] [Table 7-2] [Example]

[0080] Manufacturing method of morphological CSI 300.1 mg of Compound I solid was weighed into a 3-mL glass vial, followed by addition of 2.0 mL of methyl isobutyl ketone. After stirring at 50° C. for approximately 6 days, the solid was isolated. The resulting solid was confirmed by XRPD to be Form CSI of the present disclosure. The XRPD pattern was substantially as depicted in FIG. 3, and the XRPD data are set forth in Table 8.

[0081] [Table 8-1] [Table 8-2] [Example]

[0082] Manufacturing of CSI 300.4 mg of Compound I solid was weighed into a glass vial, followed by 3.0 mL of methyl tert-butyl ether. After stirring at 50° C. for approximately 68 hours, the solid was isolated. After drying under vacuum at 75° C. for 1 hour, the resulting solid was confirmed to be Form CSI of the present disclosure, and the XRPD data are shown in FIG. 4 and Table 9.

[0083] The TGA curve is substantially as depicted in Figure 5 and shows a weight loss of about 0.4% when heated from 31°C to 160°C.

[0084] The DSC curve is substantially as depicted in Figure 6. It shows one endothermic peak at around 170°C (onset temperature), which is the melting endothermic peak of Form CSI.

[0085] 1 The H NMR data is as follows: 1 HNMR (400MHz, DMSO) δ (ppm) 7.75 (d, 1H), 7.52-7.36 (m, 4H), 7.21 (t, 1H), 7.14 (t, J=7.8Hz, 4H), 6.98 (d, 1H), 6.91-6.76(m, 1H), 6.13(dd, J=16.5, 7.0Hz, 1H), 5.69(dd, J=16.7, 10.8Hz, 1H), 4.82(s, 2H), 4.50 (t, J = 14.3 Hz, 1H), 4.15 (dd, J = 33.9, 12.5 Hz, 2H), 3.76 (t, J = 13.0 Hz, 0.5H), 3.16 (t, J = 12.7 Hz, 0.5H), 2.79-2.61 (m, 0.5H), 2.45-2.29 (m, J = 13.0, 9.1 Hz, 1H), 2.10-1.74 (m, 2H), 1.66-1.37 (m, 1H). (According to the structure of Compound I, one piperidine hydrogen peak appears at δ 3.33-3.76 ppm. Half of this hydrogen is spitted and covered by the water signal due to its proximity to the water peak.)

[0086] [Table 9] [Example]

[0087] Physical and chemical stability of morphological CSI A fixed amount of Form CSI of the present disclosure and the prior art amorphous material were weighed and stored 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 XRPD overlays of Form CSI before and after stability evaluation are shown in Figure 7.

[0088] [Table 10]

[0089] The dose of Compound I is 60 mg once daily.

[0090] The results showed that Form CSI was stable for at least six months under conditions of 25°C / 60% RH and 40°C / 75% RH, with the solid form and purity remaining essentially unchanged, indicating that Form CSI has good stability under both long-term and accelerated conditions. After storage for one month under conditions of 60°C / 75% RH, the solid form and purity remained essentially unchanged, indicating that Form CSI has good stability even under stress conditions. The impurity content of Form CSI drug substance did not exceed the qualification threshold throughout the stability study process, meeting the requirements for pharmaceutical development. After storage at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH, the purity of the prior art amorphous significantly decreased, falling far below the requirements for pharmaceutical development. After storage in an open package at 40°C / 75% RH for six months, the purity decreased by 3.46%, and the number of impurities exceeding the qualification threshold increased to four. After storage in sealed packaging at 60°C / 75% RH for only 1 month, purity decreased by 2.76% and the number of impurities above the qualification threshold increased to 2. After storage in open packaging at 60°C / 75% RH for only 1 month, purity decreased by over 6.3% and the number of impurities above the qualification threshold increased to 4. The results show that Form CSI of the present disclosure has outstanding chemical stability when compared to prior art amorphous materials. [Example]

[0091] Stability of morphological CSI at high temperatures Approximately 10 mg of the presently disclosed form CSI and prior art amorphous were stored at 80° C. for 2 days and the initial and final purity determined by UPLC, as shown in Table 11.

[0092] [Table 11]

[0093] The results show that the chemical purity of Form CSI remains essentially unchanged for 2 days at 80° C., while significant decomposition of the amorphous material is observed under the same conditions. Form CSI of the present disclosure has superior stability at elevated temperatures compared to prior art amorphous materials. [Example]

[0094] Moisture absorption of CSI Aliquots of Form CSI of the present disclosure and the prior art amorphous were sampled for hygroscopicity testing using a dynamic vapor sorption (DVS) instrument. The weight change at each relative humidity was recorded while cycling from 0% RH to 95% RH to 0% RH at 25°C, and the experimental results are listed in Table 12. The DVS plots for Form CSI and the amorphous are depicted in Figures 8 and 9, respectively.

[0095] [Table 12]

[0096] The results show that Form CSI is slightly hygroscopic with a weight gain of 0.53% at 80% RH, while the prior art solid is hygroscopic with a weight gain of 3.69% at 80% RH. The hygroscopicity of Form CSI is superior to that of the prior art.

[0097] Description and definition of hygroscopicity (Chinese Pharmacopoeia 2020 General Notice 9103 Drug Hygroscopicity Testing Guidelines, experimental conditions: 25±1℃, 80±2%RH): Deliquescent: Absorbs enough water to become liquid. Very high hygroscopicity: Mass increase of 15.0 percent or more. Hygroscopic: Mass increase of less than 15.0 percent and more than 2.0 percent. Slightly hygroscopic: Mass increase of less than 2.0 percent and more than 0.2 percent. Non-hygroscopic or nearly non-hygroscopic: Mass increase of less than 0.2 percent. (The definition of hygroscopicity in the 10th edition of the European Pharmacopoeia, 5.11, is similar to that in the Chinese Pharmacopoeia.) [Example]

[0098] Form CSI drug product manufacturing Drug products were manufactured using appropriate amounts of Form CSI of the present disclosure according to the formulations and processes in Tables 13 and 14. XRPD was tested before and after formulation. The XRPD overlay is shown in Figure 10 and demonstrates that Form CSI of the present disclosure is physically stable before and after the formulation process.

[0099] [Table 13]

[0100] [Table 14] [Example]

[0101] Formation of CSI drug product stability To evaluate the stability of form CSI in the drug product, the packaged drug product prepared in Example 8 was stored for 3 months under conditions of 25°C / 60% RH and 40°C / 75% RH. The XRPD overlays of the drug product before and after storage are depicted in Figure 11.

[0102] The results show that the drug product in the form CSI is stable under the conditions of 25°C / 60%RH and 40°C / 75%RH. It has been shown to be stable under these conditions for at least 3 months.

[0103] The above-described examples are only intended to illustrate the technical concepts and configurations of the present disclosure, and are intended to enable those skilled in the art to understand and thereby implement the present disclosure, and should not be concluded to limit the protection scope of the present disclosure. Any equivalent variations or modifications in accordance with the spirit of the present disclosure should be encompassed by the protection scope of the present disclosure.

Claims

1. Compound I, 【Chemistry 1】 Crystalline form of.

2. 2. The crystalline form of Compound I of claim 1, wherein the X-ray powder diffraction pattern comprises at least one characteristic peak at 2-theta values ​​of 7.7°±0.2°, 11.0°±0.2°, and 22.8°±0.2° using CuKα radiation.

3. 2. The crystalline form of Compound I of claim 1, wherein the X-ray powder diffraction pattern comprises at least one characteristic peak at 2-theta values ​​of 12.0°±0.2°, 16.1°±0.2°, and 18.5°±0.2° using CuKα radiation.

4. 2. The crystalline form of Compound I of claim 1, wherein the X-ray powder diffraction pattern comprises at least one characteristic peak at 2-theta values ​​of 13.6°±0.2°, 20.1°±0.2°, and 24.8°±0.2° using CuKα radiation.

5. 2. The crystalline form of Compound I of claim 1, having an X-ray powder diffraction pattern substantially as depicted in Figure 2 using CuKα radiation.

6. 10. A method for preparing the crystalline form of claim 2, comprising: adding a solid of Compound I to a ketone or ether, stirring at a constant temperature for a period of time, and isolating to obtain the crystalline form.

7. 7. The method of claim 6, wherein the ketone is a C3-C6 ketone and the ether is a C5 ether.

8. 7. The method of claim 6, wherein the ketone is 4-methyl-2-pentanone and the ether is methyl tert-butyl ether.

9. 7. The method of claim 6, wherein the temperature of stirring is between room temperature and 55°C, and the time of stirring is more than 25 hours.

10. 10. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of claim 1 and a pharmaceutically acceptable excipient.

11. 10. Use of the crystalline form of claim 1 for the manufacture of a BTK inhibitor.

12. 10. Use of the crystalline form of claim 1 for the manufacture of a medicament for the treatment of multiple sclerosis.

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