CRYSTAL FORM OF TOLEBRUTINIB AND METHODS OF ITS PREPARATION

Abstract

The invention relates to a novel crystalline form of Tolebrutinib (hereinafter referred to as "Compound I") and a method for preparing it, and a pharmaceutical preparation containing the crystalline form. Compared with a prior technical solution, the crystalline form of Tolebrutinib according to the invention has one or more improved properties and is of substantial value for future drug optimization and development.

Description

Tolebrutinib crystal form, preparation method and use thereof Technical Field

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

[0002] 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, with significant physical, psychological, social, and economic impacts on patients and their families. MS involves an immune-mediated process in which an abnormal response of the body's immune system targets the central nervous system (CNS). During the course of the disease, sclerosis, such as lesions or scars, develop in the myelin sheath of nerve cells, interfering with the transmission of electrical signals. Sclerosis accumulates over time and leads to debilitating symptoms in people with MS.

[0003] Immunomodulatory drugs have always been the main means of treating MS, and recent clinical research results have demonstrated the effectiveness of drugs targeting B lymphocytes.

[0004] The Bruton's tyrosine kinase (BTK) pathway is crucial for signaling in B lymphocytes and myeloid cells, including central nervous system 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, inhibition of BTK can modulate both cellular and humoral immunity. Accordingly, BTK signaling inhibitors have demonstrated dual effects on both cellular and humoral immunity.

[0005] Therefore, BTK-inhibiting compounds that can suppress antigen-induced B cell activation responsible for neuroinflammation and modulate maladaptive microglia associated with neuroinflammation in the brain and spinal cord may help treat relapsing multiple sclerosis (RMS) with better efficacy than currently available therapies.

[0006] Tolebrutinib, an oral, selective small molecule BTK inhibitor, has shown safety and efficacy in the treatment of RMS patients.

[0007] The chemical name of Tolebrutinib 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 its structural formula is as follows:

[0008]

[0009] A crystal is a solid formed by the orderly three-dimensional arrangement of compound molecules within a microscopic structure, forming a lattice. Polymorphism refers to the phenomenon of a single compound existing in multiple crystal forms. A compound may exist in one or more crystal forms, but their existence and properties cannot be precisely predicted. APIs in different crystal forms have varying physicochemical properties, which can lead to varying dissolution and absorption in the body, thereby impacting the drug's clinical efficacy to a certain extent. Crystal form is particularly crucial to product performance for poorly soluble oral solid or semisolid dosage forms. Furthermore, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is a crucial aspect of pharmaceutical research and quality control.

[0010] WO2016196840A1 discloses a white solid compound I. The inventors of the present application repeated the preparation process of this compound to obtain an amorphous form of Compound I. Furthermore, the inventors of the present application conducted a systematic evaluation of the properties of this amorphous form. The results showed that the amorphous form of Compound I suffered from poor stability, high hygroscopicity, and easy degradation, making it unsuitable for pharmaceutical use.

[0011] In order to overcome the shortcomings of the prior art, the inventors of the present application conducted a systematic study on Compound I and found that the compound easily becomes amorphous and is not easy to crystallize. Specifically, the inventors of the present application designed a large number of preparation experiments, including different preparation methods, solvent systems and post-treatment processes, trying to obtain a solid form of Compound I that is not easy to crystallize, has good physicochemical stability, low hygroscopicity, and is not easy to degrade. The results were all amorphous forms of Compound I, and no pharmaceutically acceptable crystal form was obtained. The inventors of the present application further tried more preparation methods and eventually unexpectedly obtained the crystals of Compound I provided by the present invention. The crystals have advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability, especially good stability, low hygroscopicity, and not easy to degrade, which solves the problems existing in the prior art and is of great significance to the development of drugs containing Compound I.

[0012] Summary of the Invention

[0013] The main purpose of the present invention is to provide a new crystalline form of Compound I and its preparation method and use.

[0014] According to the purpose of the present invention, the present invention provides a crystalline form of Compound I.

[0015] Furthermore, the present invention provides a crystalline form of Compound I which may be crystalline form CSI (hereinafter referred to as "crystalline form CSI").

[0016] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 7.7°±0.2°, 11.0°±0.2°, and 22.8°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 7.7°±0.2°, 11.0°±0.2°, and 22.8°±0.2°.

[0017] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 12.0°±0.2°, 16.1°±0.2°, and 18.5°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 12.0°±0.2°, 16.1°±0.2°, and 18.5°±0.2°.

[0018] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 13.6°±0.2°, 20.1°±0.2°, and 24.8°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 13.6°±0.2°, 20.1°±0.2°, and 24.8°±0.2°.

[0019] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at any one of the diffraction angles 2θ values ​​of 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°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10.

[0020] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSI is substantially as shown in FIG2 .

[0021] Without limitation, the differential scanning calorimetry analysis diagram of the crystalline form CSI is substantially as shown in FIG6 , in which an endothermic peak begins to appear around 170° C., and the endothermic peak is a melting endothermic peak.

[0022] Without limitation, the thermogravimetric analysis graph of Form CSI is substantially as shown in FIG5 , which has a mass loss of about 0.4% when heated from 31° C. to 160° C.

[0023] Without limitation, the crystalline form CSI is an anhydrate.

[0024] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSI, the preparation method comprising:

[0025] The solid compound I is placed in a ketone or ether solvent, stirred for a period of time under certain temperature conditions, and the solid is separated to obtain the crystalline form CSI;

[0026] Furthermore, the ketone is preferably a C3-C6 ketone, and the ether solvent is preferably a C5 ether.

[0027] Furthermore, the ketone is preferably 4-methyl-2-pentanone, and the ether solvent is preferably methyl tert-butyl ether.

[0028] Furthermore, the stirring temperature is preferably room temperature to 55° C., and the stirring time is preferably more than 25 hours.

[0029] According to the purpose of the present invention, the present invention provides the use of the crystal form CSI for preparing other crystal forms or salts of Compound I.

[0030] According to the purpose of the present invention, the present invention also provides a pharmaceutical composition, which comprises an effective therapeutic amount of a crystalline form of Compound I and a pharmaceutically acceptable excipient.

[0031] Furthermore, the present invention provides the use of the crystalline form of Compound I in the preparation of BTK inhibitor drugs.

[0032] Furthermore, the present invention provides a use of the crystalline form of Compound I in the preparation of a drug for treating multiple sclerosis.

[0033] Furthermore, the crystalline form of Compound I is preferably crystalline form CSI.

[0034] Technical Problems Solved by the Invention

[0035] The inventors of this application studied the prior art and discovered that the prior art is an amorphous form of Compound I. Furthermore, this amorphous form of Compound I exhibits poor chemical stability, is easily degraded, and exhibits high hygroscopicity, making it unsuitable for pharmaceutical use or industrial production. To address the problems of the prior art, the present invention provides a crystalline form of Compound I with excellent physicochemical stability and low hygroscopicity, making it suitable for the development of pharmaceuticals containing Compound I.

[0036] As can be seen from Example 1, Compound I is difficult to crystallize, and a variety of crystal preparation methods can only obtain amorphous. Even if a variety of crystal preparation methods are tried during the preparation process, multiple process conditions are controlled, such as: solvent type (alcohol, ketone, ester, ether, acid, water, nitrile, amide, halogenated hydrocarbon, aromatic hydrocarbon, alkane, sulfoxide, etc.), temperature, time, volatilization rate, additives and other factors, only amorphous can be obtained. The acquisition of the crystal form CSI of the present invention is that the inventors of the present application further attempted to use a variety of unconventional solvents on the basis of existing crystal preparation experiments, while refining the preparation and post-processing conditions, and finally obtained unexpectedly. It can be seen that the acquisition of the crystal form CSI of the present invention is unpredictable for those skilled in the art.

[0037] Technical Effects

[0038] The crystalline CSI provided by the present invention has the following unexpected technical effects:

[0039] (1) The purity of the prior art solid was significantly reduced when placed under 25°C / 60% RH, 40°C / 75% RH, 60°C / 75% RH and 80°C. In particular, when placed open at 40°C / 75% RH for 6 months, the purity decreased by 3.46%, and the number of impurities exceeding the limit increased to 4; when placed sealed at 60°C / 75% RH for 1 month, the purity decreased by 2.76%, and the number of impurities exceeding the limit increased to 2; when placed open at 60°C / 75% RH for only 1 month, the purity decreased by more than 6.3%, and the number of impurities exceeding the limit increased to 4, which is far below the pharmaceutical standard.

[0040] Compared with the prior art, the crystalline CSI API and preparation provided by the present invention have good stability. The crystalline CSI API is placed sealed and exposed at 25°C / 60% RH for at least 6 months without changing its crystal form, and its chemical purity is above 99.8%, and the purity remains basically unchanged during storage. After the crystalline CSI is mixed with excipients to form a pharmaceutical preparation, it is placed at 25°C / 60% RH and the crystal form does not change for up to 3 months. This shows that the crystalline CSI API and preparation have good stability under long-term conditions, which is beneficial to the storage of the drug.

[0041] Furthermore, the crystalline CSI API exhibited no change in crystal form when stored at 40°C / 75% RH for at least six months, both sealed and unsealed, and at 60°C / 75% RH for at least one month. Furthermore, its chemical purity remained above 99.8%, maintaining substantially the same purity during storage. Furthermore, its purity remained unchanged at 80°C for at least two days. After the crystalline CSI was mixed with excipients to form a pharmaceutical preparation, the crystalline form remained unchanged for at least three months when stored at 40°C / 75% RH. This demonstrates that the crystalline CSI API and preparation exhibit improved stability under accelerated and more stringent conditions. High temperatures and high humidity, caused by seasonal variations, regional climate variations, and environmental factors, can affect the storage, transportation, and production of APIs. Therefore, the stability of APIs and preparations under accelerated and more stringent conditions is crucial for pharmaceuticals. The enhanced stability of crystalline CSI APIs and preparations under these harsh conditions helps prevent the effects of crystal transformation or purity loss during storage, which can impact drug quality.

[0042] In addition, the impurity content of the crystalline CSI raw material did not exceed the defined limit during all stability tests, and can meet the requirements of pharmaceutical development.

[0043] (2) Compared with the prior art, the crystalline CSI provided by the present invention has lower hygroscopicity. Test results show that the crystalline CSI of the present invention has a weight gain upon moisture absorption of only 1 / 7 that of the prior art solid. The crystalline CSI has a hygroscopic weight gain of 0.53% at 80% RH, which is slightly hygroscopic. The prior art solid has a hygroscopic weight gain of 3.69% at 80% RH, which is quite hygroscopic.

[0044] On the one hand, high hygroscopicity can easily cause chemical degradation and crystal transformation of APIs, directly affecting their physicochemical stability. Furthermore, high hygroscopicity can reduce the flowability of APIs, thus affecting their processing.

[0045] On the other hand, highly hygroscopic drugs require low humidity during production and storage, placing higher demands on production and incurring high costs. More importantly, high hygroscopicity can easily cause changes in the content of the active ingredient in the drug, affecting its quality.

[0046] The crystalline CSI provided by the present invention has low hygroscopicity and low requirements for storage conditions in industrial production, thereby reducing the costs of material production, storage and quality control, and has strong economic value. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 is the XRPD pattern of sample 1 in Example 1

[0048] Figure 2 is the XRPD pattern of the crystalline form CSI obtained in Example 2

[0049] Figure 3 is the XRPD pattern of the crystal form CSI obtained in Example 3

[0050] Figure 4 is the XRPD pattern of the crystal form CSI obtained in Example 4

[0051] Figure 5 is the TGA graph of crystal form CSI

[0052] Figure 6 is the DSC diagram of crystal form CSI

[0053] FIG7 is an XRPD stack of the stability of Form CSI before and after storage (from top to bottom: before storage, exposed at 25°C / 60% RH for 6 months, sealed at 25°C / 60% RH for 6 months, exposed at 40°C / 75% RH for 6 months, sealed at 40°C / 75% RH for 6 months, exposed at 60°C / 75% RH for 1 month, and sealed at 60°C / 75% RH for 1 month)

[0054] Figure 8 DVS diagram of crystal form CSI

[0055] FIG9 Amorphous DVS diagram of the prior art

[0056] Figure 10 XRPD overlays of the crystalline CSI before and after preparation (from top to bottom: blank mixed powder, crystalline CSI after preparation process, crystalline CSI)

[0057] Figure 11 XRPD stacked images of the stability of the crystalline CSI formulation before and after storage (from top to bottom: before storage, 25°C / 60% RH for 3 months, 40°C / 75% RH for 3 months) DETAILED DESCRIPTION

[0058] The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many variations in both materials and methods may be made without departing from the scope of the present invention.

[0059] The abbreviations used in the present invention are explained as follows:

[0060] XRPD: X-ray powder diffraction

[0061] DSC: Differential Scanning Calorimetry

[0062] TGA: Thermogravimetric analysis

[0063] DVS: Dynamic Water Sorption

[0064] 1 H NMR: liquid hydrogen nuclear magnetic spectroscopy

[0065] RH: relative humidity

[0066] UPLC: Ultra-Performance Liquid Chromatography

[0067] LC: Liquid chromatography

[0068] PE: Polyethylene

[0069] LDPE: Low-density polyethylene

[0070] HDPE: High-density polyethylene

[0071] Instruments and methods used to collect data:

[0072] The X-ray powder diffraction pattern of the present invention was collected on a Bruker X-ray powder diffractometer. The method parameters of the X-ray powder diffraction of the present invention are as follows:

[0073] X-ray source: Cu, Kα

[0074] Kα1 1.54060; Kα2 1.54439

[0075] Kα2 / Kα1 intensity ratio: 0.50

[0076] The thermogravimetric analysis (TGA) graphs of the present invention were collected on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

[0077] Scan rate: 10℃ / min

[0078] Shielding gas: N2

[0079] The differential scanning calorimetry (DSC) graphs of the present invention were collected on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

[0080] Scan rate: 10℃ / min

[0081] Shielding gas: N2

[0082] The dynamic moisture sorption (DVS) graphs described herein were collected using an Intrinsic dynamic moisture sorption instrument manufactured by SMS (Surface Measurement Systems Ltd.). The instrument control software was DVS-Intrinsic control software. The method parameters for the dynamic moisture sorption instrument were as follows:

[0083] Temperature: 25℃

[0084] Carrier gas, flow rate: N2, 200 ml / min

[0085] Relative humidity range: 0%RH-95%RH

[0086] H NMR data ( 1 H NMR spectra were obtained on a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a 2-10 mg / mL solution.

[0087] The related substance detection method of the present invention adopts ultra-performance liquid chromatography (UPLC) with the following instrument parameters:

[0088] Table 1

[0089]

[0090]

[0091] In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm and the mechanical stirring is preferably 100-300 rpm.

[0092] The separation is accomplished using conventional methods in the art, such as centrifugation or filtration. The centrifugation step involves placing the sample to be separated in a centrifuge tube and centrifuging at 10,000 rpm until all solids have settled to the bottom of the tube. The supernatant is then discarded, and the solids are collected.

[0093] The drying process is accomplished using conventional methods in the art, such as vacuum drying, forced air drying, or air drying. The drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 2-48 hours, or overnight. Drying is performed in a fume hood, forced air oven, or vacuum oven.

[0094] The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.

[0095] The “open” method is to place the sample in a glass bottle, cover the bottle mouth with a layer of aluminum foil and open 5-10 small holes in the aluminum foil.

[0096] The “sealing” means placing the sample in a sealed glass bottle, and sealing the glass bottle in an aluminum foil bag.

[0097] The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Kα radiation, the peak position can usually have an error of ±0.2°.

[0098] In the present invention, "crystals" or "crystal forms" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that X-ray powder diffraction patterns can vary depending on instrument conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in an X-ray powder diffraction pattern may also vary with experimental conditions, so the diffraction peak intensities cannot be the sole or decisive factor in determining a crystal form. In fact, the relative intensities of diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown herein are illustrative and not intended for absolute comparison. Therefore, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed by the present invention do not necessarily have to be identical to those in the Examples described herein; any crystal form having an X-ray powder diffraction pattern with characteristic peaks identical or similar to those in these patterns falls within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction patterns listed herein with those of an unknown crystal form to determine whether the two patterns reflect the same or different crystal forms.

[0099] In some embodiments, the crystalline form CSI of the present invention is pure and substantially free of any other crystalline form. As used herein, "substantially free" when referring to a new crystalline form means that the crystalline form contains less than 20% (by weight) of any other crystalline form, particularly less than 10% (by weight) of any other crystalline form, more particularly less than 5% (by weight) of any other crystalline form, and even more particularly less than 1% (by weight) of any other crystalline form.

[0100] The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0101] Unless otherwise specified, the following examples were all performed at room temperature.

[0102] According to the present invention, the compound I as a raw material includes but is not limited to solid form (crystalline or amorphous), oily form, liquid form and solution. Preferably, the compound I as a raw material is in solid form.

[0103] Compound I used in the following examples can be prepared according to existing technologies, for example, according to the method described in WO2016196840A1.

[0104] Example 1: Attempt to Prepare Compound 1 Solid Form

[0105] The inventors of this application have attempted various methods for preparing crystalline forms, controlling various process conditions, such as solvent type (alcohols, ketones, esters, ethers, acids, water, nitriles, amides, halogenated hydrocarbons, aromatic hydrocarbons, alkanes, sulfoxides, etc.), temperature, time, volatilization rate, additives, and other factors. Over a hundred experiments have been conducted, and all have resulted in amorphous forms. Some of these experimental methods and results are shown in Tables 2-6.

[0106] Table 2

[0107]

[0108] Method 1: Stirring

[0109] Compound 1 solids (masses shown in Table 3) were weighed and placed in a glass bottle. A certain volume of solvent was added and stirred at a certain temperature for a certain period of time. The solids were then separated and analyzed by XRPD. The resulting solids were all amorphous. The X-ray powder diffraction pattern of Sample 1 is shown in Figure 1.

[0110] Table 3

[0111]

[0112]

[0113] Method 2: Volatilization

[0114] The solid of Compound I having the mass shown in Table 4 was weighed and placed in a glass bottle. A certain volume of solvent and additive was added thereto, and the mixture was evaporated at room temperature. XRPD analysis showed that the obtained solid was amorphous.

[0115] Table 4

[0116]

[0117] Rapid evaporation: The sample bottle is not covered with a cap and is open for evaporation.

[0118] Slow evaporation: Cover the sample bottle tightly with a small hole.

[0119] Method 3: Gas-solid permeation

[0120] The solid of Compound I having the mass shown in Table 5 was weighed and placed in a glass bottle. The glass bottle was then placed in a larger glass bottle containing approximately 5 mL of the corresponding solvent. The larger glass bottle was sealed with a cap and then placed under certain temperature conditions to allow sufficient contact between the solvent atmosphere and the solid in the smaller glass bottle. After one day, the solid was removed from the bottle and XRPD analysis revealed that the obtained solid was amorphous.

[0121] Table 5

[0122] Sample mass (mg) Solvent Temperature (℃) Solid form 17.0 n-Hexane Amorphous at room temperature 28.0 Water Amorphous at room temperature 37.6 Dimethyl sulfoxide Amorphous at room temperature 49.9 N,N-dimethylacetamide Amorphous at room temperature 513.0 Benzyl alcohol 5 Amorphous 69.7 L-Ethyl lactate 5 Amorphous 713.1 Petroleum ether 5 Amorphous 811.3 1,3-Dioxolane 5 Amorphous

[0123] Method 4: Gas-Liquid Permeation

[0124] A solid of Compound I having a mass as shown in Table 6 was weighed and placed in a glass bottle. A certain volume of positive solvent was added thereto to dissolve the sample. The open glass bottle was then placed in a large glass bottle containing approximately 5 mL of antisolvent. The large glass bottle was sealed with a cap and then left at room temperature to allow the antisolvent to fully diffuse into the small glass bottle. After diffusion for different times, the solids were separated. XRPD analysis showed that the obtained solids were all amorphous.

[0125] Table 6

[0126]

[0127]

[0128] The above experimental results show that Compound I easily forms an amorphous form and is difficult to crystallize. The inventors of this application further attempted to use a variety of unconventional solvents while refining the preparation and post-processing conditions, and ultimately unexpectedly obtained the crystals of Compound I provided by the present invention. See Examples 2-4.

[0129] Example 2: Preparation method of crystalline CSI

[0130] 300.8 mg of Compound I solid was weighed into a 3 mL glass vial, followed by 2.0 mL of 4-methyl-2-pentanone. The mixture was stirred at 50°C for approximately 39 hours, and the solid was isolated. XRPD analysis confirmed that the resulting solid was Form CSI of the present invention. Its X-ray powder diffraction pattern is shown in Figure 2, and the X-ray powder diffraction data are shown in Table 7.

[0131] Table 7

[0132]

[0133]

[0134] Example 3: Preparation method of crystalline CSI

[0135] 300.1 mg of Compound I solid was weighed into a 3 mL glass vial, 2.0 mL of 4-methyl-2-pentanone was added, and the mixture was stirred at 50°C for approximately 6 days. The solid was then isolated. XRPD analysis confirmed that the resulting solid was Form CSI of the present invention. Its X-ray powder diffraction pattern is shown in Figure 3, and the X-ray powder diffraction data are shown in Table 8.

[0136] Table 8

[0137]

[0138]

[0139] Example 4: Preparation of Crystalline CSI

[0140] 300.4 mg of Compound I solid was weighed into a glass bottle, 3.0 mL of methyl tert-butyl ether was added, and the mixture was stirred at 50°C for about 68 hours. The solid was separated and dried in vacuo at 75°C for 1 hour. XRPD analysis showed that the resulting solid was Form CSI of the present invention. The X-ray powder diffraction data are shown in Table 9 and Figure 4.

[0141] As shown in FIG5 , the TGA analysis showed that the mass loss was about 0.4% when the product was heated from 31° C. to 160° C.

[0142] As shown in FIG6 , DSC shows an endothermic peak at around 170° C., which is the melting endothermic peak of crystalline form CSI.

[0143] 1 The HNMR data are: 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 of the hydrogen atoms on the piperidine ring of this compound elutes at 3.33-3.76 ppm, and the 0.5H atoms separated from the piperidine ring are close to the water peak and are therefore covered by it.)

[0144] Table 9

[0145]

[0146]

[0147] Example 5: Physicochemical stability of crystalline CSI

[0148] The crystalline Form CSI prepared in the present invention and the amorphous form prepared in the prior art were weighed and stored at 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH, respectively. UPLC and XRPD were used to determine purity and crystalline form. The results are shown in Table 10. Overlays of XRPD images of the stability of Form CSI before and after storage are shown in Figure 7.

[0149] Table 10

[0150]

[0151] Note: The limit of action is based on the International Conference on Harmonization of Technical Requirements for Regulation of Pharmaceuticals for Human Use, Impurities in New Drug Substances Q3A(R2). The dosage of Compound I is 60 mg, once daily.

[0152] Results showed that crystalline CSI was stable for at least six months at 25°C / 60% RH and 40°C / 75% RH, maintaining essentially unchanged crystal form and purity. This demonstrates that crystalline CSI maintains good stability under both long-term and accelerated conditions. At 60°C / 75% RH, it remained stable for at least one month, maintaining essentially unchanged crystal form and purity, demonstrating excellent stability even under more stringent conditions. Throughout the stability study, impurity levels in crystalline CSI remained within defined limits, meeting the requirements for pharmaceutical development. The purity of the prior art solid was significantly reduced when placed under 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH conditions. In particular, after being exposed at 40°C / 75% RH for 6 months, the purity decreased by 3.46%, and the number of impurities exceeding the limit increased to 4. After being sealed at 60°C / 75% RH for 1 month, the purity decreased by 2.76%, and the number of impurities exceeding the limit increased to 2. After being exposed at 60°C / 75% RH for only 1 month, the purity decreased by more than 6.3%, and the number of impurities exceeding the limit increased to 4, which is far below the pharmaceutical standard. This shows that the crystalline form CSI of the present invention has very superior chemical stability compared to the amorphous form of the prior art.

[0153] Example 6: High temperature stability of crystalline CSI

[0154] About 10 mg of the crystalline CSI prepared by the present invention and the amorphous form prepared in the prior art were respectively taken and placed at 80° C. for 2 days. The initial purity and final purity were determined by UPLC. The results are shown in Table 11.

[0155] Table 11

[0156]

[0157] The results showed that the chemical purity of the crystalline CSI remained essentially unchanged after being stored at 80°C for two days, while the amorphous form was observed to degrade significantly under the same conditions. This shows that compared to the amorphous form of the prior art, the crystalline CSI of the present invention has a significant advantage in high-temperature stability.

[0158] Example 7: Hygroscopicity of Crystalline CSI

[0159] Appropriate amounts of the crystalline CSI of the present invention and the amorphous form of the prior art were weighed and their hygroscopicity was tested using a dynamic moisture sorption (DVS) instrument. The hygroscopicity was cycled once at 25°C, 0% RH-95% RH-0% RH, and the mass change at each humidity was recorded. The experimental results are shown in Table 12. The DVS diagram of the crystalline CSI is shown in Figure 8, and the DVS diagram of the amorphous form is shown in Figure 9.

[0160] Table 12

[0161]

[0162] Experimental results show that the crystalline CSI has a slightly hygroscopic weight gain of 0.53% at 80% RH, compared to a 3.69% hygroscopic weight gain at 80% RH for the prior art solid, indicating moderate hygroscopicity. Crystalline CSI exhibits superior hygroscopicity to the prior art.

[0163] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition General Chapter 9103 Guiding Principles for Hygroscopicity Test of Drugs, experimental conditions: 25℃±1℃, 80%±2% relative humidity):

[0164] Deliquescent: Absorbs enough water to form a solution

[0165] Highly hygroscopic: weight gain due to moisture absorption is not less than 15.0%

[0166] Hygroscopic: Weight gain due to moisture absorption is less than 15.0% but not less than 2.0%

[0167] Slightly hygroscopic: weight gain due to moisture absorption is less than 2.0% but not less than 0.2%

[0168] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%

[0169] (The definition of hygroscopicity in 5.11 of the European Pharmacopoeia, 10th edition, is similar to that in the Chinese Pharmacopoeia)

[0170] Example 8 Preparation of Crystalline Form CSI

[0171] An appropriate amount of the crystalline form CSI of the present invention was weighed and tableted according to the formulation and process described in Tables 13 and 14. XRPD analysis was performed before and after formulation. The XRPD patterns before and after formulation are shown in Figure 10 . The results demonstrate that the crystalline form CSI of the present invention is stable before and after the formulation and process.

[0172] Table 13

[0173]

[0174] Table 14

[0175]

[0176] Example 9 Stability of Crystalline CSI Formulations

[0177] The packaged CSI formulations in Example 8 were placed at 25°C / 60% RH and 40°C / 75% RH for 3 months to investigate the stability of the crystalline CSI formulations. XRPD comparisons of the formulations before and after placement are shown in Figure 11.

[0178] The results showed that the crystalline CSI preparation could remain stable for at least 3 months under 25℃ / 60%RH and 40℃ / 75%RH conditions.

[0179] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A crystalline form of compound I 2. The crystalline form of Compound I according to claim 1, It is characterized in that The X-ray powder diffraction pattern thereof has a characteristic peak at at least one of 2θ values ​​of 7.7°±0.2°, 11.0°±0.2°, and 22.8°±0.2° using Cu—Kα radiation.

3. The crystalline form of Compound I according to claim 1, It is characterized in that The X-ray powder diffraction pattern thereof has a characteristic peak at at least one of 2θ values ​​of 12.0°±0.2°, 16.1°±0.2°, and 18.5°±0.2° using Cu—Kα radiation.

4. The crystalline form of Compound I according to claim 1, It is characterized in that Using Cu—Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 13.6°±0.2°, 20.1°±0.2°, and 24.8°±0.2°.

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

6. A method for preparing the crystal form according to claim 2, It is characterized in that The preparation method comprises: placing the solid compound I in a ketone or ether solvent, stirring for a period of time under certain temperature conditions, and separating to obtain the compound I.

7. The preparation method according to claim 6, It is characterized in that The ketone is a C3-C6 ketone, and the ether solvent is a C5 ether.

8. The preparation method according to claim 6, It is characterized in that The ketone is 4-methyl-2-pentanone, and the ether solvent is methyl tert-butyl ether.

9. The preparation method according to claim 6, It is characterized in that The stirring temperature is room temperature-55° C., and the stirring time is more than 25 hours.

10. A pharmaceutical composition comprising an effective therapeutic amount of the crystalline form of Compound I according to claim 1 and a pharmaceutically acceptable excipient.

11. Use of the crystalline form of Compound I described in claim 1 in the preparation of BTK inhibitor drugs.

12. Use of the crystalline form of Compound I as claimed in claim 1 in the preparation of a drug for treating multiple sclerosis.