New crystal form of AXL kinase inhibitor

Abstract

The invention relates to the technical field of medicine crystal forms, and particularly discloses a novel crystal form of an AXL kinase inhibitor, a dextro-camphorsulfonate crystal form I and a dextro-camphorsulfonate crystal form II are prepared, and the dextro-camphorsulfonate crystal form I and the dextro-camphorsulfonate crystal form II are both anhydrides and have good physical stability and chemical stability. After the camphor sulfonate crystal form I and the camphor sulfonate crystal form II are placed under the conditions of high temperature (60 DEG C), high humidity (92.5% RH) and illumination for 10 days, the appearance of the camphor sulfonate crystal form II has no obvious change and has no obvious difference in 0 day, and compared with the camphor sulfonate crystal form I and the camphor sulfonate crystal form II, the camphor sulfonate crystal form II is more stable in thermodynamic stability tests in ethanol and methanol supersaturated solutions.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug crystal forms, and specifically discloses a new crystal form of an AXL kinase inhibitor. BACKGROUND

[0002] The protein kinase family comprises a large group of structurally related enzymes that control a variety of signal transduction processes within cells catalyzing the phosphorylation of target protein substrates. Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include benign and malignant proliferative diseases, diseases resulting from inappropriate activation of the immune system, allograft rejection, graft-versus-host disease, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases.

[0003] Effective protein kinase inhibitors for treating the diseases have been developed in the medical field, and the inhibitors are used for the above diseases. CN113912628B proposes a class of compounds for inhibiting, regulating and / or controlling the activity of AXL kinase, and the structure is as follows: The compound is used for treating and / or preventing proliferative diseases, autoimmune diseases, allergic diseases or complications thereof, but no crystal form of the compound is proposed. CN119548503A also proposes the use of an AXL inhibitor in the preparation of a drug for treating heart failure, but neither of them proposes the preparation of a crystal form of the AXL inhibitor. The difference between crystal forms can significantly affect the physical and chemical properties, process performance and bioavailability of the drug. Different crystal forms differ in the arrangement of molecules in the crystal lattice, resulting in differences in thermodynamic stability. The crystal form with high stability is less likely to change during storage and processing, and has a longer shelf life. Crystal forms also directly affect the solubility and dissolution rate of the drug, which in turn affects its in vivo absorption and bioavailability. Some crystal forms have high solubility, which is beneficial to improve drug efficacy, while some crystal forms have low solubility but have better stability and controlled release performance. In addition, the difference between crystal forms also affects the process performance of the drug, such as powder flowability and compression molding, thereby affecting the feasibility of the preparation process. Therefore, in drug development, by systematically screening and developing different salt types and crystal forms, the physical and chemical properties of the drug can be optimized, and the quality of the preparation, the efficacy and the safety of the drug can be improved, which is of great significance for the development of new drugs and the reasonable extension of the patent protection period. SUMMARY

[0004] To solve the problems in the prior art, the present application discloses, in a first aspect, a crystalline form of an AXL kinase inhibitor represented by formula (B):

[0005]

[0006] In specific embodiments of the crystalline form of the first aspect, the crystalline form of the AXL kinase inhibitor of formula (B) is camphorsulfonic acid salt Form I or camphorsulfonic acid salt Form II.

[0007] In preferred embodiments of the crystalline form of the first aspect, the crystalline form of the AXL kinase inhibitor is d-camphorsulfonic acid salt Form I or d-camphorsulfonic acid salt Form II.

[0008] In specific embodiments of the crystalline form of the first aspect, the crystalline form is substantially pure.

[0009] In specific embodiments of the crystalline form of the first aspect, the crystalline form comprises less than 1.2082 wt% of organic solvent and / or water.

[0010] In preferred embodiments of the crystalline form of the first aspect, the crystalline form comprises less than 0.0726 wt% of organic solvent and / or water.

[0011] In specific embodiments of the crystalline form of the first aspect, the molar ratio of the AXL kinase inhibitor to camphorsulfonic acid in the crystalline form is (1-2):(2-1), preferably, the camphorsulfonic acid is d-camphorsulfonic acid.

[0012] In preferred embodiments of the crystalline form of the first aspect, wherein the XRPD pattern of the camphorsulfonic acid salt Form II measured using Cu Ka radiation comprises one or more of the following peaks at 2-theta values: 5.36 ± 0.2° 2Q, 10.92 ± 0.2° 2Q, 17.16 ± 0.2° 2Q, 19.74 ± 0.2° 2Q, 20.70 ± 0.2° 2Q.

[0013] In preferred embodiments of the crystalline form of the first aspect, wherein the camphorsulfonic acid salt Form II further comprises one or more of the following peaks at 2-theta values: 12.38 ± 0.2° 2Q, 21.94 ± 0.2° 2Q, 22.92 ± 0.2° 2Q, 24.14 ± 0.2° 2Q, 28.16 ± 0.2° 2Q.

[0014] In preferred embodiments of the crystalline form of the first aspect, wherein the camphorsulfonic acid salt Form II further comprises one or more of the following peaks at 2-theta values: 29.76 ± 0.2° 2Q, 32.32 ± 0.2° 2Q, 39.20 ± 0.2° 2Q, 45.88 ± 0.2° 2Q.

[0015] In preferred embodiments of the crystalline form of the first aspect, the camphorsulfonic acid salt Form I has a measured XRPD pattern using Cu Ka radiation comprising one or more of the following 2-theta values: 5.28±0.2° 2Q, 10.68±0.2° 2Q, 12.28±0.2° 2Q, 16.94±0.2° 2Q, 17.46±0.2° 2Q, 18.64±0.2° 2Q, 21.60±0.2° 2Q, 22.88±0.2° 2Q, and further comprising at least one, two, three, or four specific peaks selected from the following 2-theta values: 13.84±0.2° 2Q, 14.26±0.2° 2Q, 15.34±0.2° 2Q, 27.74±0.2° 2Q, 29.36±0.2° 2Q.

[0016] In preferred embodiments of the crystalline form of the first aspect, wherein the camphorsulfonic acid salt Form I further comprises one or more of the following 2-theta values: 16.14±0.2° 2Q, 19.30±0.2° 2Q, 23.92±0.2° 2Q, 24.30±0.2° 2Q, 25.04±0.2° 2Q, 26.52±0.2° 2Q, 27.08±0.2° 2Q, 30.48±0.2° 2Q, 34.42±0.2° 2Q, 37.84±0.2° 2Q, 38.72±0.2° 2Q, 41.14±0.2° 2Q.

[0017] In specific embodiments of the crystalline form of the first aspect, the TGA pattern of the camphorsulfonic acid salt Form I is substantially as shown in Figure 3 .

[0018] In specific embodiments of the crystalline form of the first aspect, the DSC pattern of the camphorsulfonic acid salt Form I has an endothermic peak with a peak value at 253.96±2°C.

[0019] In specific embodiments of the crystalline form of the first aspect, the TGA pattern of the camphorsulfonic acid salt Form II is substantially as shown in Figure 26 .

[0020] In specific embodiments of the crystalline form of the first aspect, the DSC pattern of the camphorsulfonic acid salt Form II has an endothermic peak with a peak value at 268.50±2°C;

[0021] A second aspect of the present application provides a pharmaceutical composition comprising a crystalline form of any of the first aspect and a pharmaceutically acceptable carrier, diluent, or excipient.

[0022] The third aspect of the present application provides a use of the crystalline form or the pharmaceutical composition of any one of the first aspect in preventing, treating, curing or alleviating an immune regulation imbalance in a patient, preferably, the immune regulation imbalance comprises a proliferative disease, an autoimmune disease, an allergic disease, a transplant rejection, or a histopathological remodeling disease, preferably, the histopathological remodeling disease comprises myocardial fibrosis, pulmonary fibrosis, or histopathological structural remodeling of heart tissue.

[0023] Definitions of terms

[0024]

[0025] Experimental materials and equipment

[0026]

[0027]

[0028] Experimental reagents

[0029]

[0030] Experimental equipment

[0031]

[0032] Experimental instrument parameters

[0033] X-ray powder diffraction (XRPD): the equipment is Shimadzu XRD-6000, and the sample is scanned according to the following parameters: the ray source is Cu Kα target The minimum operating voltage and current of the light tube are 40 kV and 30 mA respectively, and the 2-Theta value of the sample scanning range is from 2° to 50°. The scanning speed is 5 deg / min.

[0034] Thermogravimetric analysis (TGA): about 5 mg of sample is weighed in a crucible, and the temperature is raised from 30°C to 300°C under nitrogen protection, the temperature rising rate is 20°C / min, and 300°C is kept for 1 min.

[0035] Differential scanning calorimeter (DSC): about 1-5 mg of powder sample is weighed in a closed aluminum crucible, and a pinhole is punched on the crucible cover. Nitrogen protection, differential heat scanning from 30°C to 300°C, 300°C for 1 min. The temperature rising rate is 20°C / min.

[0036] Polarizing microscope (PLM): the sample is dispersed in a medium (silicone oil), a 10X ocular lens and a 10X objective lens are used to observe the sample, and a camera computer system is used to record the image.

[0037] Table 9 Chromatographic conditions for solubility detection of Example 1

[0038]

[0039]

[0040] Advantages of the present invention:

[0041] Two crystal forms of camphorsulfonate salt Form I (Lot E03045-18913-41-01) and Form II (E03045-18913-52-01) were obtained. Camphorsulfonate salt Form I is an anhydrous material and is a crystalline compound. DSC shows an initial melting point of 253.96°C. TGA results show a weight loss of 0.0726% from room temperature to 120°C. Camphorsulfonate salt Form II is an anhydrous material with distinct sharp diffraction peaks and an initial melting point of 268.50°C. TGA results show a weight loss of 1.2082% from room temperature to 120°C.

[0042] The results of the competitive experiment of camphorsulfonate salt Form I and Form II show that the thermodynamically more stable crystal form obtained by equilibrating in an ethanol and methanol supersaturated solution at room temperature for 3 days is camphorsulfonate salt Form II.

[0043] Camphorsulfonate salt Form I and Form II prepared according to the present invention have good physical and chemical stability. When stored at high temperature (60°C), high humidity (92.5% RH), and light for 10 days, there is no obvious change in appearance. The crystal form of Form I and Form II is not significantly different from that at 0 days. The related substances of Form I and Form II increase by 0.10% and 0.09%, respectively, compared to 0 days when stored under light for 10 days. The related substances of Form I and Form II do not change significantly compared to 0 days when stored at high temperature and high humidity for 10 days. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 XRPD results of d-camphorsulfonate salt Lot E03045-18913-41-01;

[0045] Figure 2 XRPD report of d-camphorsulfonate salt Lot E03045-18913-41-01;

[0046] Figure 3 TGA results of d-camphorsulfonate salt Lot E03045-18913-41-01;

[0047] Figure 4 DSC results of d-camphorsulfonate salt Lot E03045-18913-41-01;

[0048] Figure 5PLM results for Dextrorotatory Camphorsulfonate Lot E03045-18913-41-01;

[0049] Figure 6 Dextrorotatory camphorsulfonate Lot E03045-18913-41-01 1 HNMR results;

[0050] Figure 7 XRPD results of the crystalline form of the right-rotatory camphorsulfonate Lot E03045-18913-41-01 obtained by suspension beating at 25°C (I);

[0051] Figure 8 XRPD results of the crystal form obtained by slurrying the dextrorotatory camphorsulfonate Lot E03045-18913-41-01 at 25°C (II);

[0052] Figure 9 DSC results of Dextrorotatory Camphorsulfonate Lot E03045-18913-41-01 after slurrying in purified water at room temperature for 4 days;

[0053] Figure 10 1H NMR results of dextrorotatory camphorsulfonate Lot E03045-18913-41-01 after slurrying in purified water at room temperature for 4 days;

[0054] Figure 1150°C XRPD results of suspension beating of dextrorotatory camphorsulfonate Lot E03045-18913-41-01 (I);

[0055] FIG1 XRPD results of suspension beating of right-rotatory camphorsulfonate Lot E03045-18913-41-01 at 250°C (II);

[0056] Figure 1: DSC of right-rotatory camphorsulfonate Lot E03045-18913-41-01 after slurrying in 50% isopropanol for 2 days at 350°C;

[0057] Figure 1: Dextrorotatory camphorsulfonate Lot E03045-18913-41-01 after slurrying in 50% isopropyl alcohol for 2 days at 450℃ 1 HNMR results;

[0058] Figure 15: DSC of right-rotatory camphorsulfonate Lot E03045-18913-41-01 after slurrying in 50% ethanol for 2 days at 550°C;

[0059] Figure 16: Dextrorotatory camphorsulfonate Lot E03045-18913-41-01 after slurrying in 50% ethanol for 2 days at 50°C 1 HNMR results;

[0060] Figure 17 Overlay of XRPD of d-camphorsulfonate Lot E03045-18913-41-01 slurried in water at 25°C and 50°C at 1750C;

[0061] Figure 18 Volatilization XRPD results of d-camphorsulfonate Lot E03045-18913-41-01 ;

[0062] Figure 19 Anti-solvent XRPD results of d-camphorsulfonate Lot E03045-18913-41-01 ;

[0063] Figure 20 DSC of d-camphorsulfonate Lot E03045-18913-41-01 after dimethylsulfoxide / water anti-solvent process;

[0064] Figure 21 DSC of d-camphorsulfonate Lot E03045-18913-41-01 after dimethylsulfoxide / water anti-solvent process; 1 HNMR;

[0065] Figure 22 XRPD results of crystal form obtained from cooling crystallization of d-camphorsulfonate Lot E03045-18913-41-01 ;

[0066] Figure 23 XRPD results of d-camphorsulfonate E03045-18913-52-01 ;

[0067] Figure 24 XRPD report of d-camphorsulfonate E03045-18913-52-01 ;

[0068] Figure 25 DSC results of d-camphorsulfonate E03045-18913-52-01 ;

[0069] Figure 26 TGA results of d-camphorsulfonate E03045-18913-52-01 ;

[0070] Figure 27 XRPD results of samples of d-camphorsulfonate Lot E03045-18913-41-01 and d-camphorsulfonate E03045-18913-52-01 after 3 days of room temperature competition;

[0071] Figure 28 Solubility curve of d-camphorsulfonate Lot E03045-18913-41-01 ;

[0072] Figure 29Solubility profile of Eudragit® RS 30D Lot E03045-18913-41-01

[0073] Figure 30 Approximate solubility profile of Eudragit® RS 30D Lot E03045-18913-41-01 and E03045-18913-52-01 in the formulation

[0074] Figure 31 Eudragit® RS 30D Lot E03045-18913-41-01 impact factor pre and post sample XRPD results

[0075] Figure 32 Eudragit® RS 30D Lot E03045-18913-52-01 impact factor pre and post sample XRPD results. DETAILED DESCRIPTION

[0076] In order to make the technical personnel in the art better understand the technical solutions of the present application, some non-limiting examples are further disclosed below to further illustrate the present application in detail.

[0077] The present application is to characterize the physical and determine the related physicochemical parameters of the compound Example 1 camphorsulfonate salt. Including XRPD, TGA, DSC, PLM, and approximate solubility in different solvents. At the same time, by using a variety of crystal screening methods, such as beating method, solvent evaporation method, anti-solvent method, cooling crystallization method, etc., a variety of potential crystal forms are found. By characterizing the new crystal form, the crystal form suitable for development is evaluated and screened out.

[0078] The compound of formula B in the present application is used as a free base:

[0079] The free base structure of the present application is,

[0080] The preparation process of Example 1 Eudragit® RS 30D Lot E03045-18913-41-01 is as follows:

[0081] About 2000 mg of free base was weighed into a 100 ml glass bottle, then 80 ml of absolute ethanol (25 mg / ml) was added and stirred at 50°C to give a uniform suspension. Then dextro-camphorsulfonic acid (2 mol / L aqueous solution) was added to the suspension at a molar ratio of 1:1.05. The mixture was stirred magnetically at 50°C for 1 hour, during which time solids precipitated, and after one hour of stirring was allowed to cool to room temperature naturally and stirred magnetically at room temperature overnight. After stirring overnight, the sample was a light yellow suspension, and the solids were collected by centrifugation; the collected solids were dried under reduced pressure at 40°C for 4 hours, and the dried solids were characterized to give dextro-camphorsulfonic acid salt Lot E03045-18913-41-01 as a light yellow powder 2403 mg, with a yield of 88.5%.

[0082] XRPD, TGA, DSC, PLM and 1 HNMR was used to characterize the compound dextro-camphorsulfonic acid salt Lot E03045-18913-41-01. The XRPD results showed that the compound dextro-camphorsulfonic acid salt Lot E03045-18913-41-01 had distinct sharp diffraction peaks Figures 1-2 ), which was consistent with the results of PLM showing distinct birefringence. The TGA results Figure 3 ) showed a weight loss of 0.0726% from room temperature to 120°C, indicating that the starting compound had almost no solvent residues or moisture. The DSC results Figure 4 ) showed a distinct endothermic peak (Onset 253.96°C) which should be the melting peak of the compound. 1 The HNMR results are shown in Figure 6 , and the actual molar ratio of free base to counterion was 1.0:1.0. The initial crystal form was dextro-camphorsulfonic acid salt Lot E03045-18913-41-01, and the initial crystal form dextro-camphorsulfonic acid salt Lot E03045-18913-41-01 was defined as camphorsulfonic acid salt Form I (Form I), and in combination with the DSC and TGA results, camphorsulfonic acid salt Form I was an anhydrous substance.

[0083] Table 1 Preparation of dextro-camphorsulfonic acid salt Lot E03045-18913-41-01

[0084]

[0085] Solubility test of dextro-camphorsulfonic acid salt Lot E03045-18913-41-01

[0086] Approximate solubility test was performed on d-camphorsulfonate Lot E03045-18913-41-01, the list of solvents is shown in Table 2, the test method: about 4 mg of compound was weighed, solvent was added step by step, shaken, and observed whether it was dissolved or not, the volume that could be completely dissolved and the volume of the solvent that could not be completely dissolved before were recorded. The total amount of solvent that was poorly soluble was not more than 4 mL. The solubility was calculated.

[0087] Table 2 Approximate solubility of d-camphorsulfonate Lot E03045-18913-41-01

[0088]

[0089] Crystal form screening

[0090] Suspension slurry method (25°C)

[0091] About 30 mg of d-camphorsulfonate Lot E03045-18913-41-01 was weighed in a liquid phase vial, then 1 mL of solvent was added, and the selected solvent and sample amount are shown in Table 3. All samples were stirred at 25°C for 4 days, and the obtained suspension was collected by centrifugation (12000 rpm, 5 min) to collect the wet solid; the collected solid was further dried in a vacuum drying oven at 40°C under reduced pressure overnight, and then the XRPD of the dried solid was determined.

[0092] The experimental results are summarized in Table 3 and Figures 7-8 At 25°C, the crystal form of the camphorsulfonate obtained by slurry for 4 days in methanol, acetone, 2-butanone, ethyl propyl acetate, acetonitrile, n-heptane, 1,4 dioxane, water and 50% methanol system is shown as MeOH-Slurry-RT, Acetone-Slurry-RT, MeK-Slurry-RT, IPAc-Slurry-RT, ACN-Slurry-RT, Heptane-Slurry-RT, 1-4dioxane-Slurry-RT, Water-Slurry-RT, 50% MeOH-Slurry-RT. Combined with DSC results Figure 9 ) and 1 H NMR results Figure 10 ), the sample obtained by slurry in water for 4 days is a mixture of free base and camphorsulfonate.

[0093] Table 3 Crystal form screening by suspension slurry method (25°C)

[0094]

[0095] Approximately 30 mg of dextrocard sulfonate Lot E03045-18913-41-01 was weighed into a liquid vial, then 1 mL of solvent was added, the solvent and amount weighed are shown in Table 4. All samples were stirred at 50 °C for 2 days, the resulting suspension was collected by centrifugation (12000 rpm, 5 min) as a wet solid; the collected solid was further dried in a vacuum oven at 40 °C under reduced pressure overnight, then the XRPD of the dried solid was measured, if the measured XRPD was different from the original crystalline dextrocard sulfonate Lot E03045-18913-41-01 (Form I), further testing was conducted to confirm the new crystalline form.

[0096] The results of the experiments are summarized in Table 4 and Figures 11-12 . At 50 °C, dextrocard sulfonate Lot E03045-18913-41-01 slurried in methanol, acetone, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, water: isopropanol (1 :9) and water: ethanol (1 :9) for 2 days resulted in samples that were Figure 13 and Figure 15 ) and 1 H NMR results( Figure 14 and Figure 16 ), samples slurried in 50% isopropanol and 50% ethanol for 2 days were mixtures of free base and dextrocard sulfonate. XRPD overlay Figure 17 showed that the samples were the same crystalline form, a mixture of free base and dextrocard sulfonate, after slurrying in water at 25 °C and 50 °C.

[0097] Table 4 Crystalline form screening by slurry method (50 °C)

[0098]

[0099] Solvent evaporation method

[0100] Approximately 30 mg of dextrocard sulfonate Lot E03045-18913-41-01 was weighed into a glass vial, and a good solvent was added to completely dissolve the compound. The sample vial was then capped with an aluminum foil with small holes and placed in a fume hood to allow the solvent to evaporate naturally for about 1-3 weeks to collect the solid, which was further dried in a vacuum oven at 40 °C under reduced pressure overnight. The XRPD of the solid was measured.

[0101] The specific phenomena and treatment processes and results are shown in Table 5 and Figure 17 . The sample obtained by evaporation in dichloromethane was amorphous.

[0102] Table 5 Crystallization by evaporation method

[0103]

[0104] Weigh approximately 30 mg of right-rotating camphorsulfonate LotE03045-18913-41-01 into a glass vial and add an appropriate volume of a good solvent (dichloromethane or dimethyl sulfoxide) to completely dissolve it to form a nearly saturated solution. Then, add different types of anti-solvents shown in Table 6 dropwise until a large amount of solid precipitates, and add an anti-solvent of up to 10 times the volume of the good solvent. For samples with solid precipitation, centrifuge at 12,000 rpm for 10 minutes and collect the wet solid; for samples without solid precipitation, place them in a fume hood and collect the solid by slowly evaporating the solvent. Dry the collected solid under reduced pressure and vacuum at 40°C overnight, and measure the XRPD of the dried solid.

[0105] The experimental results are summarized in Table 6 and Figure 19 There is no significant difference in the XRPD patterns of the samples obtained by the anti-solvent method in dichloromethane / acetone and dichloromethane (good solvent) / ethyl acetate (anti-solvent) systems with the starting material dextrorotatory camphorsulfonate LotE03045-18913-41-01, such as No. 3. However, the XRPD patterns of the samples obtained in dichloromethane (good solvent) / ethanol (anti-solvent), dimethyl sulfoxide (good solvent) / ethyl acetate (anti-solvent) and dimethyl sulfoxide (good solvent) / 2-butanone (anti-solvent) systems are significantly different from the XRPD patterns of dextrorotatory camphorsulfonate LotE03045-18913-41-01; and the DSC results ( Figure 20 )and 1 H NMR results ( Figure 21 ) showed that the sample obtained in the dimethyl sulfoxide (good solvent) / water (antisolvent) system was a mixture of free base and camphorsulfonate.

[0106] Table 6 Anti-solvent method crystal screening

[0107]

[0108] Cooling method

[0109] As shown in Table 7, approximately 30 mg of the dextrorotatory camphorsulfonate salt, Lot E03045-18913-41-01, was weighed into a glass vial. Solvent (acetonitrile or tetrahydrofuran) was added and heated to 50°C to completely dissolve the solution, forming a nearly saturated solution. The temperature was then slowly lowered to room temperature and stirred overnight. For samples with solid precipitation, centrifuge at 12,000 rpm for 10 minutes, collect the wet solid, and dry it under reduced pressure and vacuum at 40°C overnight. The XRPD pattern of the dried solid was then measured.

[0110] The experimental results are summarized in Tables 7 and Figure 22The XRPD data of the sample crystal form obtained by the cooling method of camphorsulfonate in acetonitrile and tetrahydrofuran system are different from those of the right-rotatory camphorsulfonate LotE03045-18913-41-01.

[0111] Table 7 Crystal form screening by cooling method

[0112]

[0113]

[0114] Preparation of Dextrorotatory Camphorsulfonate E03045-18913-52-01

[0115] Approximately 365 mg of the free base was weighed into a 40 ml glass bottle, followed by the addition of 14.6 ml of tetrahydrofuran (25 mg / ml) and stirring at room temperature to obtain a homogeneous suspension. Dextrorotatory camphorsulfonic acid (2 mol / L aqueous solution) was then added to the suspension in a molar ratio of 1:1.05. The suspension was magnetically stirred at room temperature for 24 hours, during which time solids precipitated. After stirring overnight, the sample was a pale yellow suspension, which was collected by centrifugation. The collected solid was dried under reduced pressure at 40°C for 4 hours and characterized to yield 401.58 mg of the dextrorotatory camphorsulfonic acid salt E03045-18913-52-01 as a pale yellow powder, with a yield of 80.6%.

[0116] XRPD was used to perform physical characterization of the dextrorotatory camphorsulfonate E03045-18913-52-01. XRPD results showed that the compound dextrorotatory camphorsulfonate E03045-18913-52-01 had a distinct sharp diffraction peak ( Figure 23 ).DSC results ( Figure 25 ) shows that the initial melting point is 268.50℃. TGA results ( Figure 26 ) showed a weight loss of 1.2082% from room temperature to 120° C. Combining the DSC and TGA results, the camphorsulfonate salt form II is an anhydrous compound.

[0117] Table 8 Scale-up preparation of camphorsulfonate crystal form II in Example 1

[0118]

[0119] Investigation of stable crystal form - competition experiment with adding seed crystals

[0120] In order to study the stability of the crystal form of camphorsulfonate at room temperature, the following competition experiments were carried out for the right-rotating camphorsulfonate Lot E03045-18913-41-01 and the right-rotating camphorsulfonate E03045-18913-52-01 found in the above screening.

[0121] Take 10 mg*2 of d-camphorsulfonic acid salt Lot E03045-18913-41-01 sample, add 2 mL of anhydrous ethanol or methanol respectively, stir at room temperature for 24 h, and there are solids left in each system. Centrifuge, take the supernatant, and add 15 mg of d-camphorsulfonic acid salt Lot E03045-18913-41-01 and d-camphorsulfonic acid salt E03045-18913-52-01 respectively. Take samples after 3 days of equilibrium at room temperature, and detect the crystal form.

[0122] The results show that (Fig. 1): Figure 27 ) the solid crystal form in anhydrous ethanol and methanol at room temperature for 3 days is converted into d-camphorsulfonic acid salt E03045-18913-52-01.

[0123] Dissolution rate and equilibrium solubility test

[0124] Test method: Take 4 mg of d-camphorsulfonic acid salt Lot E03045-18913-41-01 and d-camphorsulfonic acid salt E03045-18913-52-01 respectively in 8 mL vials, add 8 mL of the solvent to be tested, and make the sample evenly dispersed. Place it on a magnetic stirrer at 37°C for 24 h, take samples at 0 min, 10 min, 30 min, 1 h, 2 h and 24 h respectively, filter with a 0.45 μm water phase needle filter, and determine the concentration by HPLC. The solubility detection method is shown in Table 9.

[0125] Table 9 Chromatographic conditions for solubility detection of Example 1

[0126]

[0127]

[0128] Linearity: Take about 10 mg of d-camphorsulfonic acid salt Lot E03045-18913-41-01 and E03045-18913-52-01, and distribute them in a 100 mL volumetric flask. Precisely weigh and add THF:MeOH (1:1, v:v) to dissolve and dilute to the mark. Shake well to obtain the stock solution. Take an appropriate amount of the stock solution, and dilute it to 25 μg / mL, 10 μg / mL, 5 μg / mL and 1 μg / mL with THF:MeOH (1:1, v:v) respectively, and analyze the samples. Draw a standard curve according to the peak area and the corresponding concentration value. The test results and the solubility curve are shown in Table 10 and Fig. 2. Figures 28-29 .

[0129] Table 10 Results of dissolution rate and equilibrium solubility of Lot E03045-18913-41-01 and E03045-18913-52-01 (37°C)

[0130]

[0131] Prescribed Solubility

[0132] 20% PEG400 + 80% (20% HP-β-CD) Medium Preparation:

[0133] Weigh 5.0 g HP-β-CD in a 25 mL volumetric flask, add water to dissolve ultrasonically, and then dilute to the calibration mark, shake well, and reserve for use. We obtain 20% HP-β-CD. We use a pipette to transfer 5 mL of PEG400 and 20 mL of 20% HP-β-CD into a 40 mL glass bottle, shake well, and add about 170 uL of 1N HCl to adjust the pH to 2.2.

[0134] Test Method: We respectively weigh 30 mg of Lot E03045-18913-41-01 and E03045-18913-52-01 into 8 mL vials, gradually add appropriate volumes of 20% PEG400 + 80% (20% HP-β-CD), shake, and observe whether it is dissolved. We record the volume that can be completely dissolved and the volume of the solvent that cannot be completely dissolved before.

[0135] Table 11 Approximate solubility results of camphorsulfonate Form I and Form II in the prescription

[0136]

[0137] Influencing Factor Experiment

[0138] Test Method: We weigh 5 mg of dextrocamphorsulfonate Form I Lot E03045-18913-41-01 and dextrocamphorsulfonate Form II Lot E03045-18913-52-01 into 8 mL glass bottles, place them in a high-temperature 60°C, high-humidity 92.5% RH (open) and light stability box, remove the bottle cap from the open sample and cover the bottle opening with an aluminum foil paper with a pinhole to avoid cross contamination. We take samples at 5 days and 10 days, dilute them with 5 mL of diluent (THF / MeOH (1 / 1) (V / V)) to completely dissolve them, and then perform HPLC analysis according to the chromatographic conditions in Table 12 and XRPD testing. The results are summarized in Table 13.

[0139] Table 12 Chromatographic conditions for influencing factor testing

[0140]

[0141] Table 13 Results summary of Form I and Form II influencing factor testing

[0142]

[0143] Note: The report limit is 0.02%, Form I is Lot E03045-18913-41-01 and Form II is E03045-18913-52-01.

[0144] Conclusion

[0145] Dexcamphorsulfonate Lot E03045-18913-41-01 is an anhydrate and is a crystalline compound. The DSC shows an initial melting point of 253.96°C. The TGA results show a weight loss of 0.0726% from room temperature to 120°C. Dexcamphorsulfonate E03045-18913-52-01 is an anhydrate with distinct sharp diffraction peaks and an initial melting point of 268.50°C. The TGA results show a weight loss of 1.2082% from room temperature to 120°C.

[0146] The results of the competitive experiment study of dexcamphorsulfonate Lot E03045-18913-41-01 and dexcamphorsulfonate E03045-18913-52-01 show that the thermodynamically most stable crystal form obtained in the room temperature equilibration of the supersaturated solutions in ethanol and methanol for 3 days is dexcamphorsulfonate E03045-18913-52-01.

[0147] The solubility test results show that there is no significant difference in the dissolution rate and solubility of dexcamphorsulfonate Lot E03045-18913-41-01 and dexcamphorsulfonate E03045-18913-52-01 in water, FaSSIF, FeSSIF and SGF.

[0148] The results of the influence factors show that there is no significant change in the appearance of dexcamphorsulfonate Lot E03045-18913-41-01 and dexcamphorsulfonate E03045-18913-52-01 after being placed at high temperature (60°C), high humidity (92.5% RH) and light for 10 days. There is no significant difference in the crystal form of dexcamphorsulfonate Lot E03045-18913-41-01 and dexcamphorsulfonate E03045-18913-52-01 compared with 0 days, and the physical stability is good.

[0149] The chemical stability shows that the related substances of dexcamphorsulfonate Lot E03045-18913-41-01 and dexcamphorsulfonate E03045-18913-52-01 increase by 0.10% and 0.09% respectively compared with 0 days under light for 10 days. There is no significant change in the related substances of dexcamphorsulfonate Lot E03045-18913-41-01 and dexcamphorsulfonate E03045-18913-52-01 compared with 0 days after being placed at high temperature and high humidity for 10 days.

[0150] Comprehensive d-camphorsulfonate Lot E03045-18913-41-01 and d-camphorsulfonate E03045-18913-52-01 physicochemical properties, thermodynamic conversion relationship, solubility and influencing factors experiment results, d-camphorsulfonate E03045-18913-52-01 as the follow-up research and development of candidate crystal potential.

[0151] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A crystalline form of an AXL kinase inhibitor represented by formula (B):

2. The crystalline form according to claim 1, characterized in that The crystalline form of the AXL kinase inhibitor of formula (B) is camphorsulfonate salt form I or camphorsulfonate salt form II, preferably, the crystalline form of the AXL kinase inhibitor is dextrorotatory camphorsulfonate salt form I or dextrorotatory camphorsulfonate salt form II; and / or wherein the crystalline form is substantially pure; and / or the crystalline form contains less than 1.2082 wt% of an organic solvent and / or water, preferably, the crystalline form contains less than 0.0726 wt% of an organic solvent and / or water; and / or, in the crystalline form, the molar ratio of the AXL kinase inhibitor to camphorsulfonic acid is (1-2):(2-1), preferably, the camphorsulfonic acid is dextrorotatory camphorsulfonic acid.

3. The crystalline form according to claim 2, characterized in that The XRPD pattern of the camphorsulfonate salt form II measured using Cu Ka radiation comprises peaks at the following 2-θ values: 5.36±0.2°2θ, 10.92±0.2°2θ, 17.16±0.2°2θ, 19.74±0.2°2θ, and 20.70±0.2°2θ.

4. The crystalline form according to any one of claims 2 or 3, characterized in that The camphorsulfonate salt form II further comprises one or more peaks at the following 2-θ values: 12.38±0.2°2θ, 21.94±0.2°2θ, 22.92±0.2°2θ, 24.14±0.2°2θ, and 28.16±0.2°2θ.

5. The crystalline form according to any one of claims 2 to 4, characterized in that The camphorsulfonate salt form II further comprises one or more peaks at the following 2-θ values: 29.76±0.2°2θ, 32.32±0.2°2θ, 39.20±0.2°2θ, and 45.88±0.2°2θ.

6. The crystalline form according to claim 2, characterized in that The XRP D pattern of the camsylate salt Form I measured using Cu Ka radiation comprises peaks at the following 2-θ values: 5.28±0.2°2θ, 10.68±0.2°2θ, 12.28±0.2°2θ, 16.94±0.2°2θ, 17.46±0.2°2θ, 18.64±0.2°2θ, 21.60±0.2°2θ, 22.88±0.2°2θ, and further comprises at least one, two, three or four specific peaks selected from the group consisting of peaks at the following 2-θ values: 13.84±0.2°2θ, 14.26±0.2°2θ, 15.34±0.2°2θ, 27.74±0.2°2θ, 29.36±0.2°2θ.

7. The crystalline form according to claim 6, characterized in that The camphorsulfonate salt form I further includes one or more peaks at the following 2-θ values: 16.14±0.2°2θ, 19.30±0.2°2θ, 23.92±0.2°2θ, 24.30±0.2°2θ, 25.04±0.2°2θ, 26.52±0.2°2θ, 27.08±0.2°2θ, 30.48±0.2°2θ, 34.42±0.2°2θ, 37.84±0.2°2θ, 38.72±0.2°2θ, and 41.14±0.2°2θ.

8. The crystalline form according to any one of claims 1 to 7, characterized in that The TGA spectrum of the camphorsulfonate salt form I is substantially as shown in Figure 3; and / or, the DSC graph of the camphorsulfonate salt form I has an endothermic peak at 253.96±2°C; and / or, the TGA spectrum of the camphorsulfonate salt form II is substantially as shown in Figure 26; and / or, the DSC graph of the camphorsulfonate salt form II has an endothermic peak at 268.50±2°C.

9. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier, diluent or excipient.

10. Use of the crystalline form or pharmaceutical composition of any one of claims 1 to 8 for preventing, treating, curing or alleviating an immune regulation imbalance or a tissue pathological remodeling disease in a patient, wherein the immune regulation imbalance preferably comprises a proliferative disease, an autoimmune disease, an allergic disease, or a transplant rejection, and the tissue pathological remodeling disease preferably comprises myocardial fibrosis, pulmonary fibrosis, or pathological structural remodeling of cardiac tissue.

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