Ritlecitinib citraconate, crystal form thereof, and preparation method therefor

Abstract

The present disclosure relates to a ritlecitinib citraconate, a crystal form thereof, and a preparation method therefor. The method for preparing the ritlecitinib citraconate of the present disclosure is simple, has a high product yield, and is suitable for industrial production. The crystal form of the ritlecitinib citraconate has a good thermal stability, water solubility, low hygroscopicity, and processability. These characteristics make the drug more suitable for storage, transportation, and pharmaceutical preparation. The present disclosure also relates to a pharmaceutical composition comprising a ritlecitinib citraconate or a crystal form thereof and the use thereof in the treatment of related diseases.

Description

A litexitinib citrate, its crystal form and preparation method Technical Field

[0001] This invention relates to the field of medicinal chemistry. Specifically, it relates to litexitinib citrate, its crystal form, and methods for its preparation. The litexitinib citrate and its crystal form of this invention possess good thermal stability, water solubility, low hygroscopicity, and processability, properties that make the drug more suitable for storage and transportation, as well as for pharmaceutical preparation. This invention also relates to pharmaceutical compositions comprising litexitinib citrate or its crystal form, and their use in the treatment of related diseases. Background Technology

[0002] Litecitinib is a novel oral targeted covalent kinase inhibitor developed by Pfizer, primarily used to treat alopecia areata in adolescents aged 12 and older and adults. In September 2018, the FDA granted litecitinib Breakthrough Therapy designation for the treatment of alopecia areata, and approved its marketing in the United States in June 2023. In October 2023, the China Food and Drug Administration approved its marketing in China.

[0003] Litexitinib's chemical name is 1-[(2S,5R)-2-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl]propyl-2-en-1-one, CAS number 1792180-81-4, and its structural formula is shown in formula (I):

[0004] Pfizer's patent application WO2015083028A1 discloses litexitinib and its derivatives, but no information on its salts or crystal forms has been reported. Patent application WO2020084435A1 discloses litexitinib p-toluenesulfonate, its crystal form, and its preparation method; it also reports litexitinib malonate and phosphate, but no information on the relevant crystal forms or other physicochemical data.

[0005] Jiangsu Ailicon Pharmaceutical Technology Co., Ltd. has disclosed three salt forms of litexitinib. Patent CN111620879B discloses a crystal form of litexitinib maleate and its preparation method, and also reports a monohydrate of litexitinib hemimaleate and its preparation method. Patent CN111732591B discloses the crystalline form of litexitinib L-tartrate and its preparation method. Patent CN111620880B discloses the crystalline form of litexitinib DL-tartrate and its preparation method.

[0006] Suzhou Jingyun Pharmaceutical Technology Co., Ltd.'s patent application WO2022012587A1 discloses the preparation methods and uses of two crystal forms, A and B, of litexitinib malonate.

[0007] Currently, there are no reports on litexitinib citrate or its crystalline form.

[0008] The solid-state form of the active pharmaceutical ingredient (API) of a specific drug is often a crucial factor determining the ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in vivo. Different salts and crystal forms of the same drug exhibit significant differences in solubility, stability, melting point, density, and hygroscopicity, thus affecting the drug's stability, homogeneity, bioavailability, efficacy, and safety to varying degrees. Therefore, comprehensive and systematic polymorph screening is an essential and indispensable research aspect in drug development.

[0009] Currently, it is impossible to predict whether a particular compound or its salt will form polymorphs, whether those polymorphs are suitable for commercial use in therapeutic compositions, or which polymorphs will exhibit the desired properties. However, understanding which crystal forms a drug will produce under specific conditions allows researchers to optimize the desired properties of the compound, such as solubility, formulation characteristics, processing characteristics, and shelf life. Understanding these factors early in drug development can mean producing more active, stable, or cheaper drugs. This invention provides a new solution for improving the pharmaceutical properties and storage stability of litexitinib. The litexitinib citrate of this invention offers more and better possibilities for the subsequent development of the drug. Summary of the Invention

[0010] In a first aspect, the present invention provides a novel compound of formula II:

[0011] The chemical name of the compound of formula II of the present invention is 1-[(2S,5R)-2-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl]prop-2-en-1-one citrate, also referred to herein as litexitinib citrate.

[0012] The present invention also provides the crystalline form of the litexitinib citrate, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at 7.0°±0.2°, 11.6°±0.2° and 15.7°±0.2°, expressed in terms of 2θ diffraction angles.

[0013] In some embodiments, the compound of formula II is in crystalline form, characterized by having characteristic diffraction peaks at 7.0°±0.2°, 11.6°±0.2°, 15.7°±0.2°, 16.2°±0.2° and 24.5±0.2° in terms of 2θ diffraction angles.

[0014] In some embodiments, the compound of formula II is in crystalline form, characterized by its X-ray powder diffraction pattern having characteristic diffraction peaks at 7.0°±0.2°, 11.6°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 23.3°±0.2°, 23.7°±0.2° and 24.5±0.2°, expressed in 2θ diffraction angles.

[0015] In some embodiments, the present invention provides the crystalline form of the compound of formula II, characterized in that, when Cu-Kα is used... Under radiation conditions of 40 kV tube voltage, 15 mA tube current, 5° / min scan speed, 0.02° step width, 0.625 slit width (DS), and a continuous θ-2θ scan range of 3-40° (2θ), it exhibits the basic X-ray powder diffraction pattern shown in Figure 1. In one embodiment, the main characteristic diffraction lines expressed in terms of 2θ diffraction angles are shown in Table 1.

[0016] Table 1: Main Characteristic Diffraction Lines of Compounds of Formula I

[0017] In some embodiments, the present invention provides a crystalline form of the compound of formula II, characterized in that it has a differential scanning calorimetry (DSC) curve substantially the same as that shown in Figure 2. In one embodiment, the DSC curve of the crystalline form of said compound of formula II exhibits an endothermic peak at 154.74 °C and reaches its peak value at 158.95 °C.

[0018] In some embodiments, the present invention provides a crystalline form of the compound of formula II, characterized in that it has substantially the same infrared spectra as shown in Figures 3A to 3C, wherein Figure 3A shows an infrared spectrum without characteristic peak wavelength values, and Figure 3B shows an infrared spectrum with characteristic peak wavelength values ​​at 400 cm⁻¹. -1 ~3500cm -1 The infrared spectrum, Figure 3C shows the characteristic peak wavelength values ​​at 400 cm⁻¹. -1 ~1700cm -1 The infrared spectrum of the compound of formula II. In one embodiment, the infrared spectrum of the crystalline form of the compound has the following characteristic peaks: υO-H: 3164 cm⁻¹ -1 ;υN-H:3129cm -1 3101cm -1 ;υC-CH3:2970cm -1 ;υC-CH2-:2877cm -1 υC=O:1634cm -1 δC-H: 1457cm -1 1435cm-1 .

[0019] In some embodiments, the compound of formula II of the present invention is reacted with deuterated DMSO reagent. 1 The H-NMR spectrum is basically as shown in Figure 4. In one embodiment, the NMR data of the compound of formula II of the present invention are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.76(s,1H),8.18(dd,J=6.7,3.6Hz,1H),7.67(d,J=8.0Hz,1H),7 .17(dd,J=3.5,1.9Hz,1H),6.81(td,J=15.9,10.2Hz,1H),6.63(dd,J=3.5,1.4Hz,1H),6.1 1(dd,J=16.7,2.4Hz,1H),5.90(q,J=1.6Hz,1H),5.68(dd,J=10.5,2.4Hz,1H),4.90–4.01( m,4H),1.94(d,J=1.7Hz,3H),1.90–1.81(m,2H),1.69(d,J=11.3Hz,2H),1.31–1.16(m,3H).

[0020] In some embodiments, the thermogravimetric analysis (TGA) curves of the compound of formula II of the present invention are essentially as shown in Figure 5. In one embodiment, the TGA curve of the compound of formula II of the present invention shows that when the temperature rises to 160°C, the sample begins to show significant weight loss, the weight loss process continues until 200°C, and the rate of mass loss tends to slow down. When the temperature reaches 370°C, the compound again shows significant weight loss and continues until a mass-stable state is reached, forming a thermally stable residue.

[0021] Secondly, the present invention provides a method for preparing a compound of formula II, the method comprising the following steps:

[0022] a) Add litexitinib and citrate to a mixture of organic solvent and water, and stir to dissolve them;

[0023] b) Add an antisolvent to the solution obtained in step a) to induce crystallization or cool the solution to induce crystallization;

[0024] c) Filter and dry to obtain compound of formula II.

[0025] The litexitinib can be in various forms, including oily, foamy, non-sticky, amorphous, and crystalline substances.

[0026] The dissolution temperature in step a) is 0-100℃, preferably 20-80℃, and more preferably 30-55℃.

[0027] The organic solvent mentioned in step a) is selected from one of methanol, ethanol, n-propanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, toluene, chlorobenzene, butanone, acetone, methyl isobutyl ketone, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, hexane, heptane, DMF, DMAC, DMSO, NMP, methyl acetate, ethyl acetate, and isopropyl acetate, or a mixture of two or more thereof. Preferably, the organic solvent is selected from tetrahydrofuran, butanone, acetone, methyl isobutyl ketone, or a combination thereof.

[0028] The volume ratio of the organic solvent to water in step a) is 100:8 to 100:12, for example, about 100:9 or about 10:1.

[0029] In step a), the molar ratio of litexitinib to citrate is approximately 2:1 to 1:2.

[0030] The antisolvent mentioned in step b) is selected from one of butanone, acetone, methyl isobutyl ketone, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, hexane, and heptane, or a mixture of two or more thereof. Preferably, the antisolvent is selected from butanone, acetone, and methyl isobutyl ketone.

[0031] In one embodiment, the antisolvent described in step b) is the same as the organic solvent described in step a).

[0032] In step b), the volume ratio of the added antisolvent to the mixed solvent of organic solvent and water described in step a) is 1:1 to 1:1.2, for example, about 1:1.1.

[0033] The drying in step c) is performed under normal pressure or under vacuum. The drying temperature is 10-50℃, preferably 25-50℃, and most preferably 35-45℃; the vacuum degree of the vacuum drying is ≤-0.1 MPa; the drying time is 3-24 hours, preferably 8-12 hours.

[0034] In one embodiment, when preparing the crystals of compound II, seed crystals prepared according to the above method are added to induce crystallization.

[0035] In one embodiment, litexitinib and citrate are added to a mixture of organic solvent and water, and the mixture is kept at a temperature of 20-80°C to dissolve it. Then, an antisolvent is added dropwise to precipitate crystals, thus obtaining crystals of compound II.

[0036] In a preferred embodiment, litexitinib and citrate are added to a mixture of organic solvent and water, and the temperature is controlled at 30-55°C to dissolve them. Then, an antisolvent is added dropwise to precipitate crystals. The mixture is kept at this temperature for 1-4 hours, then cooled to room temperature and stirred for 1-3 hours. The mixture is then filtered and dried to obtain crystals of compound II.

[0037] The present invention also relates to pharmaceutical compositions comprising litexitinib citrate or its crystal form thereof and one or more pharmaceutically acceptable carriers or excipients. Attached Figure Description

[0038] Figure 1 shows the PXRD spectrum of the compound crystal of formula II in Example 1.

[0039] Figure 2 shows the DSC spectrum of the crystal of compound II in Example 1.

[0040] Figures 3A to 3C are infrared spectra of the crystal of compound II in Example 1.

[0041] Figure 4 shows the 1H-NMR spectrum of compound II crystal in Example 1 under deuterated DMSO reagent.

[0042] Figure 5 shows the TGA spectrum of the crystal of compound II in Example 1.

[0043] Figure 6 shows the PXRD spectrum of the compound crystal of formula II in Example 2.

[0044] Figure 7 shows the PXRD spectrum of the compound crystal of formula II in Example 3.

[0045] Figure 8 shows the PXRD spectrum of the compound crystal of formula II in Example 4.

[0046] Figure 9 shows the PXRD of the crystals of compound II after a hygroscopicity study at 25°C / 60% RH.

[0047] Figure 10 shows the PXRD of the crystals of compound II after a hygroscopicity study at 25°C / 75% RH.

[0048] Figure 11 shows the PXRD pattern of the Formula II compound crystal after being placed at 20-25℃ / 60% RH for 60 days.

[0049] Figure 12 shows the PXRD pattern of the Formula II compound crystal after being placed at 30-35℃ / 75% RH for 60 days.

[0050] Figure 13 shows the morphology of compound II under a microscope. Detailed Implementation

[0051] The method of the present invention will be further illustrated by the following embodiments.

[0052] In this invention, the litexitinib compound used is commercially available or prepared by referring to the method of patent WO2015083028A1. The organic solvents and reagents used, such as acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, hexane, n-heptane, and citralic acid, are commercially available.

[0053] In this invention, h represents hours, min represents minutes, g represents grams, mL represents milliliters, mm represents millimeters, RH represents relative humidity, μL represents microliters, μg represents micrograms, and ppm represents percentage concentration.

[0054] The X-ray powder diffraction detection conditions for the aforementioned formula are as follows: using Cu-Kα Radiation, tube voltage 40kV, tube current 15mA, scanning speed 5° / min, step width 0.02°, DS (slit) 0.625, scanning range 3-40° (2θ) continuous θ-2θ scan.

[0055] The thermogravimetric analysis (TGA) was performed under a nitrogen atmosphere with a heating rate of 20°C / min, and the temperature range was from room temperature to 800°C.

[0056] The differential scanning calorimetry (DSC) was performed under a nitrogen atmosphere with a heating rate of 4 °C / min, and the temperature range was 40 °C to 300 °C.

[0057] The moisture content was determined using the Karl Fischer method (KF method). The conditions were as follows: Instruments and reagents: moisture analyzer, 1 / 100,000 balance, Karl Fischer titrant (5 mg / mL), anhydrous methanol (analytical grade); Determination method: Karl Fischer titrant concentration calibration: After pre-titration by the instrument, take approximately 10 μL of ultrapure water (equivalent to 10 μL of standard water sample) using a microsyringe, weigh it accurately, and quickly inject it into the titration vessel. Input the weight (g) and begin calibration. Perform three consecutive calibrations, calculate the average value and relative standard deviation (RSD, not exceeding 1.0%); Sample moisture determination: Pump an appropriate amount of anhydrous methanol into the titration vessel to submerge the electrode (approximately 50 mL). Take approximately 0.2 g of the test sample, weigh it accurately into the titration vessel, stir to dissolve, and determine the moisture content according to the moisture determination method. Perform two parallel operations, and use the average value as the moisture content result.

[0058] The method for testing citrine content is as follows: High-performance liquid chromatography (HPLC) method; Instrument: HPLC system equipped with UV detector; Column: Aglient Poroshell 120Aq-C18, 4.6×150mm, 2.7μm; Determination method: Preparation of diluent: water; Preparation of blank solution: diluent; Preparation of control solution: Weigh 25mg of citrine reagent accurately into a 25mL volumetric flask, add diluent and sonicate to dissolve, cool to room temperature, dilute to the mark with diluent, and mix well; transfer 1.0mL of this solution into a 100mL volumetric flask, dilute to the mark with diluent, and mix well. Preparation of test solution: Weigh 30mg of test sample accurately into a 50mL volumetric flask, add diluent and sonicate to dissolve, cool to room temperature, dilute to the mark with diluent, and mix well; transfer 5.0mL of this solution into a 50mL volumetric flask, dilute to the mark with diluent, and mix well. After the instrument system stabilizes, inject the sample in the above order, and calculate the corresponding citralic acid content using the formula.

[0059] The method for determining the residual solvent content is as follows: Gas chromatography detection; Instrument and chromatographic column: Gas chromatograph / DB-624 equipped with an FID detector, 60m × 0.32m × 1.8μm; Determination method: Prepare diluent and blank solution: Accurately transfer 1.0 mL of diluent into a 20 mL headspace vial, cap and seal. System suitability stock solution: Weigh the corresponding solvent, accurately weigh it into a 100 mL volumetric flask containing approximately 50 mL of diluent, dilute to the mark with diluent, and mix well. System suitability stock solution: Accurately transfer 5.0 mL of system suitability stock solution into a 100 mL volumetric flask, dilute to the mark with diluent, and mix well. Accurately transfer 1.0 mL of each of the above solutions into six 20 mL headspace vials, cap and seal. Preparation of the test solution: Weigh 0.05 g of the test sample accurately into a 20 mL headspace vial, accurately add 1.0 mL of diluent, cap and seal. After the instrument system stabilizes, inject the sample in the above order. The corresponding solvent residue can be calculated using the formula.

[0060] The microscope model ISH300 consists of an eyepiece, microscope tube, revolving nosepiece, objective lens, diaphragm, mirror, stage, etc. Usage: After sampling and adjusting the light, place the slide to be observed on the microscope stage and ensure the slide clamp is firmly in place. Then, by adjusting the coarse and fine adjustment knobs, the microscope tube can be raised and lowered to find the clearest image for observation.

[0061] The HMKFlow329 angle of repose measuring instrument consists of a stirrer, height gauge, funnel, funnel nozzle, level bubble, and testing platform. The funnel nozzle is available in 15mm, 12mm, and 25mm sizes, with 10mm being preferred. The testing method is as follows: Take a sample of at least 150g, slowly pour the sample into the funnel, rotate the stirrer to help the sample remain on the testing platform to form a cone, and measure the height using the height gauge after the sample has completely covered the sample. The formula for calculating the angle of repose is: Angle of repose = tan... -1 (Height of cone / Radius of cone) = Angle of repose, where the radius of the cone is the radius of the test platform, which is 50mm.

[0062] The litexitinib p-toluenesulfonate, malonate, and phosphate were prepared according to the method described in patent WO2020084435A1.

[0063] The litexitinib monomaleate and hemimaleate were prepared according to the method described in patent CN111620879B.

[0064] Preparation of Compounds of Formula II

[0065] Example 1

[0066] 43.0 g of litexitinib free base and 10.0 g of citrate were added to a mixed solvent consisting of 100 ml of methyl ethyl ketone (MEK) and 9 ml of purified water. The mixture was stirred and kept at 35-45°C until dissolved, then stirred for 2.0-3.0 h. Next, 100 ml of MEK was added dropwise over 0.5-1.0 h. After the addition was complete, the mixture was stirred to allow crystals to precipitate for 2.0-3.0 h, then allowed to cool naturally to room temperature and stirred for 1.0-3.0 h. The mixture was filtered, and the filter cake was washed with 10.0 ml of MEK to obtain a wet material. The wet material was dried at 45°C under a vacuum of ≤-0.1 MPa for approximately 12.0 h to obtain 23.3 g (80.5% yield) of litexitinib citrate, with a chromatographic purity of 99.89% (XRPD scan shown in Figure 6). The residual moisture content was 0.07%, and residual solvent analysis showed 300.02 ppm of MEK residue.

[0067] Example 2

[0068] 43.0 g of litexitinib free base and 10.0 g of citralic acid were added to a mixed solvent consisting of 100 ml acetone and 9 ml purified water. After dissolution at 35-45℃, the mixture was stirred and kept at this temperature for 2.0-3.0 h. Then, 100 ml of acetone was added dropwise over 0.5-1.0 h. After the addition was complete, the mixture was stirred to allow crystals to precipitate for 2.0-3.0 h, then allowed to cool naturally to room temperature and stirred for 1.0-3.0 h. The mixture was filtered, and the filter cake was washed with 10.0 ml of acetone to obtain a wet material. The wet material was dried at 45℃ under a vacuum of ≤-0.1 MPa for approximately 12.0 h to obtain 22.0 g (75.9% yield) of litexitinib citralic acid salt with a chromatographic purity of 99.3% (XRPD scan shown in Figure 7). The residual water content was 0.08%, and residual solvent analysis showed 500.1 ppm of acetone residue.

[0069] Example 3

[0070] Add 43.0 g of litexitinib free base and 10.0 g of citrate to a mixed solvent consisting of 100 ml of methyl isobutyl ketone and 9 ml of purified water. After dissolving completely at 35-45℃, maintain this temperature and stir for 2.0-3.0 h. Then, add 100 ml of methyl isobutyl ketone dropwise over 0.5-1.0 h. After the addition is complete, stir to allow crystals to precipitate for 2.0-3.0 h, then allow to cool naturally to room temperature and stir for 1.0-3.0 h. Filter the solution, and wash the filter cake with 10.0 ml of methyl isobutyl ketone to obtain a wet material. The obtained wet material was dried at 45°C and under a vacuum of ≤-0.1MPa for about 12.0 h to obtain 20.0 g (68.6% yield) of litexitinib citrate with a chromatographic purity of 98.7%, as shown in Figure 8 by XRPD scanning. The residual moisture content was 0.05%, and residual solvent analysis showed a residual methyl isobutyl ketone of 460.5 ppm.

[0071] Example 4

[0072] Add 43.0 g of litexitinib free base and 10.0 g of citrate to a mixed solvent consisting of 100 ml tetrahydrofuran and 9 ml purified water. After dissolving completely at 35-45°C, maintain the temperature and stir for 2.0-3.0 h. Then, add 100 ml of butanone dropwise over 0.5-1.0 h. After the addition is complete, stir to allow crystals to precipitate for 2.0-3.0 h, then allow to cool naturally to room temperature and maintain the temperature and stir for 1.0-3.0 h. Filter by suction, and wash the filter cake with 10.0 ml of butanone to obtain a wet material. The obtained wet material was dried at 45°C and under a vacuum of ≤-0.1MPa for about 12.0 h to obtain 17.6 g (60.8% yield) of litexitinib citrate with a chromatographic purity of 98.2%, as shown in Figure 9 by XRPD scanning. The residual moisture content was 0.08%, and residual solvent analysis showed 180.5 ppm of butanone and 120.6 ppm of tetrahydrofuran.

[0073] Example 5: Study on the citrate content in litexitinib citrate

[0074] The litexitinib citrate, prepared according to the method in Example 1, was used to determine the citrate content in three samples by high-performance liquid chromatography (HPLC). First, after the HPLC system stabilized, the samples were injected according to the sequence shown in Table 2:

[0075] Table 2: Sample Injection Sequence List for High Performance Liquid Chromatography

[0076] After the injection was completed, the applicability of the system was further investigated. Once the requirements were met, the test sample was tested, and the results are shown in Table 3.

[0077] Table 3: Test Data Table of Sample Parameters

[0078] Finally, calculate the content using the following formula:

[0079] In the formula: A m —Peak area of ​​citralic acid in the test solution; A s —Peak area of ​​6 injections of citraconic acid in the control solution;

[0080] W m —Concentration of the test solution, μg / mL; W s —The concentration of citraconic acid in the control solution, in μg / mL;

[0081] P – Citric acid content

[0082] Known control sample test data: A s =444.15; W s =9.996ug / ml, citralic acid (commercially purchased) content: P=99.0%, the content results of the three batches of samples obtained by calculation formula are 31.08%, 30.96%, and 30.91%, respectively, which are basically consistent with the theoretical value of 31.3% of compound II. Therefore, the ratio of free base to citralic acid in litexitinib citralic acid salt of the present invention is 1:1.

[0083] Example 6: Hygroscopicity Study of Litexitinib Citrate

[0084] Two groups of 20.00 mg litexitinib citrate of the present invention were weighed and placed in clean glass dishes, respectively, and placed open in test chambers at 25°C / 60% RH and 25°C / 75% RH. After 3 days, the samples from the 25°C / 60% RH test chamber and the 25°C / 75% RH test chamber were weighed and both showed a weight of 20.02 mg. The PXRD values ​​of the two groups of samples after hygroscopicity testing are shown in Figures 10-11. The results show that the crystal form remained consistent before and after the hygroscopicity test, indicating good humidity stability. Litexitinib citrate only increased in weight by 0.1% at 25°C / 75% RH, which, according to the pharmacopoeia, is considered to be almost non-hygroscopic, thus meeting the requirements for hygroscopicity during drug production and storage.

[0085] Different types of litexitinib salt samples were placed at 25°C and under conditions ranging from 20% RH to 80% RH, and their hygroscopic specific gravity was checked. If the weight gain was less than 0.01% within 15 minutes, it was increased by 10% further, with a maximum humidity of 80%. The results are shown in Table 4. The results indicate that litexitinib citrate exhibits better hygroscopic properties under conditions of 25°C and 20% RH to 80% RH.

[0086] Table 4. Hygroscopicity of different salt forms of litexitinib

[0087] Example 7: Stability of litexitinib citrate

[0088] 2.0 g of litexitinib citrate from Example 1 was placed in a stability chamber at temperatures and humidity levels of 20-25°C / 60% RH and 30-35°C / 75% RH, respectively, for 15, 30, and 60 days. The sample was analyzed by HPLC and X-ray powder diffraction (XPRD) to examine its solid form and compare it with its initial crystal form. The results are shown in Table 5.

[0089] Table 5. Stability of litexitinib citrate

[0090] The results show that litexitinib citrate exhibits good physicochemical stability. After 60 days of storage at 20-25℃ / 60% RH and 30-35℃ / 75% RH, no significant changes were observed in crystal form and purity, indicating stability. Therefore, it meets the stability requirements during drug production and storage. The X-ray powder diffraction patterns of the sample stored at 20-25℃ / 60% RH for 60 days are shown in Figure 11, and the X-ray powder diffraction patterns of the sample stored at 30-35℃ / 75% RH for 60 days are shown in Figure 12.

[0091] The results of crystal form analysis of different litexitinib salt samples after being placed at 30-35℃ / 75% RH for 30 days are shown in Table 6. The results indicate that the crystallinity of litexitinib citrate of the present invention remained essentially unchanged after 30 days of placement at 30-35℃ / 75% RH, demonstrating superior stability compared to other salt forms.

[0092] Table 6 Thermal stability of different litexitinib salts

[0093] Example 8: Solubility of litexitinib citrate

[0094] During drug development, different salt forms of litexitinib can be optimized to adjust its solubility, thereby improving its bioavailability.

[0095] In this invention, the solubility of litexitinib citrate was first tested. Test method: 100 mg of litexitinib citrate sample and a specified amount of solvent (see Table 7) were added to a 5 mL screw-top bottle, and the mixture was incubated in a 37°C water bath with shaking for 24 h. Then, the mixture was cooled to 25°C and held at that temperature for 4 h. After centrifugation for 5 minutes, the supernatant was diluted, and the solubility of the sample in different solvents was measured. The results are shown in Table 7.

[0096] Table 7. Solubility of litexitinib citrate

[0097] The results show that rituximab citrate exhibits better solubility in alcohol and highly polar solvent systems, while showing relatively limited solubility in ketone solvent systems.

[0098] In addition, the water solubility of other salts of litexitinib was also determined. The method was as follows: the sample was placed in 1 ml of purified water at different temperatures, followed by vigorous shaking every five minutes for thirty seconds each time, with continuous monitoring for half an hour. If no undissolved solid particles were observed visually within the half-hour observation period, the sample was considered completely dissolved in the purified water. The measurement results are shown in Table 8.

[0099] Table 8. Water solubility of different salts of litexitinib

[0100] The results showed that litexitinib citrate exhibits higher water solubility compared to currently reported typical litexitinib salts, a characteristic that is beneficial for its subsequent processing and drug formulation development.

[0101] Example 9: Processability of litexitinib citrate

[0102] The litexitinib citrate was prepared using any one of the preparation methods in Examples 1-4. Its crystal morphology, as shown in Figure 13, was observed under a microscope. The crystal particles of this compound exhibited a cubic morphology, and their distribution was relatively dispersed. This observation indicates that the crystal structure of this compound has distinct geometric features, and the spatial arrangement between the crystal particles is relatively sparse.

[0103] Angle of repose determination: Six groups of samples were tested. The first three groups tested litexitinib free base. 150g of each sample was placed in a funnel, stirred, and the height of the hammer was measured at 54.2mm, 54.6mm, and 55.3mm, respectively. The average angle of repose calculated using the angle of repose formula was 47°. The last three groups tested litexitinib citrate. 150g of each sample was placed in a funnel, stirred, and the height of the hammer was measured at 40.7mm, 40.3mm, and 41.1mm, respectively. The average angle of repose calculated using the angle of repose formula was 39°. The fluidity changed from poor (46°≤angle of repose≤55°) to good (36°≤angle of repose≤40°).

[0104] Studies have shown that, compared to the free base of litexitinib, litexitinib citrate has a smaller angle of repose and better flowability in the test, which is therefore more beneficial for formulation preparation.

[0105] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. Compounds of Formula II:

2. The compound according to claim 1, characterized in that, The compound of formula II is crystalline.

3. The compound according to claim 2, characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at 7.0°±0.2°, 11.6°±0.2° and 15.7°±0.2°, expressed in terms of 2θ diffraction angles.

4. The compound according to claim 2, characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at 7.0°±0.2°, 11.6°±0.2°, 15.7°±0.2°, 16.2°±0.2° and 24.5±0.2°, expressed in terms of 2θ diffraction angles.

5. The compound according to claim 2, characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at 7.0°±0.2°, 11.6°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 23.3°±0.2°, 23.7°±0.2° and 24.5±0.2°, expressed in terms of 2θ diffraction angles.

6. The compound according to claim 2, having an X-ray powder diffraction pattern as shown in Figure 1.

7. A method for preparing the compound of formula II according to claim 1 or 2, comprising the following steps: a) Add litexitinib and citrate to a mixture of organic solvent and water, and stir to dissolve them; b) Add an antisolvent to the solution obtained in step a) to induce crystallization or cool the solution to induce crystallization; c) Filter and dry to obtain compound of formula II.

8. The method according to claim 7, wherein the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, toluene, chlorobenzene, butanone, acetone, methyl isobutyl ketone, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, hexane, heptane, DMF, DMAC, DMSO, NMP, methyl acetate, ethyl acetate, and isopropyl acetate, or mixtures thereof, preferably the organic solvent is selected from tetrahydrofuran, butanone, acetone, methyl isobutyl ketone, or combinations thereof.

9. The method according to claim 7 or 8, wherein the volume ratio of the organic solvent to water in step a) is 100:8 to 100:12, for example, about 100:9 or about 10:

1.

10. The method according to any one of claims 7 to 9, wherein the molar ratio of litexitinib to citrate in step a) is about 2:1 to 1:

2.

11. The method according to any one of claims 7 to 10, wherein the antisolvent is selected from one of butanone, acetone, methyl isobutyl ketone, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, hexane and heptane, or a mixture of two or more thereof, preferably the antisolvent is selected from butanone, acetone and methyl isobutyl ketone.

12. A pharmaceutical composition comprising a compound of formula II as described in any one of claims 1-6 and one or more pharmaceutically acceptable carriers or excipients.

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