Crystal form of zasocitinib, preparation method therefor and use thereof

Abstract

Provided are a crystal form of zasocitinib and a preparation method therefor, a pharmaceutical composition containing the crystal form, and a use of the crystal form in preparation of a TYK2 inhibitor drug and a drug for treating psoriasis, psoriatic arthritis, inflammatory bowel diseases, and other autoimmune diseases.

Description

Zasocitinib 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 crystalline form of Zasocitinib, a preparation method thereof, and uses thereof. Background Art

[0002] Zasocitinib is a TYK2 inhibitor developed by Nimbus Lakshmi for the treatment of psoriasis, psoriatic arthritis, inflammatory bowel disease, and other autoimmune diseases. It has shown positive results in clinical trials.

[0003] The chemical name of Zasocitinib is N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2′-bipyridyl]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (hereinafter referred to as “Compound I”), and its structural formula is as follows:

[0004] 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.

[0005] According to the FDA's guidance on pharmaceutical cocrystals, pharmaceutical cocrystals are crystalline materials composed of two or more different molecules (one of which is an active pharmaceutical ingredient (API)) bound together in a stoichiometric ratio within a single crystal lattice via non-ionic and non-covalent bonds. One advantage of pharmaceutical cocrystals is that they can be used to improve drug bioavailability and stability, as well as enhance the processing performance of APIs during drug production. Another advantage of pharmaceutical cocrystals is that they offer a wider range of solid-state forms for APIs that lack ionizable functional groups and are difficult to form into salts.

[0006] WO2023183910A1 discloses crystal forms A to J. Except for crystal forms A, C, D, and J, which are hydrates or anhydrates, the remaining crystal forms are solvates, have poor crystallinity, or are mixed crystals. WO2023183910A1 discloses that crystal forms A, D, and J can transform into crystal form C under certain conditions.

[0007] To overcome the shortcomings of the prior art, a new crystalline form that meets pharmaceutical requirements is still needed for the development of drugs containing Compound I. The crystalline form of Compound I provided by the present invention offers advantages in at least one of solubility, hygroscopicity, stability, adhesion, and compressibility, thus overcoming the problems of the prior art and having significant implications for the development of drugs containing Compound I.

[0008] Summary of the Invention

[0009] The present invention provides a co-crystal of Compound I, a method for preparing the same, and a pharmaceutical composition comprising the co-crystal.

[0010] According to the purpose of the present invention, the present invention provides a co-crystal of Compound I and citric acid. Without limitation, the co-crystal is crystal form CSVI (hereinafter referred to as "crystal form CSVI").

[0011] In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 6.7°±0.2°, 11.1°±0.2°, and 17.2°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at diffraction angles 2θ of 6.7°±0.2°, 11.1°±0.2°, and 17.2°±0.2°.

[0012] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 18.1°±0.2°, 20.6°±0.2°, and 26.4°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at diffraction angles 2θ of 18.1°±0.2°, 20.6°±0.2°, and 26.4°±0.2°.

[0013] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 16.1±0.2°, 19.0°±0.2°, and 22.3°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at diffraction angles 2θ of 16.1±0.2°, 19.0°±0.2°, and 22.3°±0.2°.

[0014] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the diffraction angle 2θ values ​​of 6.7°±0.2°, 11.1°±0.2°, 17.2°±0.2°, 18.1°±0.2°, 20.6°±0.2°, 26.4°±0.2°, 16.1±0.2°, 19.0°±0.2°, 22.3°±0.2°, 15.6°±0.2°, 17.0°±0.2°, 23.9°±0.2°, and 24.2°±0.2°.

[0015] Without limitation, using Cu-Ka radiation, the XRPD pattern of Form CSVI is substantially as shown in FIG1 .

[0016] Without limitation, the TGA graph of Form CSVI is substantially as shown in FIG. 2 , and when heated to about 150° C., it has a mass loss of about 0.11%.

[0017] Without limitation, Form CSVI is an anhydrous co-crystal of Compound 1 and citric acid.

[0018] Without limitation, the molar ratio of Compound I to citric acid in the crystalline form CSVI is 1:0.5-1:1.5, preferably 1:0.8-1:1.2, and more preferably 1:1.

[0019] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSVI, which comprises:

[0020] Compound I and citric acid are placed in an ester solvent and stirred, filtered, and then dried to obtain crystalline form CSVI.

[0021] Furthermore, the ester solvent is preferably ethyl acetate; the molar ratio of compound I to citric acid is preferably 1:0.5-1:1.5, more preferably 1:0.8-1:1.2; the stirring temperature is preferably 5-50°C; and the drying temperature is preferably room temperature-100°C.

[0022] The crystalline form CSVI provided by the present invention has the following advantages:

[0023] (1) Compared with the prior art, the crystalline form CSVI provided by the present invention has higher solubility. In PBS buffer (pH 6.8), ABS buffer (pH 4.5), and 0.1N HCl aqueous solution, the solubility of crystalline form CSVI is 3 to 5 times that of the prior art crystalline form C.

[0024] The crystalline CSVI provided by the present invention has higher solubility, which is beneficial for improving drug absorption in the human body and increasing bioavailability. In addition, the higher solubility can reduce the dosage of the drug while ensuring the drug's efficacy, thereby reducing the drug's side effects and improving the drug's safety.

[0025] (2) Compared with the prior art, the crystalline form CSVI provided by the present invention has lower hygroscopicity. Test results show that the crystalline form CSVI has a hygroscopic weight gain of 0.83% under 0-95% RH conditions. The hygroscopic weight gain of the prior art crystalline form is more than twice that of the crystalline form CSVI.

[0026] High hygroscopicity can easily cause chemical degradation and crystal transformation of APIs, thereby affecting the physicochemical stability of the API. Furthermore, high hygroscopicity can reduce the fluidity of the API, thus affecting its processing. The crystalline form of CSVI provided by the present invention has low hygroscopicity, is less demanding on drug production and storage, reduces drug production, storage, and quality control costs, and has strong economic value.

[0027] (3) The crystalline form CSVI provided by the present invention has good stability. Crystalline form CSVI maintained its crystalline form unchanged for at least six months at 40°C / 75% RH and for at least three months at 60°C / 75% RH. Furthermore, its chemical purity was above 99.7%, and the purity remained essentially unchanged during storage. This indicates that crystalline form CSVI has good stability under accelerated conditions and even more stringent conditions.

[0028] At the same time, the crystalline form CSVI has good humidity stability. After the crystalline form CSVI of the present invention cycles once at 0% RH-95% RH-0% RH, the crystalline form does not change.

[0029] High temperatures and high humidity conditions caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs and drug products. Therefore, the stability of APIs and drug products under accelerated and even more stringent conditions is crucial for pharmaceuticals. The CSVI crystal form exhibits improved stability under these harsh conditions, helping to prevent drug quality from being affected by crystal transformation or purity loss during storage. The excellent physical and chemical stability of the API crystal form ensures that the drug product will not undergo crystal transformation and is essentially free of impurities during production and storage. The excellent physical and chemical stability of the CSVI crystal form ensures consistent and controllable quality of the API and drug product, minimizing changes in drug quality, bioavailability, and toxic side effects caused by changes in crystal form or impurities.

[0030] According to the purpose of the present invention, the present invention provides a co-crystal of Compound I and tartaric acid.

[0031] Without limitation, the co-crystal of Compound I and tartaric acid is Form CSVII (hereinafter referred to as "Form CSVII").

[0032] In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 7.3°±0.2°, 13.0°±0.2°, and 17.1°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angles 2θ of 7.3°±0.2°, 13.0°±0.2°, and 17.1°±0.2°.

[0033] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 6.3°±0.2°, 16.1°±0.2°, and 18.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angles 2θ of 6.3°±0.2°, 16.1°±0.2°, and 18.9°±0.2°.

[0034] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 11.5±0.2°, 23.0°±0.2°, and 12.5±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angles 2θ of 11.5±0.2°, 23.0°±0.2°, and 12.5±0.2°.

[0035] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 of the diffraction angle 2θ values ​​of 7.3°±0.2°, 13.0°±0.2°, 17.1°±0.2°, 6.3°±0.2°, 16.1°±0.2°, 18.9°±0.2°, 11.5±0.2°, 23.0°±0.2°, 12.5±0.2°, 4.5°±0.2°, and 25.3°±0.2°.

[0036] Without limitation, using Cu-Ka radiation, the XRPD pattern of Form CSVII is substantially as shown in FIG6 .

[0037] Without limitation, the DSC graph of Form CSVII is substantially as shown in FIG7 , with a first endothermic peak appearing at approximately 51.3° C. and a second endothermic peak beginning to appear at approximately 114.7° C.

[0038] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSVII, which comprises:

[0039] Compound I and tartaric acid are placed in ethanol or an ethanol / n-heptane mixed solution, stirred, and filtered. The resulting solid is dried or purged with nitrogen to obtain Form CSVII.

[0040] The crystalline form CSVII provided by the present invention has the following advantages:

[0041] Compared to the prior art, the crystalline form CSVII provided by the present invention has higher solubility. In PBS buffer (pH 6.8), ABS buffer (pH 4.5), and 0.1N HCl aqueous solution, the solubility of the crystalline form CSVII is 3 to 6 times that of the prior art crystalline form C.

[0042] The crystalline form CSVII provided by the present invention has higher solubility, which is beneficial to improving the absorption of the drug in the human body and improving the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.

[0043] According to the purpose of the present invention, the present invention provides a crystalline form CSV of Compound I (hereinafter referred to as "crystalline form CSV").

[0044] In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at one, two, three, or four of the diffraction angles 2θ of 8.8°±0.2°, 9.3°±0.2°, 13.8°±0.2°, and 11.9°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at diffraction angles 2θ of 8.8°±0.2°, 9.3°±0.2°, 13.8°±0.2°, and 11.9°±0.2°.

[0045] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at one or two of the diffraction angles 2θ of 4.7°±0.2° and 15.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at diffraction angles 2θ of 4.7°±0.2° and 15.9°±0.2°.

[0046] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at one, two, or three of the diffraction angles 2θ of 15.1±0.2°, 18.0°±0.2°, and 22.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at diffraction angles 2θ of 15.1±0.2°, 18.0°±0.2°, and 22.9°±0.2°.

[0047] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSV has characteristic peaks at one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the diffraction angle 2θ values ​​of 8.8°±0.2°, 9.3°±0.2°, 13.8°±0.2°, 11.9°±0.2°, 4.7°±0.2°, 15.9°±0.2°, 15.1±0.2°, 18.0°±0.2°, 22.9°±0.2°, 10.2°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 25.3°±0.2°, and 26.9°±0.2°.

[0048] Without limitation, using Cu-Ka radiation, the XRPD pattern of Form CSV is substantially as shown in FIG8 .

[0049] Without limitation, the DSC graph of the crystalline form CSV is substantially as shown in FIG9 , wherein there is a first endothermic peak at around 142.6° C., and a second endothermic peak begins to appear at around 246.0° C.

[0050] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSV, which comprises:

[0051] The solid compound I was placed in nitromethane and stirred, filtered and dried to obtain the crystalline form CSV.

[0052] Furthermore, the stirring temperature is preferably 5-50°C; and the drying temperature is preferably 30-100°C.

[0053] The crystalline CSV provided by the present invention has the following advantages:

[0054] (1) Compared with the prior art, the crystalline form CSV provided by the present invention has higher solubility. In PBS buffer (pH 6.8), ABS buffer (pH 4.5), and 0.1N HCl aqueous solution, the solubility of crystalline form CSV is 1 to 3 times that of the prior art crystalline form C.

[0055] The crystalline CSV provided by the present invention has higher solubility, which is beneficial to improving the absorption of the drug in the human body and improving the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.

[0056] (2) Compared with the prior art, the crystalline CSV provided by the present invention has lower hygroscopicity. Test results show that the crystalline CSV has a hygroscopic weight gain of 1.25% under 0-95% RH conditions. The hygroscopic weight gain of the prior art crystalline form is 1.4 times that of the crystalline CSV provided by the present invention.

[0057] High hygroscopicity can easily cause chemical degradation and crystal transformation of APIs, thereby affecting the physicochemical stability of the API. Furthermore, high hygroscopicity can reduce the fluidity of the API, thereby affecting its processing. The crystalline CSV provided by the present invention has low hygroscopicity, is less demanding on drug production and storage, reduces drug production, storage, and quality control costs, and has strong economic value.

[0058] (3) The crystalline CSV provided by the present invention exhibits excellent stability. Crystalline CSV maintained its crystalline form unchanged after storage at 40°C / 75% RH for at least six months, and its chemical purity was above 99.8%. This purity remained essentially unchanged during storage. This demonstrates that crystalline CSV exhibits excellent stability under accelerated and more stringent conditions.

[0059] At the same time, the crystalline CSV has good humidity stability. After the crystalline CSV of the present invention is cycled once at 0% RH-95% RH-0% RH, the crystal form does not change.

[0060] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can affect the storage, transportation, and production of APIs and drug products. Therefore, the stability of APIs and drug products under accelerated conditions is crucial. The excellent physical and chemical stability of the API crystal form ensures that the drug product does not undergo crystal transformation and is essentially free of impurities during production and storage. The excellent physical and chemical stability of the CSV crystal form ensures consistent and controllable quality of the API and drug product, minimizing variations in drug quality, bioavailability, and toxic side effects caused by changes in crystal form or impurities.

[0061] At the same time, the crystalline CSV exhibits excellent physical stability under mechanical forces. The crystalline CSV API exhibits excellent physical stability under varying pressures, which is beneficial for maintaining crystalline stability during the tableting process.

[0062] (4) Compared with the prior art, the crystalline CSV provided by the present invention has superior compressibility. The good compressibility of the crystalline CSV can effectively improve problems such as substandard hardness / friability and flakes in the tableting process, making the formulation process more reliable, improving product appearance, and enhancing product quality and production efficiency.

[0063] According to the purpose of the present invention, the present invention provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline form CSV, crystalline form CSVI, crystalline form VII and pharmaceutically acceptable excipients.

[0064] According to the purpose of the present invention, the present invention provides uses of the crystalline form CSV, the crystalline form CSVI, and the crystalline form VII in the preparation of TYK2 inhibitor drugs.

[0065] According to the purpose of the present invention, the present invention provides the use of crystal form CSV, crystal form CSVI, and crystal form VII in the preparation of drugs for treating psoriasis, psoriatic arthritis, inflammatory bowel disease and other autoimmune diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 is the XRPD pattern of crystalline form CSVI

[0067] Figure 2 is the TGA graph of crystal form CSVI

[0068] Figure 3 is a comparison of XRPD patterns of crystalline form CSVI before and after storage under different conditions (from bottom to top: before storage, after sealed storage at 60°C / 75% RH for 3 months, after exposed storage at 40°C / 75% RH for 6 months, and after sealed storage at 40°C / 75% RH with desiccant for 6 months)

[0069] Figure 4 is the DVS diagram of crystal form CSVI

[0070] Figure 5 is a comparison of XRPD images of the crystal form CSVIDVS before and after the test (from top to bottom: before the test, after the test)

[0071] Figure 6 is the XRPD pattern of Form CSVII

[0072] Figure 7 is a DSC diagram of Form CSVII

[0073] Figure 8 is the XRPD pattern of crystalline form CSV

[0074] Figure 9 is the DSC graph of crystal form CSV

[0075] Figure 10 is a comparison of XRPD images of the crystalline form CSV before and after storage (from bottom to top: before storage, after sealing at 40°C / 75% RH for 6 months)

[0076] Figure 11 is the DVS diagram of crystal form CSV

[0077] Figure 12 is a comparison of XRPD images of the CSV crystal before and after DVS testing (from top to bottom: before and after testing) DETAILED DESCRIPTION

[0078] 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.

[0079] The abbreviations used in the present invention are explained as follows: XRPD: X-ray powder diffraction DVS: dynamic water sorption DSC: differential scanning calorimetry TGA: thermogravimetric analysis HPLC: high performance liquid chromatography 1 H NMR: Proton nuclear magnetic resonance RH: Relative humidity

[0080] Instruments and methods used to collect data:

[0081] The X-ray powder diffraction patterns of the present invention were collected on a Bruker D8 ADVANCE X-ray powder diffractometer. The X-ray powder diffraction method parameters of the present invention are as follows:

[0082] X-ray source: Cu, Kα

[0083] 1.5406; 1.5444

[0084] Kα2 / Kα1 intensity ratio: 0.50

[0085] Voltage: 40kV

[0086] Current: 40mA

[0087] Scanning range: from 4.0 to 40.0 degrees

[0088] The TGA images of the present invention were collected on a TA Q500. The method parameters of the TGA of the present invention are as follows:

[0089] Scan rate: 10℃ / min

[0090] Shielding gas: N2

[0091] The DSC patterns of the present invention were collected on a METTLER TOLEDO DSC 3. The DSC method parameters of the present invention are as follows:

[0092] Scan rate: 10℃ / min

[0093] Shielding gas: N2

[0094] The DVS graphs described in the present invention were collected using an Intrinsic dynamic moisture sorption instrument manufactured by SMS (Surface Measurement Systems Ltd.). The method parameters of the dynamic moisture sorption instrument are as follows:

[0095] Temperature: 25℃

[0096] Carrier gas, flow rate: N2, 200mL / min

[0097] Relative humidity range: 0%RH-95%RH

[0098] The present invention 1 H NMR data were collected on a Bruker Avance II DMX 400M HZ NMR 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.

[0099] The test parameters of the solubility of the present invention are shown in Table 1.

[0100] Table 1

[0101] The test parameters of the related substances described in the present invention are shown in Table 2.

[0102] Table 2

[0103] 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.

[0104] The separation is accomplished by conventional methods in the art, such as centrifugation or filtration. The centrifugation operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all solids settle to the bottom of the centrifuge tube.

[0105] The "drying" 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 0.5-48 hours, or overnight. Drying is performed in a fume hood, forced air oven, or vacuum oven. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

[0106] The “eutectic of Compound I and citric acid” refers to a crystalline material formed by Compound I and citric acid being bonded in a certain stoichiometric ratio in the same crystal lattice through non-ionic bonds and non-covalent bonds.

[0107] The "saturated tartaric acid mixed solution" is prepared by conventional methods in the art, for example, by adding excess tartaric acid to the mixed solution, dissolving it with ultrasonic aid, and then allowing it to stand.

[0108] The "eutectic of Compound I and tartaric acid" refers to a crystalline material formed by Compound I and tartaric acid being bonded in a certain stoichiometric ratio in the same crystal lattice through non-ionic bonds and non-covalent bonds.

[0109] 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°.

[0110] 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.

[0111] In some embodiments, the crystalline Form CSV, Form CSVI, or Form CSVII of the present invention is pure and substantially free of any other crystalline forms. 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.

[0112] 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%.

[0113] Unless otherwise specified, the following examples were all performed at room temperature.

[0114] 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.

[0115] Compound I used in the following examples can be prepared according to existing technologies, for example, according to the method described in WO2023183910A1.

[0116] Example 1: Preparation method of crystalline form CSVI

[0117] Weigh 50.0 mg of Compound I solid and 22.2 mg of citric acid into a glass bottle, add 0.5 mL of ethyl acetate, stir at room temperature for 1 day, add 0.5 mL of ethyl acetate again, continue stirring at room temperature for 8 days, separate the solid, and place it at 25 ° C. under vacuum and dry for about 4 hours to obtain a crystalline solid.

[0118] The obtained crystalline solid was tested to be the crystal form CSVI of the present invention. Its X-ray powder diffraction data are shown in Table 3, and its X-ray powder diffraction pattern is shown in FIG1 .

[0119] The TGA graph is shown in Figure 2. When heated to approximately 150° C., the product exhibits a mass loss of approximately 0.11%. NMR results indicate that the molar ratio of Compound I to citric acid in the crystalline form CSVI is approximately 1:1.

[0120] Table 3

[0121] Example 2: Stability of Crystalline Form CSVI

[0122] Appropriate amounts of the crystalline form CSVI prepared according to the present invention were stored at 40°C / 75% RH and 60°C / 75% RH for a period of time. Purity and crystal form were determined by HPLC and XRPD at each sampling time. The results are shown in Table 4, and a comparative XRPD diagram is shown in Figure 3. These results demonstrate that crystalline form CSVI is stable for at least six months at 40°C / 75% RH and for at least three months at 60°C / 75% RH, maintaining excellent stability under both accelerated and more stringent conditions.

[0123] Table 4

[0124] Example 3: Dynamic Solubility of Crystalline Form CSVI

[0125] Appropriate amounts of the crystalline Form CSVI of the present invention and the crystalline Form C of the prior art were dispersed in PBS buffer (pH 6.8), ABS buffer (pH 4.5), and 0.1N aqueous HCl solution, respectively, to prepare suspensions. The suspensions were equilibrated at 37°C for 15 minutes and then filtered to obtain clear solutions. The concentrations of Compound I in the clear solutions were determined by high-performance liquid chromatography. The results are shown in Table 5. The results indicate that the crystalline Form CSVI had higher solubility in PBS buffer (pH 6.8), ABS buffer (pH 4.5), and 0.1N aqueous HCl solution than the crystalline Form C of the prior art.

[0126] Table 5

[0127] Example 4: Hygroscopicity and humidity stability of crystalline form CSVI

[0128] An appropriate amount of the present invention's crystalline form CSVI was weighed and tested for hygroscopicity using a DVS instrument. The test cycle was repeated at 25°C, with a 0% RH, 95% RH, and 0% RH cycle. The mass at each humidity level was recorded. XRPD analysis was also performed before and after the DVS test. The results, shown in Table 6 and Figure 4, show that compared to the prior art crystalline form C, CSVI exhibits lower hygroscopicity.

[0129] The XRPD comparison charts before and after the DVS test are shown in Figure 5. The results show that the crystalline form CSVI has good humidity stability.

[0130] Table 6

[0131] Note: The hygroscopicity data of Form C is cited from WO2023183910A1.

[0132] Example 5: Preparation of Crystalline Form CSVII

[0133] 199.7 mg of Compound I solid and 64.3 mg of tartaric acid were weighed into a glass bottle. 5 mL of a saturated tartaric acid solution in ethanol / n-heptane (1:1, volume ratio) was added and stirred at room temperature. During the stirring process, 7 mL of a saturated tartaric acid solution in ethanol / n-heptane (1:1, volume ratio) and 51.6 mg of tartaric acid were added in multiple portions. After stirring for 7 days, the solid was isolated by filtration. The solid was air-dried at 30°C for 16 hours, then purged with nitrogen at 70°C for 1 hour and returned to room temperature to obtain a crystalline solid.

[0134] After testing, the obtained crystalline solid was found to be the crystalline form CSVII of the present invention. Its X-ray powder diffraction data are shown in Table 7, and its X-ray powder diffraction pattern is shown in FIG6 .

[0135] Table 7

[0136] Example 6: DSC data of Form CSVII

[0137] The DSC graph of Form CSVII is shown in FIG7 , wherein the first endothermic peak appears at approximately 51.3° C., and the second endothermic peak begins to appear at approximately 114.7° C.

[0138] Example 7: Solubility of Form CSVII

[0139] Appropriate amounts of Form CSVII of the present invention and Form C of the prior art were dispersed in PBS buffer (pH 6.8), ABS buffer (pH 4.5), and 0.1N aqueous HCl solution, respectively, to prepare suspensions. After equilibration at 37°C for 15 minutes, the suspensions were filtered to obtain clear solutions. The concentration of Compound I in each clear solution was determined by high-performance liquid chromatography. The results are shown in Table 8. The results indicate that Form CSVII has higher solubility in PBS buffer (pH 6.8), ABS buffer (pH 4.5), and 0.1N aqueous HCl solution than Form C of the prior art.

[0140] Table 8

[0141] Example 8: Preparation of Crystalline CSV

[0142] About 200 mg of Compound I solid was weighed into a glass bottle, 4 mL of nitromethane was added thereto, and the mixture was stirred at room temperature for 5 days. The solid was separated and dried under vacuum at 30°C for 23 hours and then at 80°C for 4 hours to obtain a crystalline solid.

[0143] The obtained crystalline solid was tested to be the crystal form CSV of the present invention. Its X-ray powder diffraction data are shown in Table 9, and its X-ray powder diffraction pattern is shown in FIG8 .

[0144] 1 The H NMR data are: 1H NMR (400MHz, DMSO) δ9.01 (s, 1H), 8.72-8.60 (m, 1H), 8.32 (dd, J = 7.3, 1.7Hz, 1H), 8.21 (s, 1H), 8.06 ( ddd,J=11.6,9.4,5.5Hz,2H),7.92(d,J=4.9Hz,1H),7.84(d,J=8.1Hz,1H),7.61(dd,J=7.0,1.8Hz,1 H), 7.54 (ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 6.44 (t, J = 7.2 Hz, 1H), 6.21 (s, 1H), 4.38-4.26 (m, 1H), 3.72 (q, J = 7.3 Hz, 1H), 3.20 (s, 3H), 2.91 (d, J = 4.9 Hz, 3H), 2.10 (td, J = 19.6, 9.0 Hz, 2H), 1.58-1.33 (m, 2H). NMR results showed that Form CSV was a crystalline form of Compound I.

[0145] Table 9

[0146] Example 9: DSC data of crystalline form CSV

[0147] The DSC graph of the crystalline form CSV is shown in FIG9 , which shows a first endothermic peak at around 142.6° C. and a second endothermic peak starting to appear at around 246.0° C.

[0148] Example 10: Stability of Crystalline Form CSV

[0149] An appropriate amount of the crystalline form CSV prepared according to the present invention was sealed and stored at 40°C / 75% RH for six months. The purity and crystalline form were determined by HPLC and XRPD, respectively. The results are shown in Table 10, and the XRPD comparison chart is shown in Figure 10. These results demonstrate that crystalline form CSV is stable for at least six months at 40°C / 75% RH, demonstrating that crystalline form CSV maintains good stability under accelerated conditions.

[0150] Table 10

[0151] An appropriate amount of crystalline CSV was taken, a suitable tableting mold was selected, and the tablets were pressed under different pressures. XRPD tests were performed before and after tableting. The test results are shown in Table 11. The crystalline CSV has good mechanical stability.

[0152] Table 11

[0153] Example 11: Hygroscopicity and humidity stability of crystalline CSV

[0154] An appropriate amount of the present invention's crystalline Form CSV was weighed and tested for hygroscopicity using a DVS instrument. The test cycle was repeated at 25°C, with a 0% RH, 95% RH, and 0% RH cycle. The mass at each humidity level was recorded. XRPD analysis was also performed before and after the DVS test. The results, shown in Table 12 and Figure 11, show that Form CSV exhibits lower hygroscopicity than Form C, a crystalline form of the prior art.

[0155] The XRPD comparison charts before and after the DVS test are shown in Figure 12. The results show that the CSV crystal has good humidity stability.

[0156] Table 12

[0157] Note: The hygroscopicity data of Form C is cited from WO2023183910A1.

[0158] Example 12: Solubility of Crystalline CSV

[0159] Appropriate amounts of Form CSV of the present invention and Form C from the prior art were dispersed in PBS buffer (pH 6.8), ABS buffer (pH 4.5), and 0.1N aqueous HCl solution, respectively, to prepare suspensions. The suspensions were equilibrated at 37°C for 15 minutes and then filtered to obtain clear solutions. The concentrations of Compound I in the clear solutions were determined by high-performance liquid chromatography. The results are shown in Table 13. The results demonstrate that Form CSV has higher solubility in PBS buffer (pH 6.8), ABS buffer (pH 4.5), and 0.1N aqueous HCl solution than Form C from the prior art.

[0160] Table 13

[0161] Example 13: Compressibility of Crystalline Form CSV

[0162] Tablets were pressed using an ENERPAC manual tablet press. About 100 mg of crystalline form CSV and prior art crystalline form C were added to a Φ6 mm circular flat punch, respectively, and tablets were pressed under a pressure of 5 kN. The tablets were placed at room temperature for 24 hours. After complete elastic recovery, the diameter (D) and thickness (L) of the tablets were measured using a vernier caliper, and the radial crushing force (hardness, H) was tested using a tablet hardness tester. The tensile strength of the powder was calculated using the formula T = 2H / πDL. Under a certain pressure, the greater the tensile strength, the better the compressibility. The results are shown in Table 14. The results show that the crystalline form CSV of the present invention has a greater tensile strength.

[0163] Table 14

[0164] 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 compound I and citric acid eutectic.

2. The eutectic according to claim 1, 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 6.7°±0.2°, 11.1°±0.2°, and 17.2°±0.2°.

3. The eutectic according to claim 2, 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 18.1°±0.2°, 20.6°±0.2°, and 26.4°±0.2°.

4. The eutectic according to claim 2, 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 16.1±0.2°, 19.0°±0.2°, and 22.3°±0.2°.

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

6. A compound I Cocrystal of tartaric acid.

7. The eutectic according to claim 6, 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 7.3°±0.2°, 13.0°±0.2°, and 17.1°±0.2°.

8. The eutectic according to claim 7, 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 6.3°±0.2°, 16.1°±0.2°, and 18.9°±0.2°.

9. The eutectic according to claim 7, 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 11.5±0.2°, 23.0°±0.2°, and 12.5±0.2°.

10. The eutectic according to claim 7, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in FIG6 .

11. A compound I The crystal form, It is characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.8°±0.2°, 9.3°±0.2°, 13.8°±0.2°, and 11.9°±0.2°.

12. The crystalline form of Compound I according to claim 11, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 4.7°±0.2° and 15.9°±0.2°.

13. The crystalline form of Compound I according to claim 11, 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 15.1±0.2°, 18.0°±0.2°, and 22.9°±0.2°.

14. The crystalline form of Compound I according to claim 11, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in FIG8 .

15. A pharmaceutical composition comprising a therapeutically effective amount of the co-crystal of claim 1, the co-crystal of claim 6, or the crystal form of claim 11, and a pharmaceutically acceptable excipient.

16. Use of the co-crystal of claim 1, the co-crystal of claim 6, and the crystal form of claim 11 in the preparation of a TYK2 inhibitor drug.

17. Use of the co-crystal of claim 1, the co-crystal of claim 6, and the crystal form of claim 11 in the preparation of drugs for treating psoriasis, psoriatic arthritis, inflammatory bowel disease and other autoimmune diseases.

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