WO2021143430A1 - Bms-986165 hydrochloride crystal form, preparation method therefor and use thereof - Google Patents

Abstract

Disclosed are a crystal of a compound I hydrochloride and a preparation method therefor, a pharmaceutical composition containing the crystal, and the use of the crystal in the preparation of a TYK2 inhibitor drug and a drug for treating psoriasis, systemic lupus erythematosus, and Crohn's disease. The crystal of the compound I hydrochloride has one or more improved properties compared with the prior art, and is of great value to the future optimization and development of the drugs.

Description

A kind of BMS-986165 hydrochloride crystal form and its preparation method and application Technical field

The invention relates to the field of crystal chemistry. Specifically, it relates to the crystal form of BMS-986165 hydrochloride and its preparation method and use.

Background technique

Tyrosine kinase 2 (TYK2) is an intracellular signal transduction kinase that can mediate interleukin-23 (IL-23), interleukin-12 (IL-12) and type I interferon (IFN) These cytokines are involved in inflammation and immune response.

BMS-986165 is the first and only new type of oral selective TYK2 inhibitor, clinically used to treat autoimmune and autoinflammatory diseases (such as psoriasis, psoriatic arthritis, lupus and inflammatory bowel disease, Crowe Grace, etc.). The results of a phase III clinical study of the drug announced in November 2020 showed that BMS-986165 has shown positive clinical effects in the treatment of moderate to severe plaque psoriasis. In addition, BMS-986165 also shows good therapeutic effects in the treatment of systemic lupus erythematosus and Crohn's disease.

The chemical name of BMS-986165 is 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzene (Yl)amino)-N-(methyl-D3)pyridazine-3-carboxamide, the structural formula is shown below, and is hereinafter referred to as "compound I":

The crystal form is a solid in which the compound molecules are arranged in a three-dimensional order in the microstructure to form a crystal lattice. The phenomenon of drug polymorphism refers to the existence of two or more different crystal forms of the drug. Because of the different physical and chemical properties, different crystal forms of the drug may have different dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent. Especially for poorly soluble solid drugs, the crystal form will have a greater impact. Therefore, the crystal form of a drug must be an important content of drug research and an important content of drug quality control.

WO2019232138A1 discloses compound I hydrochloride crystal form B (hereinafter referred to as "crystal form B") and a preparation method thereof. The crystal form B disclosed in WO2019232138A1 is the only known compound I hydrochloride crystalline form, but the purity of the crystal form B changes greatly during storage. WO2019232138A1 discloses that the purity of crystalline form B drops a lot after being placed at 25°C/60%RH (relative humidity) for 4 weeks. The inventor of the present application repeated the preparation method disclosed in WO2019232138A1 to obtain and characterize the crystal form B. The results showed that the crystal form B has low solubility, low formulation dissolution, poor grinding stability, poor compressibility, and high adhesion. Therefore, in this field, there is still a need to develop a compound I hydrochloride crystalline form with high solubility, high formulation dissolution, good stability, and excellent formulation performance for the development of drugs containing compound I.

In order to overcome the shortcomings of the prior art, the inventor of the present application conducted a large number of experimental studies on Compound I through various methods in an attempt to find a more suitable crystal form for pharmaceutical use. As a result, only a variety of solvates of Compound I hydrochloride were obtained. In combination with the prior art, the inventor of the present application found that compound I hydrochloride is easily combined with a solvent to form a solvate, and it is very difficult to obtain a stable nonsolvate of compound I hydrochloride.

The inventor of the present application has paid a lot of creative work and unexpectedly discovered that the compound I hydrochloride crystal form CSII provided by the present invention has advantages in physical and chemical properties, preparation processing performance, and bioavailability, such as melting point, solubility, and solubility. There are advantages in at least one aspect of wetness, purification, stability, adhesion, compressibility, fluidity, in vivo and in vitro dissolution, and bioavailability, especially high solubility, good physical and chemical stability, and high formulation dissolution , It has good mechanical stability, good compressibility, and low adhesion, which solves the problems existing in the prior art, and is of great significance to the development of drugs containing compound I.

Summary of the invention

The main purpose of the present invention is to provide a new crystal form of compound I hydrochloride and its preparation method and application.

According to the purpose of the present invention, the present invention provides compound I hydrochloride crystal form CSII (hereinafter referred to as "crystalline form CSII").

On the one hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CSII has characteristic peaks at diffraction angle 2θ values of 7.9°±0.2°, 9.4°±0.2°, and 12.5°±0.2°.

Further, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CSII has a diffraction angle of 18.9°±0.2°, 26.1°±0.2°, 26.8°±0.2°, or 2 positions. , Or 3 characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSII has characteristic peaks at 3 of the diffraction angles 2θ of 18.9°±0.2°, 26.1°±0.2°, and 26.8°±0.2° .

Further, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CSII has a diffraction angle 2θ value of 15.3°±0.2°, 21.3°±0.2°, 24.0°±0.2° at 1 or 2 , Or 3 characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSII has characteristic peaks at 3 of the diffraction angles 2θ of 15.3°±0.2°, 21.3°±0.2°, 24.0°±0.2° .

On the other hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CSII has diffraction angle 2θ values of 7.9°±0.2°, 9.4°±0.2°, 12.5°±0.2°, 18.9°±0.2°, 3, or 4, or 5, or 6, or 7 of 26.1°±0.2°, 26.8°±0.2°, 15.3°±0.2°, 21.3°±0.2°, 24.0°±0.2° , Or 8 or 9 characteristic peaks.

Without limitation, the X-ray powder diffraction pattern of the crystal form CSII is basically as shown in FIG. 1.

In a non-limiting manner, the thermogravimetric analysis chart of the crystal form CSII is basically as shown in FIG. 2, when heated to 130° C., there is a mass loss of about 0.3%.

In a non-limiting manner, the differential scanning calorimetry diagram of the crystal form CSII is basically as shown in FIG. 3, and an endothermic peak appears near 233°C.

Without limitation, the crystal form CSII is anhydrous.

According to the objective of the present invention, the present invention also provides a preparation method of the crystal form CSII, and the preparation method is:

Method 1: Put compound I hydrochloride solid in alcohol, ether or alkane solvent, stir and separate the solid to obtain crystal form CSII; or

Method 2: Disperse the compound I solid in a nitrile solvent, add hydrochloric acid to the system, stir, stand still, separate the solid, and dry to obtain the crystal form CSII.

Further, the alcohol solvent in Method 1 is preferably C2-C8 alcohol; the ether solvent is preferably C2-C7 ether; and the alkane solvent is preferably C5-C8 alkane. The nitrile solvent in Method 2 is preferably C2-C4 nitriles.

Further, in method 1, the alcohol solvent is preferably n-butanol and isobutanol; the ether solvent is preferably tetrahydrofuran; the alkane solvent is preferably n-heptane; the stirring time is preferably 2-24 hours, more preferably 19h. In method 2, the nitrile solvent is preferably acetonitrile; the standing temperature is preferably -30°C to room temperature.

The crystal form CSII provided by the present invention has the following advantages:

(1) Compared with the prior art, the crystal form CSII provided by the present invention has higher solubility after equilibrating in FaSSIF medium and FeSSIF medium for 4 hours and 24 hours. Especially after equilibrating in FaSSIF medium for 24 hours, the solubility of crystal form CSII provided by the present invention is 1.85 times that of crystal form B.

The hydrochloride salt of compound I is a poorly water-soluble drug. The higher solubility is beneficial to improve the absorption of the drug in the human body, increase the bioavailability, and enable the drug to exert a better therapeutic effect; in addition, the higher solubility can ensure that the drug At the same time of curative effect, the dosage of the medicine is reduced, thereby reducing the side effects of the medicine and improving the safety of the medicine.

(2) Compared with the prior art, the crystal form CSII provided by the present invention has better in vitro dissolution rate and dissolution rate. The dissolution rates of the crystal form CSII preparation and the crystal form B preparation in the acetic acid buffer solution (ABS) medium of pH=4.5 were 63.4% and 54.8% respectively at 45 minutes.

Different crystal forms may lead to different dissolution rates of drugs in the body, which directly affect the absorption, distribution, metabolism, and excretion of drugs in the body, and ultimately lead to differences in clinical efficacy due to their different bioavailability. Dissolution rate and dissolution rate are important prerequisites for drug absorption. Good in vitro dissolution rate indicates that the drug has a higher degree of in vivo absorption and better exposure characteristics in vivo, thereby improving bioavailability and improving drug efficacy; high dissolution rate enables the drug to reach the highest concentration in plasma quickly after administration Value to ensure that the drug takes effect quickly.

(3) The crystalline CSII bulk drug provided by the present invention has good stability. The crystalline CSII bulk drug is placed in an open place under the conditions of 25°C/60% relative humidity (RH). The crystalline form has not changed for at least 6 months, and the chemical purity only changes 0.03%. The purity remains basically unchanged during storage. It shows that the crystalline CSII bulk drug has good stability under long-term conditions, which is beneficial to the storage of the drug. WO2019232138A1 discloses that the purity of crystal form B after being placed at 25°C/60%RH for 4 weeks is 0.13% lower than that after being placed for 2 weeks.

At the same time, the crystal form of the CSII raw material has not changed after being placed at 40℃/75%RH for at least 6 months, the chemical purity only changes by 0.04%, and the purity remains basically unchanged during storage; the crystal form CSII is at 60℃ /75%RH closed for at least 1 month, the crystal form has not changed, and the purity remains basically unchanged during storage. It shows that the crystalline CSII bulk drug still has good stability under accelerated conditions and more severe conditions. Seasonal differences, climate differences in different regions and weather factors brought about high temperature and high humidity conditions will affect the storage, transportation, and production of APIs. Therefore, the stability of the bulk drug under accelerated conditions and harsh conditions is very important for the drug. The crystalline CSII bulk drug has better stability under harsh conditions, which is beneficial to avoid the impact of deviation from the storage conditions on the label on the quality of the drug.

At the same time, the crystal form CSII has good mechanical stability. The crystal form of the crystal form CSII raw material medicine remains unchanged before and after grinding, and has good physical stability. The preparation process often requires the grinding and pulverization of the drug substance, and the good physical stability can reduce the risk of crystallinity change and crystal transformation of the drug substance in the preparation process. Under different pressures, the crystalline CSII bulk drug has good physical stability, which is beneficial to maintain the stability of the crystalline form during the preparation and tableting process.

The transformation of the crystal form will cause changes in the absorption of the drug, affect the bioavailability, and even cause the toxic and side effects of the drug. Good chemical stability can ensure that there are basically no impurities generated during storage. The crystal form CSII has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and minimizing changes in drug quality, bioavailability, and even drug side effects caused by changes in crystal form or impurities.

(4) Compared with the prior art, the crystal form CSII provided by the present invention has better adhesion. The adhesion evaluation results show that the adhesion amount of crystal form CSII is much lower than that of crystal form B. The better adhesion of crystalline CSII can effectively improve or avoid sticky wheels, sticky punches and other phenomena caused by dry granulation and tablet compression, which is beneficial to improve product appearance and weight differences. In addition, the better adhesion of crystalline CSII can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and appliances, facilitate the dispersion of raw materials and the mixing with other auxiliary materials, and increase the uniformity of the mixing of materials and the final product. The content uniformity.

(5) Compared with the prior art, the crystal form CSII provided by the present invention has better compressibility. The better compressibility of the crystalline CSII can effectively improve the hardness/fragility unqualified, chipping and other problems in the tableting process, making the formulation process more reliable, improving the appearance of the product, and improving the quality of the product. The better compressibility can also increase the tableting speed and thus the production efficiency, and at the same time can reduce the cost of auxiliary materials used to improve the compressibility.

(6) Compared with the prior art, the crystal form CSII provided by the present invention has a greater density. The experimental results show that the bulk density and tap density of the crystal form CSII of the present invention are significantly better than that of the crystal form B. The high density of crystalline CSII is conducive to mass production, and the greater density can reduce dust, reduce occupational hazards, and ensure production safety.

According to the purpose of the present invention, the present invention also provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline CSII and pharmaceutically acceptable excipients.

Further, the present invention provides the use of crystal form CSII in the preparation of TYK2 inhibitor drugs.

Furthermore, the present invention provides the use of crystalline CSII in the preparation of drugs for treating psoriasis, systemic lupus erythematosus and Crohn's disease.

In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50-1800 revolutions per minute, wherein the magnetic stirring is preferably 300-900 revolutions per minute, and mechanical stirring Preferably it is 100-300 revolutions per minute.

The "drying" can be performed at room temperature or higher. The drying temperature is from 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 carried out in a fume hood, blast oven or vacuum oven.

The "separation" is accomplished by conventional methods in the art, such as centrifugation or filtration. The operation of "centrifugation" is: place the sample to be separated in a centrifuge tube and centrifuge at a rate of 10,000 rpm until all solids sink to the bottom of the centrifuge tube.

The "characteristic peak" refers to a representative diffraction peak used to discriminate crystals, and usually can have an error of ±0.2°.

In the present invention, "crystal" or "crystal form" can be characterized by X-ray powder diffraction. Those skilled in the art can understand that the X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample, and the purity of the sample. The relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the intensity of the diffraction peaks cannot be the only or decisive factor for determining the crystal form. In fact, the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystals. The intensity of the diffraction peaks shown in the present invention is illustrative rather than used for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the protected crystal form of the present invention does not have to be exactly the same as the X-ray powder diffraction pattern in the embodiment referred to here, and any characteristic peaks in these patterns. The crystal forms of the same or similar X-ray powder diffraction patterns fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.

In some embodiments, the crystalline form CSII of compound I hydrochloride of the present invention is pure, and substantially no other crystalline forms are mixed. In the present invention, "substantially no" when used to refer to a new crystal form means that this crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less. Other crystal forms that are less than 5% by weight, and even other crystal forms that are less than 1% by weight.

The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means a certain range of fluctuations around the specific value, and the range can be ±10%, ±5% , ±1%, ±0.5%, or ±0.1%.

Description of the drawings

Figure 1 is an XRPD diagram of the crystal form CSII obtained according to Example 1

Figure 2 is a TGA diagram of the crystal form CSII obtained according to Example 1

Figure 3 is a DSC chart of the crystal form CSII obtained according to Example 1

Figure 4 is an XRPD diagram of the crystal form CSII obtained according to Example 2

Figure 5 is the XRPD comparison diagram of the crystalline CSII before and after being placed under different conditions (from top to bottom: before placement, placed at 25°C/60%RH for 6 months, and placed at 40°C/75%RH for 6 months. 60℃/75%RH closed for 1 month)

Figure 6 shows the XRPD comparison of crystalline CSII before and after tableting at different pressures (from top to bottom: before tableting, 3kN tableting, 7kN tableting, 14kN tableting)

Figure 7 is the XRPD comparison diagram of crystal type CSII before and after polishing (top: after polishing, bottom: before polishing)

Figure 8 is a comparison of XRPD before and after the crystalline CSII formulation (from top to bottom: blank excipient powder mixing, after formulation, powder mixing, crystal CSII)

Figure 9 is the in vitro dissolution profile of crystal form CSII preparation and crystal form B preparation

Detailed ways

The present invention will be described in detail in conjunction with the following examples, which describe in detail the preparation and use methods of the crystal form of the present invention. It is obvious to those skilled in the art that many changes to both materials and methods can be implemented without departing from the scope of the present invention.

The explanations of the abbreviations used in the present invention are as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric Analysis

¹ H NMR: Liquid nuclear magnetic hydrogen spectroscopy

HPLC: High Performance Liquid Chromatography

Instruments and methods used to collect data:

The X-ray powder diffraction patterns described in Examples 1-4 and 9 of the present invention were collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of the X-ray powder diffraction are as follows:

X-ray light source: Cu, Kα

Kα1

1.54060; Kα2

1.54439

Kα2/Kα1 intensity ratio: 0.50

Voltage: 30 thousand volts (kV)

Current: 10 milliampere (mA)

Scanning range (2θ): from 3.0 to 40.0 degrees

The X-ray powder diffraction patterns described in Examples 7, 8, and 11 of the present invention were collected on a Bruker D8 DISCOVER X-ray powder diffractometer. The method parameters of the X-ray powder diffraction are as follows:

X-ray light source: Cu, Kα

Kα1

1.54060; Kα2

1.54439

Kα2/Kα1 intensity ratio: 0.50

Voltage: 40 thousand volts (kV)

Current: 40 milliampere (mA)

Scanning range (2θ): from 4.0 to 40.0 degrees

The differential scanning calorimetry (DSC) chart of the present invention was collected on TA Q2000. The method parameters of the differential scanning calorimetry (DSC) are as follows:

Scanning rate: 10℃/min

Shielding gas: N ₂

The thermogravimetric analysis (TGA) graph of the present invention is collected on TA Q500. The described thermal gravimetric analysis (TGA) method parameters are as follows:

Scanning rate: 10℃/min

Shielding gas: N ₂

Proton nuclear magnetic resonance data ( ¹ H NMR) was collected from Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of sample and dissolve it with 0.5 mL of deuterated chloroform to make a solution of 2-10 mg/mL.

The test parameters of the dynamic solubility, the dissolution of the preparation and the detection of related substances according to the present invention are shown in Table 1:

Table 1

Unless otherwise specified, the following examples are all operated at room temperature. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

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

The compound I and/or its salt used in the following examples can be prepared according to the prior art, for example, according to the method disclosed in WO2019232138A1.

Detailed ways

Example 1-4: Preparation method of crystal form CSII

The compound I hydrochloride solid was dissolved in chloroform to form a solution, and the solid was obtained by rotary evaporation at 40° C., and the obtained solid was dried under vacuum at room temperature. Weigh a certain mass of dry solid, add a certain amount of solvent as shown in Table 2, suspend and stir at room temperature for a certain period of time, and collect the solid by centrifugation. The experimental parameters of Examples 1-4 are summarized in Table 2. After testing, the solids obtained in Examples 1-4 are all the crystal form CSII of the present invention.

The X-ray powder diffraction patterns of the crystalline form CSII obtained in Example 1 and Example 2 are shown in Figs. 1 and 4, and the X-ray powder diffraction data are shown in Tables 3 and 4.

The TGA of the crystal form CSII obtained in Example 1 is shown in FIG. 2, and it has a mass loss of about 0.3% when heated to 130°C.

The DSC of the crystalline form CSII obtained in Example 1 is shown in Fig. 3, and the first endothermic peak appears when heated to around 233°C.

Table 2

table 3

Diffraction angle 2θ	d value	strength%
7.93	11.14	100.00
9.39	9.42	3.19
12.51	7.08	26.46
14.87	5.96	0.53
15.34	5.78	1.35
15.63	5.67	1.72
15.90	5.57	3.53
16.84	5.26	0.64
18.85	4.71	3.82
19.19	4.62	1.04
19.51	4.55	1.13
19.68	4.51	0.85
20.80	4.27	1.33
21.01	4.23	1.25
21.24	4.18	1.80
22.01	4.04	0.65
22.83	3.90	0.95
23.25	3.83	0.82

23.54	3.78	1.45
23.95	3.72	3.45
24.21	3.68	1.01
25.16	3.54	2.53
26.08	3.42	14.10
26.81	3.32	5.03
27.79	3.21	0.84
28.08	3.18	0.79
28.76	3.10	1.38
30.83	2.90	1.28
31.56	2.83	0.65
32.11	2.79	3.66
33.64	2.66	1.35
35.17	2.55	1.24
37.83	2.38	1.16
39.67	2.27	0.79

Table 4

Diffraction angle 2θ	d value	strength%
7.93	11.14	100.00
9.40	9.41	4.64
12.51	7.08	28.65
14.32	6.19	0.76
14.88	5.95	1.33
15.34	5.78	2.93
15.61	5.68	2.88
15.91	5.57	2.77
16.87	5.26	0.83
17.55	5.05	0.40
18.85	4.71	4.55
19.20	4.62	1.98
19.66	4.51	1.71
20.81	4.27	2.73
21.28	4.18	2.84
22.03	4.04	0.96
22.82	3.90	1.64

23.25	3.83	1.22
23.55	3.78	1.89
23.96	3.71	4.38
24.26	3.67	1.72
25.17	3.54	2.73
26.09	3.42	25.22
26.82	3.32	7.83
27.79	3.21	1.31
28.15	3.17	1.69
28.83	3.10	2.31
30.87	2.90	1.25
31.50	2.84	1.10
32.13	2.79	2.45
33.67	2.66	1.28
35.18	2.55	0.90
36.36	2.47	0.60
37.88	2.38	1.03

Example 5

Mix 2.2886g of the compound I free base solid and 15mL of acetonitrile to form a suspension, add 5.9mL of hydrochloric acid (1M) to the suspension, stir overnight at room temperature, then stand at -20°C to allow the solid to precipitate, and filter. The obtained solid was vacuum dried at 25° C. to obtain the crystal form CSII.

The NMR data of crystal form CSII are: ¹ H NMR (400MHz, CDCl ₃ ) δ 12.66 (s, 1H), 12.02 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.99 (dd ,J=7.9,1.4Hz,1H),7.69(s,1H),7.50(dd,J=7.9,1.2Hz,1H),7.35(t,J=7.9Hz,1H),4.03(s,3H) , 3.81 (s, 3H), 2.06-1.95 (m, 1H), 1.15-1.08 (m, 2H), 1.06-0.99 (m, 2H).

Example 6: Dynamic solubility of crystal form CSII and crystal form B

Simulated gastrointestinal fluids such as FaSSIF (simulated fasting state intestinal fluid) and FeSSIF (simulated feeding state intestinal fluid) are biologically related media, which can better reflect the impact of the physiological environment of the gastrointestinal tract on drug release. The solubility tested in the medium is closer to the solubility in the human environment.

Take about 25 mg of each of the crystal form CSII and crystal form B of the present invention dispersed in 2.5 mL of FaSSIF and 2.5 mL of FeSSIF to prepare a suspension, equilibrate for 4 hours and 24 hours, respectively, test the content of the sample in the solution by HPLC (mg/mL ), the results are shown in Table 5.

table 5

The results show that in FaSSIF, the solubility of crystal form CSII is equivalent to crystal form B at 4 hours, and is about twice that of crystal form B at 24 hours. In FeSSIF, the solubility of crystal form CSII was significantly higher than that of crystal form B at 4 hours and 24 hours, indicating that crystal form CSII has higher solubility.

Example 7: Stability of crystal form CSII

Weigh about 5 mg of the crystal form CSII prepared by the present invention, and place them under the conditions of 25°C/60%RH, 40°C/75%RH, 60°C/75%RH, and use HPLC and XRPD to determine the purity and crystal form. The results are shown in Table 6, and the XRPD comparison chart is shown in Figure 5.

Table 6

The results show that the crystal form CSII can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystal form CSII can maintain good stability under long-term and accelerated conditions.

In addition, the crystal form CSII can be stable for at least one month at 60°C/75%RH, which shows that the stability is also very good under more severe conditions.

Example 8: Pressure stability of crystal form CSII

Take an appropriate amount of crystal form CSII, select a suitable tableting die, and press them at different pressures of 3kN, 7kN and 14kN respectively. XRPD tests are performed before and after tableting. The test results show that the crystal form CSII has better performance under different pressures. The stability of the XRPD comparison chart is shown in Figure 6.

Example 9: Grinding stability of crystal form CSII

Place the crystal form CSII in a mortar and manually grind for 5 minutes. Perform XRPD tests before and after grinding. The results show that the crystal form of the solid is still crystal form CSII after manual grinding, and the crystallinity remains basically unchanged. The XRPD comparison chart is shown in Figure 7. Shown.

Example 10: Density of crystal form CSII and crystal form B

Gently load 500mg of powder into a 5mL graduated cylinder and measure the volume before tapping with a ZS-2E tapping meter; use the tapping method to tap 1250 times to make the powder in the tightest state, measure the volume after tapping; calculate the bulk density ρ ₀ and tap density ρ _f .

The density evaluation results of crystal form CSII and crystal form B are shown in Table 7.

Table 7

Crystal form	Bulk density (g/mL)	Tap density (g/mL)
Form B	0.2472	0.3259
Crystal Form CSII	0.2852	0.4278

The results show that the density of crystal form CSII is greater than that of crystal form B.

Example 11: Preparation of crystalline form CSII

The preparation prescription and preparation process of crystal form CSII are shown in Table 8 and Table 9, respectively. The XRPD patterns before and after the crystalline CSII preparation are shown in Figure 8. The results showed that the crystal form of the crystal form CSII remained unchanged before and after the preparation.

Table 8

Table 9

Example 12: In vitro dissolution of crystal form CSII preparation and crystal form B preparation

The in vitro dissolution of CSII-containing preparations and crystalline form B-containing preparations were tested. The dissolution was determined in accordance with the Chinese Pharmacopoeia 2020 Edition 0931 Dissolution and Release Determination Method. The test conditions are shown in Table 10:

Table 10

Dissolution Apparatus	Sotax AT7
method	Paddle method
Specification	25mg
Medium volume	900mL
Rotating speed	50rpm
Medium temperature	37°C
Sampling point	pH 4.5 ABS: 5, 10, 30, 45min
Supplementary medium	none

The in vitro dissolution conditions of the crystal form CSII preparation and the crystal form B preparation are shown in Table 11, and the dissolution curve is shown in Fig. 9. The results show that the preparation using the crystal form CSII of the present invention as the active ingredient has better dissolution rate and faster dissolution rate.

Table 11

Example 13: Adhesion of crystal form CSII and crystal form B

Approximately 30 mg of crystal form CSII and crystal form B raw materials were added to the 8mm round flat punch, and the ENERPAC manual tablet press was used for tableting with a pressure of 10kN. After the tablet was compressed, it stayed for about half a minute. The amount of powder. After using this method for two consecutive pressings, record the accumulated final adhesion amount, the highest adhesion amount and the average adhesion amount during the pressing process, and the results are shown in Table 12. The results show that the adhesion of crystal form CSII is better than crystal form B.

Table 12

Crystal form	Average adhesion amount (mg)	Maximum adhesion (mg)
Form B	0.190	0.230
Crystal Form CSII	0.170	0.200

Example 14: Compressibility of crystal form CSII and crystal form B

Use ENERPAC manual tablet press for tableting. When tableting, choose Φ6mm round flat punch, add 80mg crystal form CSII and crystal form B respectively, press 10kN pressure to make round tablets, place at room temperature for 24h, use vernier caliper to measure The diameter (D) and thickness (L) of the tablet are tested for the radial crushing force (hardness, H) with a tablet hardness tester after they are completely elastically restored. Use the formula T=2H/πDL*9.8 to calculate the tensile strength of the powder. Under a certain pressure, the greater the tensile strength, the better the compressibility. The results are shown in Table 13.

Table 13

Crystal form	Thickness(mm)	Diameter (mm)	Hardness (kgf)	Tensile strength (MPa)
Form B	2.25	6.13	0.54	0.24
Crystal Form CSII	2.30	6.12	6.36	2.82

The results show that crystal form CSII has better compressibility than crystal form B.

The above-mentioned embodiments are only to illustrate the technical concept and characteristics of the present invention, and their purpose is to enable those familiar with the art to understand the content of the present invention and implement them accordingly, and should not limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered by the protection scope of the present invention.

Claims (10)

1. A compound I hydrochloride crystal form CSII, characterized in that Cu-Kα radiation is used, and its X-ray powder diffraction pattern has 2θ values of 7.9°±0.2°, 9.4°±0.2°, 12.5°±0.2° Characteristic peaks

   
2. The compound I hydrochloride crystalline form CSII according to claim 1, characterized in that Cu-Kα radiation is used, and its X-ray powder diffraction pattern has a 2θ value of 18.9°±0.2°, 26.1°±0.2°, 26.8° There are characteristic peaks at 1 or 2 or 3 of ±0.2°.
3. The compound I hydrochloride crystalline form CSII according to claim 1, characterized in that Cu-Kα radiation is used, and its X-ray powder diffraction pattern has a 2θ value of 15.3°±0.2°, 21.3°±0.2°, 24.0° There are characteristic peaks at 1 or 2 or 3 of ±0.2°.
4. The compound I hydrochloride crystal form CSII according to claim 1, wherein its X-ray powder diffraction pattern is basically as shown in FIG. 1.
5. A method for preparing compound I hydrochloride crystal form CSII according to claim 1, characterized in that:

   Method 1: Put compound I hydrochloride solid in alcohol, ether or alkane solvent, stir and separate the solid to obtain crystal form CSII; or

   Method 2: Disperse the compound I solid in a nitrile solvent, add hydrochloric acid to the system, stir, stand still, separate the solid, and dry to obtain the crystal form CSII.
6. The preparation method according to claim 5, wherein the alcohol solvent in method 1 is a C2-C8 alcohol; the ether solvent is a C2-C7 ether; and the alkane solvent is a C5-C8 The nitrile solvent in Method 2 is a C2-C4 nitrile.
7. The preparation method according to claim 5, wherein the alcohol solvent in method 1 is n-butanol or isobutanol; the ether solvent is tetrahydrofuran; the alkane solvent is n-heptane; The stirring time is 2-24 hours, the nitrile solvent in method 2 is acetonitrile, and the standing temperature is -30°C to room temperature.
8. A pharmaceutical composition comprising an effective therapeutic amount of the compound I hydrochloride crystal form CSII described in claim 1 and pharmaceutically acceptable excipients.
9. The use of compound I hydrochloride crystal form CSII described in claim 1 in the preparation of TYK2 inhibitor drugs.
10. Use of the compound I hydrochloride crystal form CSII described in claim 1 in the preparation of a medicine for treating psoriasis, systemic lupus erythematosus and Crohn's disease.

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