WO2022078269A1 - Crystal form of avacopan, preparation method therefor, and use thereof - Google Patents

Abstract

Provided are a new crystal form of Avacopan (referred to as "compound I") and a preparation method therefor, a pharmaceutical composition containing the crystal form, and a use of the crystal form in the preparation of a C5aR inhibitor drug and a drug for treating antineutrophil cytoplasmic antibody associated vasculitis. Compared with the prior art, the provided new crystal form of the compound I has one or more improved properties, solves problems existing in the prior art, and has a great value for the optimization and development of drugs containing the compound I.

Description

Crystal form of Avacopan and its preparation method and use technical field

The present invention generally relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of Avacopan and its preparation method and use.

Background technique

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, serious and often fatal autoimmune disease caused by autoantibodies called antineutrophil cytoplasmic antibodies, It is characterized by inflammation that affects many different organ systems, usually involving the kidneys. C5a is thought to play a pro-inflammatory role in AAV by interacting with its receptor (C5aR). The C5aR pathway is an important part of pathogenic pathology.

C3 glomerulopathy (C3G) is an extremely rare kidney disease characterized by the deposition of C3 protein in the glomerulus, or the filtering unit of the kidney, leading to kidney damage.

Hidradenitis suppurativa (HS) is a neutrophil-driven chronic disabling skin disease that often results in keloids, contractures, and immobility. C5a promotes inflammatory mediators and is a strong activator of neutrophils.

Avacopan is an oral antagonist that inhibits C5aR and is being developed for the treatment of inflammatory and autoimmune diseases. The chemical name for Avacopan is (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methyl-benzoyl)-N-(4-methyl) -3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (hereinafter referred to as "Compound I"), its structural formula is as follows:

A crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice. Polymorphism is the phenomenon in which a compound exists in more than one crystal form. Compounds may exist in one or more crystalline forms, but their existence and identity cannot be specifically expected. APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. Especially for some insoluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.

Amorphous is an amorphous material without long-range order, and its XRPD (X-ray powder diffraction) pattern usually shows a broad "steamed bread peak". Compared with crystals, amorphous drugs are less thermodynamically stable, so amorphous drugs tend to crystallize during production and storage. The poor stability of amorphous form may change the bioavailability and dissolution rate of the drug, and ultimately lead to changes in the clinical efficacy of the drug.

The preparation method of compound I disclosed in WO2010075257A1 in the prior art, the inventors of the present application repeated this method to obtain the amorphous form of compound I. WO2021092286A1 discloses Compound I free crystalline form (hereinafter referred to as "prior art form A") and amorphous. Prior art WO2016053890A1 discloses various methods for preparing solid compound I. The inventor of the present application repeats the method disclosed in WO2016053890A1, and the obtained solids are all the prior art crystal form A disclosed in WO2021092286A1, which is different from the crystal form CSIII of the present application.

WO2021092286A1 discloses stability data for Compound I amorphous, whose unspecified impurities at RRT=0.90 (relative retention time) increased from 0.05% to 0.20% after 12 months storage at 25°C/60%RH. However, according to the ICH guidelines for impurity limits, for drugs with a maximum daily dose of ≤2g, no single non-specific impurity should exceed the identification limit (0.10% or 1.0mg daily intake, whichever is lower). The impurity limit of Compound I amorphous during storage exceeds the identification limit, which is not suitable for the development of Compound I-containing drugs. Meanwhile, WO2021092286A1 discloses solubility data for amorphous, whose solubility in FaSSGF (pH 1.64) and FeSSIF (pH 4.90) is only 9.9 μg/mL at maximum.

WO2021092286A1 discloses the solubility data of the prior art crystal form A, the solubility in FaSSGF (pH 1.64) and FeSSIF (pH 4.90) is very low, both below the detection limit. It can be seen from this that the solid disclosed in WO2016053890A1, namely the prior art crystal form A, is almost insoluble in FaSSGF and FeSSIF media.

By analyzing the content disclosed in the prior art and further research, the inventors of the present application found that the amorphous compound I has defects such as poor stability, high impurity content, and poor compressibility. There is a defect of extremely poor solubility, therefore, neither the amorphous nor the prior art Form A is suitable for pharmaceutical development.

In order to overcome the shortcomings of the prior art, there is still a need in the art for a new crystal form that meets the pharmaceutical needs for the development of medicines containing Compound I. The inventors of the present application have unexpectedly discovered that the crystal form of Compound I provided by the present invention has the advantages of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability, etc. At least one aspect of it has advantages, especially high solubility, good purification effect, good physical and chemical stability, good mechanical stability, and good compressibility, which solves the problems existing in the prior art, and has great advantages for the development of drugs containing compound I. Significance.

SUMMARY OF THE INVENTION

The present invention provides a new crystal form of compound I, a preparation method thereof, and a pharmaceutical composition comprising the new crystal form.

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

In one aspect, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form CSIII has characteristic peaks at diffraction angle 2θ values of 6.2°±0.2°, 8.9°±0.2°, 9.8°±0.2°.

Further, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CSIII has a diffraction angle 2θ value of 11.0°±0.2°, 12.1°±0.2°, 14.8°±0.2° at 1 place, or at 2 places , or 3 places have characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSIII has characteristic peaks at 3 places in the diffraction angle 2θ of 11.0°±0.2°, 12.1°±0.2°, 14.8°±0.2° .

Further, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CSIII has a diffraction angle 2θ value of 16.5°±0.2°, 17.7°±0.2°, 18.5°±0.2° at 1 place, or at 2 places , or 3 places have characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSIII has characteristic peaks at 3 places in the diffraction angle 2θ of 16.5°±0.2°, 17.7°±0.2°, 18.5°±0.2° .

On the other hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form CSIII has diffraction angle 2θ values of 6.2°±0.2°, 8.9°±0.2°, 9.8°±0.2°, 11.0°±0.2°, 12.1°±0.2°, 14.8°±0.2°, 16.5°±0.2°, 17.7°±0.2°, 18.5°±0.2° any 3 places, or 4 places, or 5 places, or 6 places, or 7 places , or 8, or 9 with characteristic peaks.

Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII is substantially as shown in FIG. 1 .

Without limitation, the thermogravimetric analysis diagram of the crystalline form CSIII is substantially as shown in FIG. 2 , which has a mass loss of about 2.6% when heated to 115°C.

On the other hand, the present invention also provides a preparation method of the crystal form CSIII, the preparation method comprising:

(1) Dissolving compound I solid in methanol, cooling to -30°C-5°C to obtain crystal form CSIII; or

(2) The solid compound I was placed in methanol and stirred at -20°C to 30°C to obtain crystal form CSIII.

According to the purpose of the present invention, the present invention provides the use of crystal form CSIII in preparing other crystal forms or salts of compound I.

According to the purpose of the present invention, the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of crystal form CSIII and pharmaceutically acceptable excipients.

Further, the present invention provides the use of crystal form CSIII in the preparation of C5aR inhibitor medicines.

Furthermore, the present invention provides the use of crystal form CSIII in the preparation of anti-neutrophil cytoplasmic antibody-related vasculitis drugs.

beneficial effect

The crystal form CSIII provided by the invention has the following advantages:

(1) Compared with the prior art, the crystal form CSIII provided by the present invention has higher solubility. The solubility of the prior art crystal form A in FaSSGF medium with pH=1.64 and FeSSIF medium with pH=4.90 after equilibration for 1 hour is lower than the detection limit. The crystal form CSIII of the present invention has a solubility of 22.9 μg/mL in a pH=1.8 SGF medium for 1 hour, and a solubility of 13.0 μg/mL in a pH=5.0 FeSSIF medium for 1 hour.

Compound I is a poorly water-soluble drug belonging to BCS II or BCS IV. The crystal form CSIII provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.

(2) Compared with the prior art, the crystal form CSIII provided by the present invention has better purification effect. After the raw material is prepared into the crystal form CSIII of the present invention, the purity is significantly improved and the types of impurities are reduced. In a specific embodiment, after the crystal form CSIII of the present invention is prepared by using raw materials with a purity of 99.23%, the purity is increased to 99.46%. Compared with the raw material, the purity of the crystal form CSIII is increased by 0.23%, and the types of impurities are reduced by 6, especially the content of impurities at RRT=0.70-0.72 is reduced by 71%. While the starting material was prepared as amorphous, there was little change in purity.

The chemical purity of the drug is of great significance to ensure the efficacy and safety of the drug and prevent the occurrence of adverse drug reactions. Different pharmaceutical regulations have strict requirements on impurity content. The crystal form CSIII provided by the invention has good purification effect and strong impurity removal ability. The crude drug with higher purity can be obtained by crystallization, which effectively overcomes the disadvantages of low drug stability, poor efficacy and high toxicity caused by low drug purity.

(3) Compared with the prior art, the crystal form CSIII provided by the present invention has better compressibility. The good compressibility of crystal form CSIII can effectively improve the unqualified hardness/brittleness, splits and other problems in the tableting process, make the formulation process more reliable, improve product appearance, and improve product quality and production efficiency.

(4) The crystalline form CSIII bulk drug provided by the present invention has good physical and chemical stability. The bulk drug of crystal form CSIII is placed under closed and open conditions at 25°C/60% RH, and the crystal form has not changed for at least 3 months, and the purity remains basically unchanged during storage. After the crystal form CSIII is mixed with excipients to make a pharmaceutical preparation, and placed under the condition of 25°C/60% RH, the crystal form does not change for at least 1 month, and the purity basically remains unchanged during the storage process. It shows that the crystalline form CSIII API and preparation have good stability under long-term conditions, which is beneficial to the storage of the drug.

The crystalline form CSIII bulk drug was placed under the closed and open conditions of 40°C/75%RH for at least 3 months, and the crystalline form did not change, and the purity remained basically unchanged during the storage process. The crystal form of the bulk drug of crystal form CSIII did not change for at least one month under the closed condition of 60°C/75%RH, and the crystal form did not change for at least one week under the open condition of 60°C/75%RH. Whereas the prior art amorphous crystallized in only one week under 60°C/75%RH open conditions. It shows that the crystalline form CSIII API has better stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug. The crystalline form CSIII API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.

Meanwhile, the crystalline form CSIII has good humidity stability. After the crystal form CSIII of the present invention is cycled once under a relative humidity of 50%-95%-0%-95%, the crystal form does not change.

The good physical and chemical stability of the crystalline form of the bulk drug can ensure that the drug will not be crystallized during the production and storage process, and basically no impurities will be generated. Crystal form CSIII has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and reducing drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.

(5) The crystal form CSIII provided by the present invention has good mechanical stability. The crystal form CSIII API has good physical stability after grinding. In the process of preparation processing, it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process. Under different pressures, the crystalline form CSIII API has good physical stability, which is conducive to maintaining the crystal form stability in the preparation and tableting process.

Description of drawings

Fig.1 XRPD pattern of crystal form CSIII

Figure 2 TGA diagram of crystal form CSIII

Figure 3. XRPD comparison chart of crystal form CSIII before and after placing under different conditions (from bottom to top: before placing, 25℃/60%RH closed for 3 months, 25℃/60%RH open for 3 months, 40 ℃/75%RH closed for 3 months, 40℃/75%RH open for 3 months, 60℃/75%RH closed for 1 month, 60℃/75%RH open for 1 week)

Figure 4. XRPD comparison diagram of crystal form CSIII before and after DVS (top: before DVS, bottom: after DVS)

Figure 5. XRPD comparison diagram of crystal form CSIII before and after grinding (top: before grinding; bottom: after grinding)

Figure 6. XRPD comparison diagram of crystal form CSIII before and after pressing by 10KN pressure (top: before pressing; bottom: after pressing)

Figure 7 XRPD comparison diagram of crystal form CSIII before and after preparation (from top to bottom: blank mixed powder, after preparation process, crystal form CSIII)

Figure 8. XRPD comparison chart of crystal form CSIII preparation under 25℃/60%RH closed condition plus 1g desiccant for 1 month (top: before placing; bottom: after placing)

Detailed ways

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

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

XRPD: X-ray Powder Diffraction

TGA: Thermogravimetric Analysis

DVS: Dynamic Moisture Sorption

HPLC: High Performance Liquid Chromatography

BCS: Biopharmaceutical Classification System

RH: relative humidity

RRT: Relative retention time

ICH: International Conference on Harmonization of Technical Requirements for the Registration of Medicinal Products for Human Use

Instruments and methods used to collect data:

The X-ray powder diffraction pattern of Example 6 of the present invention was collected on a Bruker D8DISCOVER X-ray powder diffractometer. The method parameters of X-ray powder diffraction of the present invention are as follows:

X-ray light source: Cu, Kα

1.54060;

1.54439

Kα2/Kα1 intensity ratio: 0.50

Voltage: 40 thousand volts (kV)

Current: 40 milliamps (mA)

Scanning range: from 4.0 to 40.0 degrees

X-ray powder diffraction patterns of other examples described herein were collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of X-ray powder diffraction of the present invention are as follows:

X-ray light source: Cu, Kα

1.54060;

1.54439

Kα2/Kα1 intensity ratio: 0.50

Voltage: 30 thousand volts (kV)

Current: 10 milliamps (mA)

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

The TGA map of the present invention was collected on a TA Q500. The method parameters of TGA of the present invention are as follows:

Scan rate: 10°C/min

Shielding gas: N ₂

The test parameters of the solubility of crystal form CSIII of the present invention are shown in Table 1:

Table 1

The test parameters of the related substance detection of the present invention are shown in Table 2 and Table 3:

Table 2

table 3

In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring speed is preferably 300-900 rev/min, and the mechanical stirring The speed is preferably 100-300 revolutions per minute.

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

The "drying" is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural drying. The drying temperature may be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, blast oven or vacuum oven.

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

The "volatilization" is accomplished by conventional methods in the art, such as slow volatilization or rapid volatilization. Slow volatilization is to seal the container with sealing film, poke holes, and stand to volatilize; rapid volatilization is to leave the container open to volatilize.

The "characteristic peak" refers to a representative diffraction peak used to identify crystals. When using Cu-Kα radiation to test, the peak position can usually 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 will appreciate that the X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. The relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with the experimental conditions, so the intensity of the diffraction peaks cannot be used as the only or decisive factor for determining the crystal form. In fact, the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. A person skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an 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 CSIII of the present invention is pure, substantially free from admixture with any other crystalline forms. In the present invention, "substantially free" when used to refer to a new crystal form means that the 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 More than 5% (weight) of other crystal forms, more refers to less than 1% (weight) of other crystal forms.

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

Unless otherwise specified, the following examples are operated at room temperature.

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

Compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2010075257A1 patent.

Example 1: Preparation method of crystal form CSIII

Weigh 30.7 mg of compound I solid into a glass vial, add 1.0 mL of methanol, heat at 50 °C to dissolve and filter, store the filtrate at -20 °C for 1 day, separate the solid and dry the solid at 25 °C under vacuum for 4.5 hours. The crystal form CSIII of the present invention is obtained, and its XRPD diagram is shown in FIG. 1 , and the XRPD data is shown in Table 4.

As shown in Fig. 2, TGA has a mass loss of about 2.6% when the crystalline form CSIII is heated to 115 °C.

Table 4

Diffraction angle 2θ	d value	strength%
3.72	23.75	12.39
6.18	14.30	20.98
7.35	12.02	6.51
8.85	10.00	90.65
9.84	8.99	65.72
10.53	8.40	11.49
11.02	8.03	35.79
12.07	7.33	80.59
12.34	7.17	25.05
13.44	6.59	3.96
14.80	5.98	100.00
15.27	5.80	15.52
15.55	5.70	23.14
15.93	5.56	14.41
16.52	5.37	28.79
17.45	5.08	19.50

17.73	5.00	40.08
18.49	4.80	17.75
19.09	4.65	27.72
19.40	4.58	16.26
20.11	4.42	14.93
20.35	4.36	14.19
20.93	4.25	30.26
21.20	4.19	18.81
21.93	4.05	14.52
22.42	3.97	12.38
22.73	3.91	19.45
23.18	3.84	8.27
23.73	3.75	11.14
24.27	3.67	9.29
24.75	3.60	10.30
25.87	3.44	7.98
26.76	3.33	5.01
27.17	3.28	11.45
27.79	3.21	4.04
28.93	3.09	3.38
30.14	2.96	6.69
30.78	2.91	4.96
32.79	2.73	2.99
33.49	2.68	2.52
35.20	2.55	0.48

Example 2: Preparation method of crystal form CSIII

Weigh 9.9 mg of solid compound I into a glass vial, add 0.3 mL of methanol, and stir at room temperature for about 6 days to obtain a crystalline solid. The obtained solid is the crystal form CSIII of the present invention.

Example 3: Solubility of Form CSIII

When conducting drug solubility tests to predict drug performance in vivo, it is important to simulate in vivo conditions as closely as possible. For oral drugs, SGF (simulating gastric fluid) and FeSSIF (simulating intestinal fluid in fed state) can simulate in vivo conditions and predict the effect of feeding. The solubility tested in such media more closely matches the solubility in the human environment.

Take a certain mass of the crystal form CSIII of the present invention and be suspended in 3.5mL of SGF and 3.5mL of FeSSIF to prepare a suspension, and after equilibrating for 1 hour, test the content (μg/mL) of the sample in the solution by high performance liquid chromatography. The experimental results As shown in Table 5.

table 5

medium	test temperature	Crystal form CSIII (μg/mL)
SGF pH=1.8	room temperature	22.9

FeSSIF pH=5.0

13.0

From the results, after equilibrating in SGF and FeSSIF media for 1 hour, the solubility of crystalline form CSIII was 22.9 μg/mL and 13.0 μg/mL, respectively.

Example 4: Purification effect of crystal form CSIII and amorphous

The crystalline form CSIII and amorphous of the present invention are prepared from the same starting materials. HPLC was used to determine the chemical purity of the raw material, the crystal form CSIII of the present invention and the amorphous form, and the test results are shown in Table 6.

Table 6

The results show that the crystal form CSIII of the present invention prepared from the same raw material has higher purity, and the crystal form CSIII can significantly reduce the content of impurities at RRT=0.70-0.72, while the amorphous form has no obvious effect on the purification of impurities at RRT=0.70-0.72 . Compared with the amorphous form, the crystalline form CSIII has better purification effect.

Example 5: Physicochemical Stability of Form CSIII and Amorphous

About 5 mg of crystal form CSIII and amorphous of the present invention were taken and placed at 25°C/60%RH, 40°C/75%RH and 60°C/75%RH respectively, and the purity and crystal form were determined by HPLC and XRPD.

Table 7 shows the stability results of crystal form CSIII under the conditions of 25°C/60%RH and 40°C/75%RH. The stability results of the crystal form CSIII under the conditions of 60° C./75% RH are shown in Table 8, and the XRPD comparison diagram is shown in FIG. 3 . The stability results of the amorphous form are shown in Table 9.

Table 7

Placement conditions	put time	Crystal form	Purity change (area %)
start	N/A	Form CSIII	N/A
25℃/60%RH (closed)	3 months	Form CSIII	0.06
25℃/60%RH(open)	3 months	Form CSIII	0.01
40℃/75%RH (closed)	3 months	Form CSIII	0.03
40℃/75%RH(open)	3 months	Form CSIII	0.06

The results show that the crystalline form CSIII is stable for at least 3 months at 25°C/60%RH and 40°C/75%RH, and maintains good stability under both long-term and accelerated conditions.

Table 8

Placement conditions	put time	Crystal form
start	N/A	Form CSIII
60℃/75%RH (closed)	1 month	Form CSIII
60℃/75%RH(open)	1 week	Form CSIII

Table 9

Placement conditions	put time	Crystal form
start	N/A	Amorphous

60℃/75%RH(open)

1 week

Partially crystallized

Form CSIII is stable for at least one week under 60°C/75%RH opening conditions, and also has good physical stability under more severe conditions. The state-of-the-art amorphous is partially crystallized after being placed for one week under the open condition of 60°C/75%RH.

Example 6: Humidity Stability of Crystal Form CSIII

Weigh about 10 mg of the crystal form CSIII of the present invention and use a DVS instrument to test its hygroscopicity and stability, and cycle it once under 50%-95%-0%-95% relative humidity. The XRPD comparison chart before and after DVS is shown in Figure 4.

The results showed that the crystal form CSIII did not change before and after the DVS test.

Example 7: Mechanical stability of crystal form CSIII

An appropriate amount of crystalline form CSIII was placed in a mortar and manually ground for 5 minutes. The XRPD comparison charts before and after grinding are shown in Figure 5.

The results showed that the crystal form CSIII did not change before and after grinding.

Take an appropriate amount of the crystal form CSIII of the present invention and press it with 10KN, and the XRPD comparison chart before and after pressing is shown in Figure 6.

The results showed that the crystalline form CSIII did not change before and after pressing.

Example 8: Compressibility of Form CSIII and Amorphous

The ENERPAC manual tablet press was used for tablet compression. When tableting, select a Φ6mm circular flat punch, add 80 mg of the present invention's crystal form CSIII and amorphous respectively, and use a pressure of 10 kN to compress into circular tablets, which are placed at room temperature for 24 hours until complete. After elastic recovery, the diameter (D) and thickness (L) of the tablet were measured with a vernier caliper, and its radial breaking force (hardness, H) was measured with a tablet hardness tester. The tensile strength of the powder is calculated using the formula T=2H/πDL. Under a certain pressure, the higher the tensile strength, the better the compressibility. The compressibility results of crystalline form CSIII and amorphous are shown in Table 10. The results show that the crystalline form CSIII has better compressibility compared to the amorphous form.

Table 10

Crystal form	Average tensile strength (MPa)
Form CSIII	1.2
Amorphous	0.6

Example 9: Preparation of Formulation CSIII

The formulation formula and formulation process of crystal form CSIII are shown in Table 11 and Table 12, respectively. The XRPD comparison chart of the crystalline form CSIII before and after the preparation is shown in FIG. 7 .

The results showed that the crystal form CSIII did not change before and after the preparation, and the purity basically did not change.

Table 11

Table 12

Example 10: Formulation stability of Form CSIII

The preparation made of crystal form CSIII was placed for 1 month at 25°C/60% RH with 1 g of desiccant.

Table 13

The results show that the crystalline form CSIII preparation can remain stable for at least 1 month under the condition of 25℃/60%RH.

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

Claims (9)

1. Compound I

   

   The crystalline form CSIII is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 6.2°±0.2°, 8.9°±0.2°, and 9.8°±0.2°.
2. The crystalline form CSIII according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has 2θ values of 11.0°±0.2°, 12.1°±0.2°, 14.8°±0.2° There are characteristic peaks at 1 or 2 or 3 places.
3. The crystalline form CSIII according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has 2θ values of 16.5°±0.2°, 17.7°±0.2°, 18.5°±0.2° There are characteristic peaks at 1 or 2 or 3 places.
4. The crystal form CSIII according to claim 2, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has 2θ values in the range of 16.5°±0.2°, 17.7°±0.2°, 18.5°±0.2° There are characteristic peaks at 1 or 2 or 3 places.
5. The crystal form CSIII according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in FIG. 1 .
6. A preparation method of the described crystal form CSIII of claim 1, is characterized in that:

   (1) Dissolving compound I solid in methanol, cooling to -30°C-5°C to obtain crystal form CSIII; or

   (2) The solid compound I was placed in methanol and stirred at -20°C to 30°C to obtain crystal form CSIII.
7. A pharmaceutical composition comprising an effective therapeutic amount of the crystal form CSIII described in claim 1 and pharmaceutically acceptable excipients.
8. Use of the crystal form CSIII of claim 1 in the preparation of a C5aR inhibitor medicine.
9. Use of the crystal form CSIII of claim 1 in the preparation of a drug for anti-neutrophil cytoplasmic antibody-related vasculitis.

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