WO2020177705A1 - Filgotinib maleate crystal form csi, preparation method therefor and use thereof - Google Patents

Abstract

A new Filgotinib maleate crystal form, a preparation method therefor, a pharmaceutical composition containing said crystal form, and use of the crystal form in the preparation of a JAK selective inhibitor and pharmaceutical formulations for treating rheumatoid arthritis, Crohn's disease, etc. Said Filgotinib maleate crystal form has one or more improved properties compared with the crystal forms in the art.

Description

Filgotinib maleate crystal form CSI and preparation method and application thereof Technical field

The invention relates to the field of medicinal chemistry. Specifically, it relates to the maleate crystal form of Filgotinib and its preparation method and application.

Background technique

Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of joints and other parts of the body, and can lead to permanent joint destruction and deformity. Crohn’s disease is an inflammatory bowel disease that can cause digestive tract inflammation, abdominal pain, severe diarrhea, intestinal obstruction, ulcers, fistulas, anal cracks and other diseases, and it is easy to recur.

"JAK" refers to the Janus kinase (JAKs) family, including the following four JAK family members: JAK1, JAK2, JAK3 and TYK2. Among them, the inhibition of JAK1 is essential for the treatment of inflammation, while the inhibition of JAK2, JAK3 and TYK2 is not necessary for the treatment of inflammation. JAK1 is a target of immune-inflammatory diseases, and its inhibitors are beneficial for the treatment of rheumatoid arthritis, Crohn's disease and other immune disorders inflammatory diseases.

Filgotinib (GLPG0634) is a selective JAK1 inhibitor, which shows high selectivity for inhibiting JAK1. Gilead's clinical trials have proved that Filgotinib does not cause anemia and abnormal increase in low-density lipoprotein (LDL), and the clinical data of the drug shows that Filgotinib is effective in treating rheumatoid arthritis and Crohn's disease. It has very good application prospects.

The chemical name of Filgotinib is: N-[5-[4-[(1,1-dioxo-1-thiomorpholin-4-yl)methyl]phenyl][1,2,4]triazolo [1,5-a]pyridin-2-yl]cyclopropanamide (hereinafter referred to as "Compound I"), its structural formula is as follows:

The crystal form is a solid in which 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 will 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.

WO2018169875A1 discloses the maleate crystalline form I of Compound I. In addition, no other maleate crystalline forms of Compound I have been reported. In the course of research, the inventors of the present application discovered that the maleate crystal form I disclosed in the prior art has poor solubility, high hygroscopicity, low density, and poor fluidity, compressibility, adhesion and pressure stability . The dissolution effect of the pharmaceutical preparation prepared from the crystal form I of the prior art is poor, which affects the clinical effect and safety of the medicine.

In order to overcome the shortcomings of the prior art, the inventor of the present application unexpectedly discovered the maleate crystalline form CSI of Compound I, which 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 and dissolution rate, low moisture absorption, and crystal flow It has good properties, adhesion and compressibility, which provides a new and better choice for the development of maleate containing compound I, which is of great significance.

Summary of the invention

The main purpose of the present invention is to provide a new crystalline form of the maleate salt of Compound I as shown below and its preparation method and application.

According to the purpose of the present invention, the present invention provides the maleate crystalline form CSI of Compound I (hereinafter referred to as "crystalline form CSI").

On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form CSI has characteristic peaks at diffraction angle 2θ values of 9.3°±0.2°, 20.7°±0.2°, and 7.8°±0.2°.

Further, the X-ray powder diffraction pattern of the crystal form CSI has characteristic peaks at one or two of the diffraction angle 2θ values of 23.5°±0.2° and 18.6°±0.2°; preferably, the crystal form CSI For example, the X-ray powder diffraction has characteristic peaks at two of the diffraction angles of 23.5°±0.2° and 18.6°±0.2°.

Furthermore, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at 1 or 2 or 3 of the diffraction angle 2θ values of 18.0°±0.2°, 26.3°±0.2°, 15.8±0.2° Preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at three of the diffraction angles 2θ of 18.0°±0.2°, 26.3°±0.2°, and 15.8±0.2°.

Furthermore, the X-ray powder diffraction pattern of the crystalline form CSI has a characteristic peak at a diffraction angle 2θ value of 17.5°±0.2°.

On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form CSI has diffraction angle 2θ values of 9.3°±0.2°, 20.7°±0.2°, 7.8°±0.2°, 23.5°±0.2° , 18.6°±0.2°, 18.0°±0.2°, 26.3°±0.2°, 15.8±0.2°, 17.5°±0.2°, any 3 locations, or 4 locations, or 5 locations, or 6, or 7 locations , Or 8 or 9 characteristic peaks.

Without limitation, the X-ray powder diffraction spectrum of the crystalline form CSI is basically as shown in FIG. 1.

Without limitation, the crystalline form CSI has a weight loss of 1.1% when heated to 120°C and a weight loss of 21.8% when heated to 230°C. The thermogravimetric analysis chart is basically shown in FIG.

According to the purpose of the present invention, the present invention also provides a method for preparing the crystal form CSI, and the preparation method includes the following two methods:

Method 1: Mix compound I, maleic acid with ketones, ethers, ketones and water or ethers and water, then stir and separate, and dry the obtained solid at room temperature, and then at no less than 100°C Heat under conditions to obtain crystal form CSI;

Method 2: Mix compound I, maleic acid and ester solvent, then stir, separate, and dry to obtain crystal form CSI.

Further, the molar ratio of compound I to maleic acid in method one is preferably 1:1.5-1:2.5; the molar ratio of compound I to maleic acid in method two is preferably 1:1.1 to 1:1.7;

Further, the ketones in method one are preferably acetone, the ethers are preferably 1,4-dioxane, and the volume ratio of the ketones to water or ethers to water is not less than 4:1; in method two The ester solvent is preferably isopropyl acetate;

Further, the stirring temperature in method one is preferably -20-50°C, and the stirring time is preferably 1-5 days; the stirring temperature in method two is preferably 40-60°C;

Furthermore, in the first method, the stirring temperature is preferably 5°C, the stirring time is preferably 3.5 days, and the heating temperature is preferably 160-165°C.

The crystalline CSI provided by the present invention has the following beneficial effects:

(1) Compared with the prior art, the crystal form CSI of the present invention has higher solubility. Whether in SGF or in water, the solubility is twice or more than that of the prior art crystal form I.

Higher solubility is conducive to improving the absorption of the drug in the human body, increasing the bioavailability, and making the drug play a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug Side effects and improve the safety of drugs.

(2) Compared with the prior art, the crystal form CSI of the present invention has better in vitro dissolution rate and dissolution rate. In 0.1mol/L hydrochloric acid, the inherent dissolution rate of the crystalline form CSI bulk drug is about twice that of the prior art form I. The dissolution rate of the crystalline CSI preparation in a 0.1mol/L hydrochloric acid medium reaches 84.1% at 30 minutes.

Different crystal forms may lead to different dissolution rates of the preparations in the body, directly affecting the absorption, distribution, metabolism, and excretion of the preparations 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. A good in vitro dissolution rate indicates that the drug has a higher degree of in vivo absorption and better exposure characteristics in the body, 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) Compared with the prior art, the crystalline CSI of the present invention has lower hygroscopicity. The test results show that the hygroscopicity of the crystal form CSI of the present invention is far lower than that of the crystal form I of the prior art. The crystalline CSI has a moisture-absorbing weight gain of 1.36% under 80% RH conditions, which is slightly moisture-absorbing, and the prior art solid has a moisture-absorbing weight gain of 2.15% under 80% RH conditions, which is considered to be moisture-absorbing.

The hygroscopicity directly affects the physical and chemical stability of the drug, and the high hygroscopicity can easily cause chemical degradation and crystal transformation. In addition, high hygroscopicity will reduce the fluidity of the drug, thereby affecting the processing technology of the drug. Not only that, drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements on production and requires high costs. More importantly, high hygroscopicity can easily cause changes in the content of active ingredients in the medicine, which affects the quality of the medicine. The low hygroscopicity crystal type is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.

(4) The crystalline CSI bulk drug provided by the present invention has good stability. The crystalline CSI bulk drug is placed open/closed under the conditions of 25°C/60% relative humidity. The crystal form has not changed for at least 6 months, and the chemical purity is above 99%, and the purity remains basically unchanged during storage. It shows that the crystalline CSI bulk drug has good stability under long-term conditions, which is beneficial to the storage of the drug.

At the same time, the crystalline CSI bulk drug has been left open/closed at 40°C/75% relative humidity for at least 6 months without any change in the crystal form, and the chemical purity is about 99%, and the purity remains basically unchanged during storage. It shows that the crystalline CSI bulk drug has good stability under accelerated conditions.

At the same time, crystalline CSI has good mechanical stability. The crystalline CSI bulk drug has good physical stability after grinding. In addition, the crystal form of the crystalline CSI bulk drug remains unchanged before and after the tableting, and has good physical stability. The preparation process often requires the grinding and pulverization of the drug substance. 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 CSI bulk drug has good physical stability, which is conducive to maintaining the stability of the crystalline form during the preparation process.

The transformation of crystal form will cause changes in drug absorption, affect bioavailability, and even cause drug side effects. Good chemical stability can ensure that almost no impurities are generated during storage. Crystalline CSI 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 toxic side effects caused by changes in crystal form or impurities. .

Further, the crystalline CSI provided by the present invention also has the following beneficial effects:

(1) Compared with the prior art, the crystalline CSI provided by the present invention has better compressibility. The good compressibility of crystalline CSI 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 product quality. 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 for improving the compressibility.

(2) Compared with the prior art, the crystal type CSI provided by the present invention has a greater density. Experimental results show that the bulk density and tap density of the crystal form CSI of the present invention are significantly better than the crystal form I of the prior art. The high density of crystalline CSI is conducive to large-scale production. A greater density can reduce dust, reduce occupational hazards, and ensure production safety.

(3) Compared with the prior art, the crystalline CSI of the present invention has better fluidity. The fluidity evaluation results show that the fluidity of the crystal form CSI is significantly better than that of the prior art crystal form I. Better fluidity can avoid clogging production equipment and improve production efficiency; the better fluidity of crystalline CSI ensures the uniformity and content uniformity of the formulation, reduces the weight difference of the formulation, and improves product quality.

(4) Compared with the prior art, the crystalline CSI of the present invention has better adhesion. The adhesion evaluation result shows that the adsorption capacity of the crystal form CSI is much lower than that of the prior art crystal form I. The better adhesion of crystalline CSI can effectively improve or avoid sticky wheels and sticking caused by dry granulation and tablet compression, which is beneficial to improve product appearance and weight differences. In addition, the better adhesion of crystalline CSI 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.

According to the objective of the present invention, the present invention also provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline CSI and a pharmaceutically acceptable carrier, diluent or adjuvant.

Further, the use of the crystal form CSI provided by the present invention in the preparation of JAK inhibitor pharmaceutical preparations.

Furthermore, the crystal form CSI provided by the present invention is used in the preparation of pharmaceutical preparations for treating rheumatoid arthritis 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 "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 "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 2-48 hours, or overnight. Drying is carried out in a fume hood, blast oven or vacuum oven.

In the present invention, "crystal" or "polymorph" refers to a solid confirmed by X-ray powder diffraction characterization. Those skilled in the art can understand that the physical and chemical properties discussed here can be characterized, and the experimental error depends on the condition of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known by those skilled in the art that the X-ray powder diffraction pattern usually changes with the different instrument conditions. In particular, it should be pointed out that 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 order of the diffraction peak intensities cannot be the only or decisive factor. 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 for absolute comparison. In addition, the experimental error of the position of the diffraction peak is usually 5% or less, and the error of these positions should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to the influence of experimental factors such as sample thickness, the overall angle of the diffraction peak will be shifted, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of a crystal form in 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 of CSI 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, 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 the mass, time, temperature, etc. of the compound and preparation, means that there can be a certain range of fluctuation around the specific value, and the range can be ±10% , ±5%, ±1%, ±0.5%, or ±0.1%.

Description of the drawings

Fig. 1 is an XRPD diagram of the crystal form CSI in Example 1.

2 is a TGA diagram of the crystal form CSI in Example 1.

3 is an XRPD diagram of the crystal form CSI in Example 2.

4 is an XRPD diagram of the crystal form CSI in Example 3.

Figure 5 shows the inherent dissolution curves of crystal form CSI and prior art crystal form I.

Figure 6 is a DVS diagram of the crystal form CSI.

FIG. 7 is a DVS diagram of crystal form I of the prior art.

Figure 8 is the XRPD overlay images of crystalline CSI before and after the tablet is made (from top to bottom: blank mixed powder, crystalline CSI preparation, and XRPD images of crystalline CSI).

Figure 9 is an XRPD overlay image of the prior art crystal form I under different pressure conditions (from top to bottom: 14KN, 7KN, 3KN and 0KN XRPD images).

Figure 10 is an XRPD overlay image of the crystalline CSI under different pressure conditions (from top to bottom: 14KN, 7KN, 3KN and 0KN XRPD images).

Figure 11 is an XRPD overlay of the crystal type CSI before and after polishing (the top image is before polishing; the bottom image is after polishing).

detailed description

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 the material and the method 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

TGA: Thermogravimetric Analysis

DVS: Dynamic moisture adsorption

IDR: Intrinsic dissolution rate

HPLC: high performance liquid chromatography

Instruments and methods used to collect data:

The X-ray powder diffraction patterns of Examples 1-3, 10, and 14 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

1.54060;

1.54439

Kα2/Kα1 intensity ratio: 0.50

Voltage: 30 thousand volts (kV)

Current: 10 milliampere (mA)

Scan range: from 3.0 to 40.0 degrees

The X-ray powder diffraction pattern of Example 12 of the present invention was collected on a Bruker D8DISCOVER X-ray powder diffractometer. The method parameters of the X-ray powder diffraction 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 milliampere (mA)

Scan range: from 4.0 to 40.0 degrees

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

Scanning rate: 10℃/min

Protective gas: nitrogen

The dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS (Surface Measurement Systems Ltd.). The instrument control software is DVS-Intrinsic control software. The method parameters of the dynamic moisture adsorption instrument are as follows:

Temperature: 25℃

Carrier gas, flow rate: N ₂ ,200 ml/min

Mass change per unit time: 0.002%/min

Relative humidity range: 0%RH-95%RH

The parameters of the HPLC method for testing dynamic solubility in Example 4 of the present invention are as follows:

The HPLC method parameters for testing the inherent dissolution rate in Example 5 of the present invention are as follows:

The parameters of the HPLC method for testing dissolution in Example 11 of the present invention are as follows:

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 free base of 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 free base of Compound I used in the following examples was prepared according to the method described in the document WO2015117981A1.

Example 1 Preparation method of crystalline CSI

Weigh 15.4mg compound I free base and 9.2mg maleic acid into a 1.5-mL glass vial, add 0.5mL 1,4-dioxane/water (84:16, v/v) mixed solvent, 5 Suspended and stirred at ℃ for 3.5 days. The solid was separated and dried at room temperature for 1 day to obtain a pale yellow solid. The obtained solid was heated to 165°C to obtain a maleate crystalline solid.

After testing, the obtained crystalline solid is the crystalline CSI described in the present invention. The XRPD diagram is shown in Figure 1, and the XRPD data is shown in Figure 1. The TGA of this crystal form is shown in Fig. 2 and has a weight loss of 1.1% when heated to 120°C and a weight loss of 21.8% when heated to 230°C.

Table 1

Diffraction angle 2θ	d value	strength%
7.84	11.28	45.37
9.31	9.49	100.00
10.26	8.62	6.93
11.82	7.48	7.63
15.79	5.61	17.06
17.51	5.07	52.17
18.05	4.91	25.21
18.62	4.77	26.25
19.48	4.56	12.11
19.79	4.49	15.35
20.65	4.30	28.24
22.92	3.88	11.39
23.54	3.78	32.84
26.32	3.39	22.07
27.84	3.20	16.87
29.30	3.05	6.98
31.21	2.87	6.37

Example 2 Preparation method of crystalline CSI

Weigh 16.1 mg of compound I free base and 7.3 mg of maleic acid into a 1.5-mL glass vial, add 0.5 mL of acetone solvent, suspend and stir at 5°C for 3.5 days, separate the solid and dry at room temperature for 1 day to obtain a pale yellow Solid, the obtained solid is heated to 160° C. to obtain maleate crystalline solid.

After testing, the obtained crystalline solid is the crystalline CSI described in the present invention. The XRPD pattern is shown in Figure 3, and the XRPD data is shown in Figure 2.

Table 2

Diffraction angle 2θ	d value	strength%
7.83	11.29	47.46
9.31	9.49	100.00
10.23	8.65	5.87
11.83	7.48	9.86
15.81	5.61	13.25
17.11	5.18	7.31
17.45	5.08	20.80
18.04	4.92	43.97
18.58	4.78	17.24
19.81	4.48	15.77
20.68	4.30	34.79
22.93	3.88	16.04
23.52	3.78	22.54
26.35	3.38	20.10
27.84	3.21	16.29
28.62	3.12	6.16
31.22	2.87	4.40

Example 3 Preparation method of crystalline CSI

Mix 520.2 mg of compound I free base, 166.3 mg of maleic acid and 15.0 mL of isopropyl acetate solvent. After stirring for about 3 days at 50°C, add 5.0 mL of isopropyl acetate again, and continue to suspend and stir at 50°C for about 9 Then, the solid was separated and dried under vacuum at 50°C for about 7 hours to obtain solid crystals.

After testing, the obtained crystalline solid is the crystalline form of CSI according to the present invention, and its X-ray powder diffraction data are shown in Figure 4 and Table 3.

¹ H NMR data is: ¹ H NMR (400MHz, DMSO) δ 11.03 (s, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.76-7.66 (m, 2H), 7.54 (d, J = 8.2Hz, 2H), 7.30 (dd, J = 6.6, 1.9 Hz, 1H), 6.25 (s, 2H), 3.83 (s, 2H), 3.17 (d, J = 4.9 Hz, 4H), 2.98 (s, 4H), 2.09–1.97 (m, 1H), 0.82 (d, J=6.2 Hz, 4H).

table 3

Diffraction angle 2θ	d value	strength%
7.81	11.31	49.12

8.92	9.92	31.30
9.31	9.49	100.00
10.30	8.59	6.28
11.74	7.53	4.93
15.75	5.63	12.63
17.51	5.06	46.07
18.02	4.92	56.25
18.68	4.75	35.87
19.62	4.52	22.83
20.68	4.30	52.60
22.96	3.87	24.42
23.50	3.79	38.83
26.30	3.39	37.74
27.89	3.20	19.85
29.48	3.03	6.12
31.25	2.86	6.87
34.65	2.59	2.94
36.48	2.46	3.27

Example 4 Dynamic solubility of crystalline CSI

Simulated gastrointestinal fluids such as SGF (simulated gastric juice) are biologically related media. Such media can better reflect the influence of the gastric physiological environment on drug release. The solubility tested in such media is closer to that in the human environment. .

Disperse 20 mg each of the crystal form CSI of the present invention and the prior art crystal form in 4 mL of SGF and 4 mL of water to prepare a saturated solution. After equilibrating for 15 minutes, 1 hour, and 2 hours, the saturated solution is tested by high performance liquid chromatography. The content of the sample in mg/mL, the results are shown in Table 4.

Table 4

The results show that compared with the prior art crystal form I, crystal form CSI has higher solubility in SGF and water.

Example 5 The inherent dissolution rate of crystalline CSI

Weigh about 60 mg each of crystalline form CSI and prior art crystalline form I, pour them into an inherent dissolution mold, and hold for 1 min under a pressure of 10 kN to form a sheet with a surface area of 0.5 cm ² , and transfer the mold with the sheet to the dissolution apparatus for testing. The dissolution rate and dissolution conditions are shown in Table 5, the dissolution curve is shown in Figure 5, and the dissolution data is shown in Table 6. The slope is calculated based on the measurement point between 1 and 10 min, expressed in μg/min, and the inherent slope is further calculated. The dissolution rate (IDR) is expressed in μg/min/cm ² and the IDR results are shown in Table 7.

table 5

Dissolution Apparatus	Agilent 708DS
Medium volume	900mL
Rotating speed	100rpm
Medium temperature	37° C
Sampling point	1,3,5,8,10min
Supplementary medium	No

Table 6

Table 7

batch number	Slope (μg/min)	IDR(μg/min/cm2)
Crystal CSI	515.2362	1030.4724
Prior Art Form I	328.5508	657.1016

The results show that the dissolution rate of the crystal form CSI is much greater than that of the prior art crystal form I.

Example 6 Hygroscopicity of crystalline CSI

Weigh about 10 mg each of the crystalline form CSI of the present invention and the prior art crystalline form I. Use a dynamic moisture adsorption (DVS) instrument to test its moisture absorption, cycle once at a relative humidity of 0-95%-0, and record the mass under each humidity Variety. The experimental results are shown in Table 8 and Figures 6-7. The crystal form of the CSI of the present invention does not change before and after the DVS detection.

Table 8

Regarding the description of hygroscopicity characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2015 Edition General Chapter 9103 Guidelines for Drug Hygroscopicity Tests, experimental conditions: 25℃±1℃, 80% relative humidity, European Pharmacopoeia Ninth Edition 5.11 The definition of is consistent with the Chinese Pharmacopoeia):

Deliquescence: absorb enough water to form a liquid

Extremely moisture-absorbing: moisture-absorbing weight gain is not less than 15.0%

Has moisture absorption: moisture absorption weight gain is less than 15.0% but not less than 2.0%

Slight moisture absorption: moisture absorption weight gain is less than 2.0% but not less than 0.2%

No or almost no moisture absorption: the weight gain is less than 0.2%

()

Crystal form CSI has a moisture-absorbing weight gain of 1.36% under 80% RH conditions, which is slightly hygroscopic. The prior art crystal form I has a moisture-absorbing weight gain of 2.15% under 80% RH conditions, which is hygroscopic. The crystal form CSI of the present invention has better moisture absorption properties than the prior art crystal form I.

Example 7 Fluidity and density of crystalline CSI

During the preparation process, the compressibility index or Carr index can usually be used to evaluate the fluidity of powder or intermediate particles. The measurement method is to lightly load a certain amount of powder into a graduated cylinder and measure initial loose bulk; tapping method using the powder in the most compact state, measure the final volume; calculated bulk density and tap density ρ ₀ ρ _f; calculated according to the formula _{c = (ρ f -ρ 0)} / ρ f Compressible Sex coefficient.

Refer to ICH Q4B Appendix 13 for the definition of compressibility coefficient for powder fluidity, see Table 9 for details.

Table 9

Compressibility coefficient (%)	fluidity
≦10	Excellent
11-15	it is good
16-20	general
21-25	Acceptable
26-31	difference
32-37	Very bad
>38	Very bad

The fluidity evaluation results of the crystal form CSI and the prior art crystal form I are shown in Table 10. The results show that the fluidity of the crystal form CSI is significantly better than the prior art crystal form I.

Table 10

Crystal form	Bulk density (g/ml)	Tap density (g/ml)	Karl coefficient	fluidity
Prior Art Form I	0.140	0.199	30%	difference
Crystal CSI	0.211	0.269	twenty two%	Acceptable

Example 8 Adhesion of crystalline CSI

Add about 30mg of crystal form CSI and prior art crystal form I API into a Φ8mm round flat punch, use 10kN pressure for tableting treatment, stay for about half a minute after tableting, and weigh the amount of powder absorbed by the punch . After using this method for two consecutive pressings, record the highest and average sticking amount during the punch pressing process. The specific experimental results are shown in Table 11.

Table 11

Crystal form	Maximum adhesion (mg)	Average adhesion amount (mg)
Prior Art Form I	1.50	0.95
Crystal CSI	0.00	0.00

The experimental results show that the adhesion of the crystal form CSI of the present invention is very low, and there is no residue on the punch after two consecutive pressings. The average adsorption capacity of the prior art crystal form I is 0.95 mg, and the maximum adsorption capacity is as high as 1.5 mg, which is much higher than The adsorption capacity of the crystal form CSI of the present invention.

Example 9 Compressibility of crystalline CSI

Use a manual tablet press to compress tablets. When compressing tablets, choose a Φ6mm round flat punch, add about 80mg crystal form CSI, prior art crystal form I, and press 10kN to form round tablets, and place them at room temperature for 24 hours. After complete elastic recovery, the tablet hardness tester is used to test its radial crushing force (hardness, H). The diameter (D) and thickness (L) of the tablet are measured with a vernier caliper, and the tensile strength of the powder is calculated by the formula T=2H/πDL. Under a certain pressure, the greater the tensile strength, the better the compressibility. The results are shown in Table 12 below.

Table 12

Crystal form	Thickness(mm)	Diameter (mm)	Hardness (N)	Tensile strength (MPa)
Prior Art Form I	2.23	6.08	14.7	0.69
Crystal CSI	2.22	6.06	25.8	1.22

The results show that the crystal form CSI has better compressibility than the prior art crystal form I.

Example 10 Formulation preparation of crystalline CSI

According to the prescription dosage of the tablet in Table 13, the crystalline CSI and the auxiliary materials were mixed uniformly, and the ENERPAC manual tablet press was used for tablet compression.

Formulation prescription

Table 13

Preparation technology

Table 14

The crystal form of the CSI of the present invention remains unchanged before and after the tablet is prepared, and the detection result is shown in FIG. 8.

Example 11 In vitro dissolution of crystalline CSI preparation

The CSI-containing tablets obtained in Example 10 were tested for in vitro dissolution. At the same time, the formulation and method of Example 10 were used to prepare prior art crystal form I tablets and tested for in vitro dissolution. The dissolution is determined in accordance with the Chinese Pharmacopoeia 2015 Edition 0931 Dissolution and Release Determination Method, and the conditions are as follows:

Dissolution medium: 0.1N HCl

Dissolution method: paddle method

Medium volume: 500mL

Speed: 50rpm (after 60min, the speed is adjusted to 200rpm and stirring for 30min)

Medium temperature: 37℃

The in vitro dissolution of the crystal form CSI preparation is shown in Table 15 below, which indicates that the tablet with the crystal form CSI of the present invention as an active ingredient has a better dissolution rate than the prior art crystal form I.

Table 15

Example 12 Pressure stability of crystalline CSI

Use a manual tablet press to compress tablets. When compressing tablets, choose a Φ6mm round flat punch, add about 20mg of the prior art crystal form I and crystal form CSI API, and use 3KN, 7KN, and 14KN pressure for tableting treatment. Detect the crystal form transformation of API under different pressure conditions. The experimental results are shown in Figures 9 and 10.

The results show that the crystal form of the crystal form CSI of the present invention remains unchanged before and after the tablet is pressed, and some peaks of the prior art crystal form I disappear after the tablet is pressed, and the crystal structure is changed, as shown by the arrow in FIG. 9. It shows that the pressure stability of the crystal form CSI of the present invention is better than that of the prior art crystal form I.

Example 13 Long-term and accelerated stability of crystalline CSI

Weigh 5 mg each of the crystal form CSI prepared by the present invention, and place them under the conditions of 25° C./60% RH and 40° C./75% RH, and determine the purity and crystal form by HPLC and XRPD methods. The results are shown in Table 16.

Table 16

Starting crystal form	Placement conditions (open or closed)	Set time	Crystal form	purity
Crystal CSI	Start	——	Crystal CSI	99.10

Crystal CSI	25℃/60% relative humidity (closed)	6 months	Crystal CSI	99.13
Crystal CSI	25℃/60% relative humidity (open)	6 months	Crystal CSI	99.24
Crystal CSI	40℃/75% relative humidity (closed)	6 months	Crystal CSI	99.03
Crystal CSI	40℃/75% relative humidity (open)	6 months	Crystal CSI	98.97

It shows that the crystal form CSI 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 CSI can maintain good stability under long-term and accelerated conditions.

Example 14 Polishing stability of crystalline CSI

The crystalline CSI was placed in a mortar, and manually ground for 5 minutes, and XRPD test was performed before and after the grinding. The results show that the crystal form of the crystal form CSI remains unchanged before and after grinding, indicating that the crystal form CSI has good grinding stability.

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 technology 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 covered by the protection scope of the present invention.

Claims (11)

1. Filgotinib maleate crystalline form CSI is characterized by using Cu-Kα radiation, and its X-ray powder diffraction pattern is characterized at 2θ values of 9.3°±0.2°, 20.7°±0.2°, 7.8°±0.2° peak.
2. The maleate crystalline form of Filgotinib according to claim 1, characterized in that Cu-Kα radiation is used, and its X-ray powder diffraction pattern has a 2θ value of 23.5°±0.2°, 18.6°±0.2°. There are characteristic peaks in one or two places.
3. The maleate crystalline form of Filgotinib according to claim 1, characterized in that Cu-Kα radiation is used, and its X-ray powder diffraction pattern has a 2θ value of 18.0°±0.2°, 26.3°±0.2°, 15.8 There are characteristic peaks in one or two or three of ±0.2°.
4. The method for preparing the maleate crystalline form CSI of Filgotinib according to claim 1, wherein the preparation method includes the following two:

   Method 1: Mix the free base and maleic acid of Filgotinib with ketones, ethers, ketones and water, or ethers and water, then stir and separate, and dry the obtained solid at room temperature, and then Heating at 100°C to prepare the maleate crystalline form of Filgotinib;

   Method 2: Mixing the free base of Filgotinib, maleic acid and ester solvents, then stirring, separating and drying to obtain the maleate crystalline form of Filgotinib.
5. The method for preparing the maleate crystalline form CSI of Filgotinib according to claim 4, wherein the molar ratio of the free base of Filgotinib to maleic acid in the first method is 1:1.5-1:2.5; The molar ratio of the free base of Filgotinib to maleic acid described in the second paragraph is 1:1.1-1:1.7.
6. The method for preparing the maleate crystalline form CSI of Filgotinib according to claim 4, wherein the ketone in the first method is acetone, the ether is 1,4-dioxane, and the The volume ratio of ketones to water or ethers to water in the mixed solvent is not less than 4:1; the ester solvent in the second method is isopropyl acetate.
7. The method for preparing the maleate crystalline CSI of Filgotinib according to claim 4, wherein the stirring temperature in method one is -20-50°C, and the stirring time is 1-5 days; method two The stirring temperature in the above is 40-60°C.
8. The method for preparing the maleate crystalline form CSI of Filgotinib according to claim 4, wherein the stirring temperature in method 1 is 5°C, the stirring time is 3.5 days, and the heating temperature is 160- 165°C.
9. A pharmaceutical composition comprising an effective therapeutic amount of the maleate crystalline form CSI of Filgotinib described in claim 1 and at least one pharmaceutically acceptable carrier, diluent or adjuvant.
10. The use of the maleate crystalline form of Filgotinib described in claim 1 in the preparation of JAK inhibitor drugs.
11. Use of the maleate crystal form CSI of Filgotinib according to claim 1 or the pharmaceutical composition according to claim 9 in the production of a pharmaceutical preparation for treating rheumatoid arthritis and Crohn's disease.

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