WO2021135346A1 - New crystal form of acalabrutinib, preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a novel crystal form of Acalabrutinib, a preparation method therefor, a pharmaceutical composition having the crystal form, and uses of the crystal form in preparing a Bruton's tyrosine kinase inhibitor and a pharmaceutical preparation for treating mantle cell lymphoma. The new crystal form provided in the present invention has obvious cost advantages, and has one or more improved properties over the prior art, and is of great value for the optimization and development of the drug in the future.

Description

New crystal form of Acalabrutinib and its preparation method and use Technical field

The invention relates to the technical field of drug crystals. Specifically, it relates to the crystal form of Acalabrutinib and its preparation method and use.

Background technique

Mantle Cell Lymphoma (MCL) is a type of non-Hodgkin's lymphoma. MCL is a lymphoproliferative disorder derived from a subpopulation of naive germinal center cells located in the primary follicle or in the mantle area of the secondary follicle. MCL is characterized by specific chromosomal translocations. MCL is a type of lymphoma that is difficult to cure. For patients with relapsed or refractory disease, there are only limited treatment options. Patients respond poorly to standard therapies such as CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone), have a poor prognosis, and urgently need new drugs.

BTK is a member of the Tec family of tyrosine kinases and has been shown to be a key regulator of early B cell development and mature B cell activation and survival. Functional mutations in human BTK lead to X-linked gammaglobulinemia (XLA). These patients are immunocompromised and show impaired B cell maturation, reduced immunoglobulin and peripheral B cell levels. In addition, BTK has been reported to play a role in cell apoptosis, and therefore BTK inhibitors can be used to treat certain B-cell lymphomas and leukemias.

Acalabrutinib was developed by Acerta and was launched in the United States in October 2017. The marketing of Acalabrutinib provides a new treatment option for patients with relapsed drug-resistant mantle cell lymphoma. Acalabrutinib is a second-generation BTK inhibitor. Compared with the first-generation BTK inhibitor Ibrutinib, Acalabrutinib has higher drug selectivity and lower side effects. In previous clinical trials, Acalabrutinib has achieved a very high remission rate. The chemical name of Acalabrutinib is: (S)-4-(8-amino-3-(1-but-2-ynylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl )-N-(pyridin-2-yl)benzamide (hereinafter referred to as "Compound I"), its structural formula is shown in the figure below:

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.

In order to overcome the shortcomings of the prior art, the inventor of the present application unexpectedly discovered that the compound I crystal form K3 provided by the present invention has advantages in physical and chemical properties, preparation processing properties, 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, bioavailability, etc., especially (specifically achieved beneficial effects), which contains Acalabrutinib The drug development of China provides new and better options, which is of great significance.

Summary of the invention

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

According to the purpose of the present invention, the present invention provides a crystalline form K3 of Acalabrutinib (hereinafter referred to as "crystalline form K3").

On the one hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form K3 has characteristic peaks at diffraction angle 2θ values of 7.8°±0.2°, 15.6°±0.2°, and 17.3°±0.2°.

Further, the X-ray powder diffraction of the crystal form K3 has characteristic peaks at one or more of the diffraction angle 2θ values of 20.6°±0.2°, 16.6°±0.2°, 18.2°±0.2°; preferably, The X-ray powder diffraction of the crystal form K3 has characteristic peaks at the diffraction angle 2θ values of 20.6°±0.2°, 16.6°±0.2°, and 18.2°±0.2°.

Further, the X-ray powder diffraction of the crystal form K3 has characteristic peaks at one or more of the diffraction angle 2θ values of 14.4°±0.2°, 9.3°±0.2°, 11.0°±0.2°; preferably, The X-ray powder diffraction of the crystal form K3 has characteristic peaks at the diffraction angle 2θ values of 14.4°±0.2°, 9.3°±0.2°, and 11.0°±0.2°.

On the other hand, using Cu-Kα radiation, the characteristic peaks of the crystal form K3 include X-ray powder diffraction at diffraction angle 2θ values of 7.8°±0.2°, 15.6°±0.2°, 17.3°±0.2°, 20.6° ±0.2°, 16.6°±0.2°, 18.2°±0.2°, 14.4°±0.2°, 9.3°±0.2°, 11.0°±0.2°Any 3 locations, or 4 locations, or 5 locations, or 6 locations , Or 7, or 8, or 9 have characteristic peaks.

Without limitation, the XRPD pattern of the crystal form K3 is shown in FIG. 1.

In a non-limiting manner, the crystal form K3 is a hemiacetonitrile solvate.

According to the purpose of the present invention, the present invention also provides a preparation method of the crystal form K3, characterized in that the preparation method includes:

Add Acalabrutinib free base solid to acetonitrile or a mixed solvent of acetonitrile and other solvents, stir, separate, and dry to obtain a white powdery solid, which is crystal form K3.

Preferably, in the mixed solvent, the other solvent may be a solvent miscible with acetonitrile.

Preferably, the other solvents may be alcohols and alkanes.

Preferably, the stirring temperature is 4°C-90°C, more preferably 50°C.

In the present invention, "crystalline" or "polymorphic" refers to those confirmed by X-ray powder diffraction pattern 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 to 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 diffraction peaks in X-ray powder diffraction patterns may also change with changes in experimental conditions, so the order of 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 this article are 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 crystal form K3 of the present invention is pure, and substantially no other crystal 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.

In the present invention, the term "about", 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 fluctuations around the specific value, and the range may be ±10% , ±5%, ±1%, ±0.5%, or ±0.1%.

In addition, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the crystal form K3 of the present invention and a pharmaceutically acceptable carrier, diluent or excipient.

Further, the present invention provides the use of crystal form K3 in the preparation of Bruton's tyrosine kinase inhibitor drugs.

Furthermore, the present invention provides the use of crystal form K3 in the preparation of a medicine for treating mantle cell lymphoma.

In addition, the present invention provides the use of crystal form K3 for preparing crystal form K1.

Further, the crystal form K1 is the crystal form described in WO2019205812A1.

The present invention relates to crystal form K3 of Acalabrutinib which has advantages in at least one aspect of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processing performance, formulation production, etc. The preparation of Acalabrutinib's pharmaceutical preparations provides a new and better choice, which is of great significance for drug development.

Description of the drawings

Figure 1 XRPD pattern of crystal form K3

Figure 2 TGA diagram of crystal form K3

Detailed ways

The parameters of the test equipment involved in the embodiment are described.

The present invention is further defined with reference to 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

Instruments and methods used to collect data:

The X-ray powder diffraction pattern of the present invention is collected on a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method 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 milliampere (mA)

Scan range: from 3.0 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) of the present invention are as follows:

Scanning rate: 10℃/min

Shielding gas: nitrogen

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

Scanning rate: 10℃/min

Shielding gas: nitrogen

According to the present invention, the Acalabrutinib 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 Acalabrutinib free base solid used in the following examples can be prepared according to the prior art, for example, according to the method described in the WO2017002095A1 document.

Detailed ways

Example 1 Preparation method of crystal form K3

Add 24.35 g of Acalabrutinib free base to 390 mL of acetonitrile solvent, stir at 20.5°C for 8 hours, vacuum filter, wash the solid with 100 mL of acetonitrile, and then vacuum dry at 80°C for 13 hours to obtain white solid crystals.

After testing, the obtained crystalline solid is the crystal form K3 of the present invention, and its X-ray powder diffraction pattern is shown in Figure 1, and the XRPD data is shown in Table 1.

TGA is shown in Figure 2. When heated to 100°C, it has a mass loss of 0.8%, corresponding to the removal of adsorbed water or solvent on the surface; heating from 100°C to 200°C, has a mass loss of 4.1%, corresponding to the crystal form Removal of acetonitrile solvent in K3 lattice.

Table 1

Diffraction angle 2θ	d value	strength%
6.75	13.10	8.61
7.78	11.37	83.40
9.27	9.54	16.05

9.55	9.26	2.14
11.04	8.01	13.78
11.48	7.71	13.60
11.71	7.56	4.34
12.70	6.97	3.54
13.33	6.64	18.19
13.54	6.54	7.09
14.43	6.14	19.36
14.95	5.93	12.59
15.64	5.67	98.72
16.60	5.34	29.72
17.33	5.12	100.00
17.79	4.99	5.80
18.20	4.87	34.58
18.62	4.77	9.05
19.21	4.62	8.34
19.45	4.56	11.38
20.22	4.39	32.78
20.60	4.31	55.89
20.98	4.24	10.47
21.35	4.16	16.42
22.13	4.02	23.83
22.90	3.88	12.15
23.16	3.84	16.49
23.49	3.79	12.55
23.78	3.74	9.88
24.12	3.69	20.34
25.44	3.50	14.28
25.73	3.46	7.98

26.63	3.35	8.70
26.87	3.32	17.32
27.23	3.28	8.68
28.25	3.16	5.21
29.74	3.00	6.71
30.42	2.94	3.26
31.70	2.82	3.78
32.31	2.77	4.15
32.92	2.72	4.72
34.31	2.61	2.03

Dynamic solubility of crystal form K3

Solubility is one of the key properties of drugs, which directly affects the absorption of drugs in the human body. The solubility of different crystalline drugs may be significantly different, and the absorption dynamics in the body will also change, resulting in differences in bioavailability, and ultimately affecting the clinical safety and efficacy of the drugs.

Especially for a poorly soluble drug, improving the solubility is more important. The increase in solubility will help to increase the bioavailability of the drug, thereby improving the drug's drug-making properties. In addition, the improvement of solubility also reduces the difficulty of formulation process development. Crystal forms with sufficiently high solubility can be developed using traditional formulation processes. For crystal forms with lower solubility, in order to achieve the desired bioavailability, more advanced methods are required. Complex preparation process. In addition, the increased solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.

In order to test the solubility of the crystal form K3 of the present invention, the inventors made the following experiments:

Specifically:

Refer to the solubility determination method in the appendix of "Chinese Pharmacopoeia"; combine the pH value changes of different organs in the body. According to the above two reference basis, the present invention is equipped with a solvent system with 4 pH values ranging from 1.2 to 7.5. Specifically: SGF (simulated gastric juice) with a pH of 1.8, FeSSIF (artificial intestinal fluid under simulated feeding state) with pH of 5.0, FaSSIF (artificial intestinal fluid simulated under fasting state) with pH 6.5, and water.

Precisely weigh 5 mg of the crystal form K3 prepared by the present invention, place it in a vial, and use SGF (simulated gastric juice) with a pH of 1.8, FeSSIF (artificial intestinal fluid with a simulated feeding state) of pH 5.0, and FaSSIF (with a pH of 6.5). Simulate artificial intestinal juice under fasting conditions) and water to mix. The rotator was rotated at a rate of 25 revolutions per minute, and samples were taken at 1 hour, 4 hours, and 24 hours respectively. After centrifugal separation using a 0.45 μm polytetrafluoroethylene (PTFE) filter, the filtrate was collected for HPLC analysis.

Long-term and accelerated stability of crystal form K3

The stability of the drug is very important, especially during the effective period of the market, maintaining good stability can reduce the risk of changes in the dissolution rate and bioavailability of the drug due to changes in the crystal form of the drug, which is important for ensuring the efficacy and safety of the drug and preventing The occurrence of adverse drug reactions is of great significance. The more stable crystal form is more controllable during the crystallization process, and mixed crystals are not easy to appear, and it is not easy to transform into other crystal forms during the preparation process and storage process, so as to ensure that the quality of the sample is consistent and controllable, and to ensure the preparation of the product The dissolution profile will not change with the storage time.

Influencing factor experiment: accurately weigh 5 mg of the crystal form K3 prepared by the present invention, and place them under the conditions of 25°C/60% relative humidity, 40°C/75% relative humidity, and 60°C/75% relative humidity, and sample after a period of time , Using HPLC and XRPD methods to determine the changes in crystal form and purity.

Speed up the experiment: place it open. The above-mentioned crystal form K3 of the present invention was placed under 40°C/75% relative humidity conditions, and the changes in crystal form and purity at 2 weeks, 2 months, 3 months, and 6 months were determined by HPLC and XRPD methods. The above-mentioned crystal form was placed under the condition of 60° C./75% relative humidity, and the changes in crystal form and purity were determined by HPLC and XRPD methods after acceleration for 2 weeks.

Long-term experiment: the above-mentioned crystal form K3 of the present invention was placed under 25°C/60% relative humidity conditions for 12 months. Samples were taken at 1 month, 3 months, 6 months, and 12 months, and the changes in crystal form and purity were determined by HPLC and XRPD methods.

Pressure stability of crystal form K3

Take an appropriate amount of the crystal form K3 of the present invention, select a suitable tableting die, press to shape it under different pressures, and perform XRPD tests before and after receiving the pressure.

From the perspective of product quality, the crystal form with good pressure stability can effectively improve the hardness/fragility unqualified during processing and reduce the requirements for the previous processing (such as raw material crushing particle size control, drying moisture control, Particle size and particle size distribution control) to make the process more robust, improve product appearance, and enhance product quality.

From the perspective of production efficiency and cost, good pressure stability can increase processing speed and increase production efficiency; there is no need to use some expensive special auxiliary materials to improve pressure stability during the process and reduce the cost of auxiliary materials; the processing process only needs to be small The pressure can reach the expected hardness, which can effectively reduce energy consumption, extend the service life of the equipment, and reduce equipment maintenance costs; in addition, the crystal type with good pressure stability improves the feasibility of direct processing, and direct processing greatly simplifies The preparation process reduces the cost of R&D and production.

Hygroscopicity of crystal form K3

Hygroscopicity is one of the key properties of the drug crystal form. The drug crystal form with high hygroscopicity absorbs more water and changes its weight, which makes it difficult to determine the content of the raw material crystal form component. In addition, the crystal form of the drug substance is easy to absorb water and agglomerate due to its high hygroscopicity, which affects the particle size distribution of the sample during the preparation process and the uniformity of the drug substance in the preparation, thereby affecting the dissolution and bioavailability of the sample. APIs with high hygroscopicity have strict requirements on packaging and storage conditions, leading to increased production costs of drugs. Therefore, the preparation of drug crystal forms with low hygroscopicity is essential for drug production.

The hygroscopicity study of the crystal form K3 of the present invention is as follows:

Weigh about 10 mg each of the crystal form K3 of the present invention and use a dynamic moisture adsorption (DVS) instrument to test its moisture absorption. The measurement conditions are: temperature of 25°C±1°C and relative humidity of 80%±2%.

The general rule 9103 of the Chinese Pharmacopoeia describes the characteristics of moisture absorption and the definition of weight gain:

Deliquescence: Absorb enough water to form a liquid.

Very moisture-absorbing: moisture-absorbing weight gain is not less than 15%.

Has moisture absorption: moisture absorption weight gain is less than 15% but not less than 2%.

Slight moisture absorption: moisture absorption weight gain is less than 2% but not less than 0.2%.

No or almost no hygroscopicity: the weight gain is less than 0.2%.

Mechanical stability of crystal form K3

Before grinding, XRPD was used to test the crystal form K3 of the present invention to determine the crystal form and crystallinity of the sample in the initial state. The crystal form K3 of the present invention was respectively placed in a mortar, manually ground for 5 minutes, and XRPD was used to test the crystal form after grinding.

Better mechanical stability shows that under certain mechanical stress, stable physical and chemical properties can still be maintained. Crystalline drugs with good mechanical stability have low requirements on crystallization equipment, do not require special post-processing conditions, are more stable in the preparation process, can significantly reduce drug development costs, improve drug quality, and have strong economic value.

Particle size distribution (PSD) of crystal form K3

Take 10-30mg of the prepared crystal form K3 of the present invention, and then add 10mL Isopar G (containing 0.2% lecithin), mix the sample to be tested thoroughly and add it to the SDC sampling system to make the sample volume indicator reach the appropriate position , Start the experiment and test the particle size distribution to obtain the average particle size calculated by volume, the particle size corresponding to 10% of the particle size distribution (volume distribution), and 50% of the particle size distribution (volume distribution). Corresponding particle size. The particle size and crystal type particle size distribution diagram corresponding to 90% of the particle size distribution (volume distribution).

Different crystal forms may exhibit different compressibility, bulk density, fluidity, and stability to grinding, pressure, and pulverization due to their different particle properties, thereby affecting the process in the formulation. For example: a narrower particle size distribution can improve the uniformity of the drug substance components in the preparation, and at the same time make the difference between different batches of preparations smaller, such as more uniform dissolution; smaller crystal size can increase the specific surface area of the drug , Improve the dissolution rate of the drug, which is conducive to the absorption of the drug, thereby increasing the bioavailability. Large agglomerates of crystals are usually easy to encapsulate residual solvents or other impurities. In addition, when preparing the preparation, the bulk crystal powder cannot be uniformly dispersed, and it is difficult to mix uniformly with the auxiliary materials, which is not conducive to the preparation of the preparation.

The fluidity of crystal form K3

After measuring the bulk density and tap density of the crystal form K3 of the present invention prepared by the present invention through the compressibility coefficient according to the "United States Pharmacopoeia", the compressibility coefficient is calculated according to the following formula.

Compressibility coefficient (%) = (tap density-bulk density)/tap density × 100%

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

From the perspective of production efficiency and cost, the crystal form with good fluidity can effectively increase the production speed of tableting and filling, and improve production efficiency; there is no need to use some expensive special auxiliary materials to improve fluidity and reduce the cost of auxiliary materials; in addition, It can improve the feasibility of direct compression and direct powder filling, greatly simplify the production process and reduce production costs.

From the perspective of product quality, a crystal form with good fluidity can ensure the uniformity and content uniformity of the preparation, reduce the weight difference of the dosage form, and improve the quality of the product.

Adhesion of crystal form K3

Choose an appropriate mold, use an appropriate amount of the crystal form K3 of the present invention to continuously press tablets under an appropriate pressure, and measure the cumulative adsorption amount of the punch powder for comparison.

From the perspective of product quality, the low-adhesive crystal form can effectively improve or avoid sticky wheels and sticking caused by dry granulation and tablet compression. It is beneficial to improve the appearance, weight difference, etc. product quality. In addition, the low-adhesive crystal form can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and the mixing with other auxiliary materials, and increase the uniformity of the mixing of materials and the content of the final product. Evenness.

Formulation K3

Take an appropriate amount of the crystal form K3 of the present invention and mix it evenly with the auxiliary materials, press the roller into thin slices and crush them into granules, mix them evenly with the external auxiliary materials, and fill them into capsules of suitable size. Determine the in vitro dissolution, crystal form and related substances. Next, examine its storage stability.

During the preparation process of the preparation, the physical and chemical stability is good, which is convenient for industrial production; the dissolution in vitro is good, which is beneficial to improve the bioavailability of the drug. The stability is excellent, which is conducive to the production, packaging, storage and transportation of medicines and guarantees the quality of the products.

The present invention provides a crystalline form K3 of Acalabrutinib, which has advantages in at least one aspect of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processing performance, preparation production, etc., It provides a new and better choice for the preparation of pharmaceutical preparations containing Acalabrutinib, which is of great significance for drug development.

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 (7)

1. A crystalline form K3 of Acalabrutinib is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 7.8°±0.2°, 15.6°±0.2°, and 17.3°±0.2°.
2. The crystal form K3 of claim 1, wherein the X-ray powder diffraction pattern has one or more 2θ values of 20.6°±0.2°, 16.6°±0.2°, 18.2°±0.2° With characteristic peaks.
3. The crystal form K3 of claim 1, wherein the X-ray powder diffraction pattern has one or more 2θ values of 14.4°±0.2°, 9.3°±0.2°, 11.0°±0.2° With characteristic peaks.
4. A method for preparing crystalline form K3 according to claim 1, wherein the method is: adding Acalabrutinib free base solid to acetonitrile or a mixed solvent of acetonitrile and other solvents, stirring, separating, and drying to obtain a white The powdery solid is the crystal form K3.
5. A pharmaceutical composition comprising an effective therapeutic amount of the crystal form K3 described in claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
6. The use of the crystal form K3 described in claim 1 in the preparation of Bruton's tyrosine kinase inhibitor drugs.
7. The use of the crystal form K3 described in claim 1 in the preparation of a medicine for treating mantle cell lymphoma.

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