WO2013078973A1

WO2013078973A1 - Large particle diameter dasatinib and preparation and use thereof

Info

Publication number: WO2013078973A1
Application number: PCT/CN2012/085282
Authority: WO
Inventors: 安晓霞; 吕峰; 申淑匣; 张静; 李小强
Original assignee: 上海创诺制药有限公司
Priority date: 2011-11-29
Filing date: 2012-11-26
Publication date: 2013-06-06

Abstract

Disclosed are a large particle diameter Dasatinib and preparation and use thereof, the particle diameter range of the large particle diameter Dasatinib being: D (0.1)=3.0-10µm, D (0.5)=15-60µm, D (0.9)=100-150µm. With high fluidity and compressibility and moderate solubility, the large particle diameter Dasatinib facilitates the preparation of qualified formulation and reduces raw material and formulation preparation costs, thus satisfying the requirements for industrialized production. The large particle diameter Dasatinib of the present invention can be used to prepare Dasatinib tablets, and the prepared tablets solve the problems of too quick dissolution rate, unwanted reaction caused by burst drug release, shortened drug effective time, and easy occurrence of unqualified dissolution.

Description

Large particle size dasatinib and its preparation and application

The invention relates to a large particle size dasatinib and its preparation and application, and belongs to the technical field of pharmaceutical preparations.

Dasatinib/Sprycel, chemical name N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl ]-2-methylpyrimidin-4-yl]amino]-1,3-thiazol-5-carboxamide (monohydrate), the molecular formula is

C ₂₂ H ₂₈ ClN ₇ O ₃ SH ₂ O, molecular weight 506.02, its chemical structural formula is as follows:

Dasatinib is a potent carcinogenic kinase inhibitor developed by Bristol-Myers Squibb and has been used clinically to treat imatinib mesylate/Gleevec resistance. Treatment of adult patients with all stages of chronic myeloid leukemia (chronic phase, accelerated phase, lymphoid cell blast phase, and myelocyte blast crisis), Philadelphia chromosome-positive acute lymphoblastic leukemia, and solid tumor patients. Among the approved drugs, Sprycel is the first oral chemotherapeutic drug that inhibits multiple configurations of the tyrosine kinase Abl. At nanomolar concentrations, the drug inhibits multiple kinases such as Bcr-Abl, the SRC kinase family (SRC, LCK, YES, FYN), c-KIT, EPHA2 and PDGFR-B. By inhibiting the action of these kinases, Sprycel inhibits the proliferation of leukemia cells in CML and Ph+ ALL bone marrow. It has the advantages of long-lasting efficacy and high safety, and has been approved for use in most countries around the world.

Chinese patent CN200580011916.6 discloses five crystalline forms of dasatinib (monohydrate, butanol solvate, ethanol solvate, pure form N-6, pure form TIHI-7) and disclosed The preparation method of the corresponding crystalline form:

Monohydrate: 48 g of dasatinib, 1056 ml (22 ml/g) of ethanol and 144 ml of water were added, heated to 75 ° C to dissolve, and purified by filtration and transferred to a receiver. The dissolution reactor and transfer line were rinsed with a mixture of 43 ml of ethanol and 5 ml of water. The solution was heated to 75-80 ° C to completely dissolve, 384 ml of water was added and the solution temperature was maintained between 75 and 80 ° C. Cool to 75 ° C, add monohydrate seed crystals, cool to 70 ° C for 1 h, cool to 5 ° C in 2 h and incubate between 0 ~ 5 ° C for 2 h, filter the slurry, with 96 ml of ethanol and 96 ml The mixture of water was washed with a filter cake, and dried under reduced pressure at ≤ 50 ° C to obtain 41 g. Pure form of N-6: to compound 5D (175.45, 0.445 mol) and hydroxyethylpiperazine (289.67 g,

2. 225 mol) DIPEA (155 ml, 0.89 mmol) was added to a mixture of NMP (1168 ml). The suspension was heated at 1 10 ° C for 25 min to obtain a solution, which was then cooled to about 90 °C. The resulting hot solution was added dropwise to hot water (80 ° C, 801 Oml) and stirred at 80 ° C for 15 minutes while slowly cooling to room temperature. The solid was collected by vacuum filtration, washed with water (2× 1600 ml), and dried in vacuo.

Pure form of TIHI-7 (pure form and pharmaceutically acceptable carrier): The dasatinib monohydrate is prepared by heating at a temperature above the dehydration temperature.

It can be seen from the above reports that the preparation process of dasatinib monohydrate is complicated and the preparation conditions are demanding, and the pure form of dasatinib N-6 (ie, anhydrate) is simple in preparation process and low in preparation cost. Industrial batch production requirements for satinib raw materials. However, for drugs, different crystal forms have different physical and chemical properties, including melting point, chemical stability, apparent solubility, dissolution rate, and the like. These properties can directly affect the handling or production of the formulation and can affect the stability, solubility and bioavailability of the formulation.

For dasatinib, the saturated solubility of anhydrate in water is greater than that of monohydrate (anhydrous

3.25mg/ml; monohydrate 1.02mg/ml), tablets which are easy to prepare anhydrate have a dissolution rate too fast, produce adverse reactions caused by drug burst release, shorten the time to maintain efficacy, and prone to dissolution Unqualified issues. Therefore, the existing dasatinib tablets are made of dasatinib monohydrate as a raw material, how to use dasatinib anhydrate as a raw material to prepare quality dasatinib tablets, which has not been seen yet. Related reports.

Moreover, the solid physical properties of the drug also have an important influence on the dissolution rate of the preparation and the difficulty of tableting. For example, the particle size of a drug can affect the fluidity and compressibility of the drug. In addition, in the filtration and separation process, the filtration and washing treatment of small particles takes a long time and the loss is large, which tends to lead to an increase in the production cost, which is disadvantageous for industrial production requirements. Summary of the invention

In view of the above problems in the prior art, it is an object of the present invention to provide a large particle size dasatinib and a method for preparing a large particle size dasatinib to reduce the preparation cost and meet the performance requirements of the preparation. .

Another object of the present invention is to provide a quality-compliant dasatinib tablet prepared by using dasatinib anhydrate as a raw material to meet the requirements of industrial mass production of dasatinib raw materials and preparations: low cost The process is simple and the quality meets the requirements.

In order to achieve the above object, the technical solution adopted by the present invention is as follows:

The first aspect of the present invention provides a large particle size dasatinib having a particle size range of: D (0.1) = 3.0~ ΙΟμιη, D(0.5)=15~60 m, D(0.9)=100~150μιη.

In another preferred embodiment, the dasatinib is obtained by the following method, comprising the steps of: a) adding dasatinib to an organic solvent to obtain a slurry;

b) heating to reflux to obtain a clear solution;

c) cooling, the temperature of the solution is lowered by 5~15 ° C, and a suspension is obtained;

d) cooling to room temperature after 5 to 15 hours;

e) filtering, drying the obtained solid under vacuum at 40~60 ° C;

Or the dasatinib is obtained by the following method, including the steps:

1) adding dasatinib to an organic solvent to obtain a slurry;

2) heating to reflux to obtain a clear solution;

3) Cool down, reduce the temperature of the solution by 5~15 °C, and obtain a suspension;

4) heating, so that the temperature of the suspension rises 0~5 °C;

5) Cool down again, and reduce the temperature of the suspension by 5~10 °C;

6) After heating for 1 hour, heat again to increase the temperature of the solution by 10 °C;

7) Cool down to room temperature after 3 to 5 hours;

8) Filtration, and the obtained solid was dried under vacuum at 40 to 60 °C.

In another preferred embodiment, 1 gram of dasatinib is added with 10 to 50 ml of an organic solvent.

In another preferred embodiment, the dasatinib is any known crystal form.

In another preferred embodiment, the organic solvent is a low boiling organic solvent; preferably, the organic solvent is any one of acetone, ethyl acetate, methanol, ethanol, isopropanol, and acetonitrile.

In another preferred embodiment, the dasatinib is an anhydrate; preferably, the dasatinib is obtained by the following method, comprising the steps of:

a) adding dasatinib anhydrate to an organic solvent to obtain a slurry;

b) heating to reflux to obtain a clear solution;

d) cooling to room temperature after 5 to 15 hours;

e) Filtration, and the obtained solid was dried under vacuum at 40 to 60 °C.

A second aspect of the present invention provides a method for preparing a large particle size dasatinib, comprising the steps of: a) adding dasatinib to an organic solvent to obtain a slurry;

b) heating to reflux to obtain a clear solution;

c) cooling, reducing the temperature of the solution by 5~15 ° C, to obtain a suspension; d) cooling to room temperature after 5 to 15 hours;

e) Filtration, and the obtained solid was dried under vacuum at 40 to 60 °C.

Or, include the following steps:

1) adding dasatinib to an organic solvent to obtain a slurry;

2) heating to reflux to obtain a clear solution;

4) heating, so that the temperature of the suspension rises 0~5 °C;

5) Cool down again, and reduce the temperature of the suspension by 5~10 °C;

7) Cool down to room temperature after 3 to 5 hours;

8) Filtration, and the obtained solid was dried under vacuum at 40 to 60 °C.

Further, 1 gram of dasatinib needs to be added with 10 to 50 ml of an organic solvent.

The dasatinib is any known crystal form, for example: dasatinib monohydrate, butanol solvate, ethanol solvate, pure form N-6, pure form hydrazine-7.

The organic solvent is preferably a low boiling point solvent, and is preferably any one of acetone, ethyl acetate, methanol, ethanol, isopropanol, and acetonitrile. Compared with the prior art, the particle size range obtained by the preparation method of the present invention is: D(0.1)=3.0~ ΙΟμιη, D(0.5)=15~60 m, D(0.9)=100~150μιη large particle size Dasatinib; and experiments have proved that the dasatinib obtained by the invention has good fluidity and compressibility, moderate solubility, is favorable for preparing qualified preparations, and is beneficial for reducing the production cost of raw materials and preparations. Can meet the requirements of industrial production. A third aspect of the present invention provides a dasatinib tablet, comprising dasatinib and a pharmaceutically acceptable pharmaceutical excipient, characterized in that the dasatinib is an anhydrate, and the particle size range thereof It is: D (0.1) = 3.0 to ΙΟ μιη, D (0.5) = 15 - 60 μιη, D (0.9) = 100 to 150 μιη.

Further, the dasatinib tablet comprises dasatinib and a filler, a binder, a disintegrant, and a lubricant.

Further, the dasatinib tablet has the following composition prescription:

Dasatinib 20 parts by mass

Filler 50~75 parts by mass

5 to 25 parts by mass of binder 1 to 10 parts by mass of disintegrant

Lubricant 0.5 to 1.5 parts by mass.

Further, the filler is any one or a mixture of two or more of microcrystalline cellulose, lactose, and pregelatinized starch.

Further, the binder is hydroxypropylmethylcellulose or starch.

Further, the disintegrant is crospovidone, croscarmellose sodium or sodium carboxymethyl starch.

Further, the lubricant is magnesium stearate.

The dasatinib anhydrate of the particle size range described in the present invention can be obtained by the following chemical treatment:

a) adding dasatinib anhydrate to an organic solvent to obtain a slurry;

b) heating to reflux to obtain a clear solution;

c) cooling, the temperature of the solution is lowered by 5~15 °C, and a suspension is obtained;

d) cooling to room temperature after 5 to 15 hours;

e) Filtration, and the obtained solid was dried under vacuum at 40 to 60 °C.

Further, 1 gram of dasatinib anhydrate is added with 10 to 50 ml of an organic solvent.

The organic solvent is preferably a low boiling point solvent, and is preferably any one of acetone, ethyl acetate, methanol, ethanol, isopropanol, and acetonitrile.

The dasatinib anhydrate of the particle size range described in the present invention can also be obtained by a physical sieving method or other methods.

The dasatinib tablet of the present invention can be obtained by first wet granulation and then tableting, or can be obtained by direct powder tableting.

Compared with the prior art, the present invention uses dasatinib anhydrate as a raw material to obtain a dasatinib tablet of satisfactory quality, and solves the problem that the dasatinib anhydrate has a large saturation solubility in water, and is easy to be The tablets which result in the preparation of anhydrate have a dissolution rate too fast, an adverse reaction caused by drug burst release, a shortened time for maintaining the efficacy, and a problem that the dissolution is unacceptable, and can satisfy the raw materials and preparations of dasatinib. Industrial mass production requirements: low cost, simple process, quality meets requirements. The invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentage sum unless otherwise stated The number of copies is calculated by weight. detailed description

The present invention will be further described in detail below in conjunction with the embodiments.

The particle sizes described in the examples were obtained by Malvern laser diffraction using a Mastersizer 2000 laser granulometer.

The dasatinib described in the examples is any crystal form prepared by the preparation method disclosed in Chinese Patent No. CN200580011916.6.

The dasatinib anhydrate used in the examples was prepared by the preparation method of the pure form of N-6 disclosed in Chinese Patent No. CN200580011916.6. Example 1

Into a 500 ml four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer, a mixture of N-6 10 g of dasatinib in pure form and 300 ml of absolute ethanol was added to obtain a slurry; heating to reflux to 75 ° C to obtain a clear solution; The solution was slowly cooled to 60 ° C to obtain a suspension; the temperature was slowly lowered to room temperature over 10 hours, filtered, and the obtained solid was dried at 50 ° C to obtain a dry product of 8.9 g. For: D(0.1)=3 m, ϋ(0.5)=20.1μιη, ϋ(0.9)=130.2μηΐ ο

Example 2

Adding 10 g of dasatinib ethanol solvate and 300 ml of absolute ethanol to a 500 ml four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer to obtain a slurry; heating to reflux at 75 ° C to obtain a clear solution; The solution was slowly cooled to 60 ° C to obtain a suspension; the suspension was heated to 60-65 ° C, and then cooled to 55 ° C; the temperature was stirred at 55 ° C for 1 hour; heated again to 65 ° C; After 4 hours, the temperature was slowly lowered to room temperature, filtered, and the obtained solid was dried at 50 ° C to obtain 9.1 g of a dry product. The particle size was found to be: ϋ (0.1) = 6.4 μιη, ϋ (0.5) = 55.2 μιη , Ο(0·9)=140·3μιη. Example 3

In a 1000 ml four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer, a solution of N-6 20 g in pure form of dasatinib and 700 ml of acetone was added to obtain a slurry; heating to reflux at 56 ° C to obtain a clear solution; The solution was slowly cooled to 48 ° C to obtain a suspension, which was slowly cooled to room temperature over 5 hours. The solution was filtered, and the obtained solid was dried at 50 ° C to obtain 18.5 g of a dry product. : ϋ(0.1)=4.2μιη, ϋ(0.5)=50.1 μιη, Ο(0·9)=137· 1 μιη. Example 4

In a 1000 ml four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer, 20 g of dasatinib monohydrate and 700 ml of acetone were added to obtain a slurry; the mixture was heated to reflux at 56 ° C to obtain a clear solution; then, the solution was slowly cooled. To 48 ° C, a suspension was obtained; the suspension was heated to 48 to 53 ° C, and then cooled to 43 ° C; the temperature was stirred at 43 ° C for 1 hour; heated again to 53 ° C; 3 hours later The mixture was cooled to room temperature, filtered, and the obtained solid was dried at 50 ° C to obtain 18.9 g of a dry product. The particle size was found to be:

Ο(0·9)=145·2μιη. Example 5

10 g of dasatinib anhydrate and 300 ml of ethyl acetate were added to a 500 ml four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer to obtain a slurry; heated to reflux at 78 ° C to obtain a clear solution; The temperature was slowly lowered to 65 ° C to obtain a suspension; the temperature was slowly lowered to room temperature over 15 hours, filtered, and the obtained solid was dried at 50 ° C to obtain a dry product of 9.0 g, and the particle size was found to be: D (0.1) = 3.8 m, ϋ (0.5) = 49.0 μιη, D (0.9) = l 12·3 μιη. Example 6

The performance difference between the untreated dasatinib (Α) (ie dasatinib pure form of Ν-6) and the dasatinib (Β) obtained in Example 1 was compared for the preparation of tablets:

The tablet prescription is as follows:

Dasatinib 20g

Microcrystalline cellulose 30g

Lactose 20g

Hydroxypropyl methylcellulose 5g

Cross-linked povidone 5g

Magnesium stearate 0.8g;

The above materials were uniformly mixed and subjected to direct powder tableting.

The angle of repose of the mixed powder was measured in accordance with the measurement method of the United States Pharmacopoeia USP32 angle of repose.

The hardness and disintegration time of the prepared tablets were measured by a four-way meter.

According to the dissolution test method published by the FDA, the prepared tablets were tested at pH 4.0 + 1.0% of the Tula Dissolution in the medium. The detailed comparison results are shown in Table 1.

Table 1 comparison results

Example 7

10 g of dasatinib anhydrate and 300 ml of absolute ethanol were added to a 500 ml four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer to obtain a slurry; heated to reflux at 75 ° C to obtain a clear solution; Slowly reduce the temperature to 60 ° C to obtain a suspension; slowly cool to room temperature over 10 hours, filter, and dry the obtained solid at 50 ° C to obtain 8.9 g of dry product (ie, dasatinib anhydrate). The particle size was found to be: ϋ(0.1)=3μιη, ϋ(0.5)=20μιη, Ο(0·9)=130μιη. Example 8

In a 1000 ml four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer, 20 g of dasatinib anhydrate and 700 ml of acetone were added to obtain a slurry; heating was refluxed to 56 ° C to obtain a clear solution; then, the solution was slowly cooled. At 48 ° C, a suspension was obtained, and the temperature was slowly lowered to room temperature over 5 hours, filtered, and the obtained solid was dried at 50 ° C to obtain a dry product (ie, dasatinib anhydrate) 18.5 g, tested Know that its particle size is:

Example 9

10 g of dasatinib anhydrate and 300 ml of ethyl acetate were added to a 500 ml four-necked flask equipped with a mechanical stirrer, a condenser and a thermometer to obtain a slurry; heated to reflux at 78 ° C to obtain a clear solution; Slowly reduce the temperature to 65 ° C to obtain a suspension; slowly cool down to room temperature over 15 hours, filter, and dry the obtained solid at 50 ° C to obtain 9.0 g of dry product (ie, dasatinib anhydrate). It was found that the particle size was: ϋ(0.1)=3.5μιη, ϋ(0.5)=60μιη, ϋ(0.9)=100μηΐο Example 10 The prescription of this embodiment is as follows

Dasatinib 20g

Microcrystalline cellulose 30g

Lactose 20g

Hydroxypropyl methylcellulose 5g

Cross-linked povidone 5g

Magnesium stearate 0.8g;

The dasatinib used in the present example has the particle diameter prepared as in Example 7: D(0.1)=3 m, ϋ(0.5)=20μιη, ϋ(0.9)=130μιη of dasatinib anhydrous Things.

Referring to the measurement method of the USP32 angle of repose of the United States Pharmacopoeia, the angle of repose of the mixed powder of this example was measured to be 36°, indicating that it had good fluidity.

The hardness and disintegration time of the prepared tablets were measured by a four-way meter, and the results were as follows:

Hardness 8Kg, good compressibility.

Disintegration time: 1.5min, in line with the quality requirements of the tablet.

According to the dissolution test method published by the FDA, the tablets prepared in this example and the existing tablets (the same size tablets prepared using dasatinib monohydrate as raw materials) were measured at pH 4.0 + 1.0%. The dissolution results in the Triton medium are shown in Table 2.

Table 2 Dissolution comparison results

Example 11

The prescription of this embodiment is as follows:

Dasatinib 20g

Microcrystalline cellulose 40g

Pregelatinized starch 10g

Hydroxypropyl methylcellulose 5g

Sodium Carboxymethyl Starch 5g Magnesium stearate 1.2g _;

The dasatinib used in this example has the particle diameter prepared as in Example 8: D(0.1)=4 m, ϋ(0.5)=50μιη, ϋ(0.9)=150μιη of dasatinib anhydrous Things.

With reference to the measurement method of the USP32 angle of repose of the United States Pharmacopoeia, the angle of repose of the mixed powder of this example was measured to be 33°, indicating that it had good fluidity.

Hardness 7.5Kg, good compressibility.

Disintegration time: 2.5min, in line with tablet quality requirements.

According to the dissolution test method published by the FDA, the tablets prepared in this example and the existing tablets (the same size tablets prepared using dasatinib monohydrate as raw materials) were measured at pH 4.0 + 1.0%. The dissolution results in the Triton medium are shown in Table 3.

Table 3 Dissolution comparison results

Example 12

The prescription of this embodiment is as follows:

Dasatinib 20g

Microcrystalline cellulose 30g

Starch 25g

Cross-linked carboxymethylcellulose sodium 5g

Magnesium stearate 1.2g _;

The dasatinib used in the present example has the particle diameter prepared as in Example 9: D(0.1)=3.5 m, ϋ(0.5)=60μιη, ϋ(0.9)=100μιη of dasatinib anhydrous Things.

First, the prescribed amount of dasatinib anhydrate and microcrystalline cellulose and 70% of the prescribed amount of starch are evenly mixed, and the remaining 30% of the prescribed amount of starch is made into 8% starch slurry, which is wet granulated with starch slurry. Dry, then add a prescribed amount of croscarmellose sodium and magnesium stearate, mix and compress.

The angle of repose of the mixed powder of the present example was measured with reference to the method for determining the angle of repose of the USP 32 USP. It is 30°, indicating good fluidity.

Hardness 5Kg, good compressibility.

Disintegration time: 3.5min, in line with tablet quality requirements.

According to the dissolution test method published by the FDA, the tablets prepared in this example and the existing tablets (the same size tablets prepared using dasatinib monohydrate as raw materials) were measured at pH 4.0 + 1.0%. The dissolution results in the Triton medium are shown in Table 4.

Table 4 dissolution comparison results

Example 13

The prescription of this embodiment is as follows:

Dasatinib 20g

Microcrystalline cellulose 30g

Lactose 20g

Hydroxypropyl methylcellulose 5g

Cross-linked povidone 5g

Magnesium stearate 0.8g _;

The dasatinib used in the present embodiment is directly prepared by the preparation method of the pure form of N-6 disclosed in Chinese Patent No. CN20058001 1916.6: D(0.1)=2 m, ϋ(0.5)= Dasatinib anhydrate of 14 μιη, D (0.9) = 70 m.

Referring to the measurement method of the USP32 angle of repose of the United States Pharmacopoeia, the mixed powder of the present example was measured to have an angle of repose of 48°, which was inferior in fluidity.

Hardness 10Kg, poor compressibility.

Disintegration time: 2.5min.

The tablets prepared in this example were compared with the existing tablets according to the dissolution test method published by the FDA. The dissolution results of the tablets of the same specification prepared with dasatinib monohydrate as raw materials in the pH 4.0 + 1.0% Triton medium are shown in Table 5.

Table 5 Dissolution comparison results

In summary, it can be seen that the tablet prepared by directly using the dasatinib anhydrate prepared by the prior art has a dissolution rate too fast, and is easy to produce an adverse reaction caused by drug burst release, and the maintenance time of the drug is short, and the dissolution rate is not In order to meet the requirements and the like, the present invention effectively solves the above problems, and obtains a tablet having a certain particle size range to obtain a tablet having a certain particle size range, thereby obtaining a Dashatin which is comparable or superior to the existing tablet. Niobium meets the requirements for industrial mass production of dasatinib raw materials and preparations: low cost, simple process and quality. Finally, it is necessary to point out that the above embodiments are only used to further clarify the technical solutions of the present invention, and are not to be construed as limiting the scope of the present invention. Some of the above-described contents of the present invention are made by those skilled in the art. Non-essential improvements and adjustments are within the scope of the invention.

Claims

Rights request

A large particle size dasatinib characterized by having a particle size range of D (0.1) = 3.0 to 10 m, D (0.5) = 15 to 60 m, and D (0.9) = 100 to 150 μm .

2. The large particle size dasatinib according to claim 1, wherein the dasatinib is an anhydride.

3. A method for preparing a large particle size dasatinib, comprising the steps of: a) adding dasatinib to an organic solvent to obtain a slurry;

b) heating to reflux to obtain a clear solution;

d) cooling to room temperature after 5 to 15 hours;

e) Filtration, and the obtained solid was dried under vacuum at 40 to 60 °C.

4. A method of preparing a large particle size dasatinib, comprising the steps of:

1) adding dasatinib to an organic solvent to obtain a slurry;

2) heating to reflux to obtain a clear solution;

4) heating, so that the temperature of the suspension rises 0~5 °C;

5) Cool down again, and reduce the temperature of the suspension by 5~10 °C;

7) Cool down to room temperature after 3 to 5 hours;

8) Filtration, and the obtained solid was dried under vacuum at 40 to 60 °C.

The method for preparing a large-sized dasatinib according to claim 3 or 4, wherein: 1 g of dasatinib is added with 10 to 50 ml of an organic solvent.

The method for producing a large-sized dasatinib according to claim 3 or 4, wherein the dasatinib is any known crystal form.

The method for producing a large-sized dasatinib according to claim 3 or 4, wherein the organic solvent is a low-boiling organic solvent.

The method for preparing a large particle size dasatinib according to claim 7, wherein the organic solvent is any one of acetone, ethyl acetate, methanol, ethanol, isopropanol, and acetonitrile. .

The method for producing a large-sized dasatinib according to claim 3 or 4, wherein the particle size range of the obtained dasatinib is: D (0.1) = 3.0 to 10 m, D (0.5) = 15~60 m,

D (0.9) = 100 to 150 m.

10. A dasatinib tablet comprising dasatinib and a pharmaceutically acceptable pharmaceutical excipient, characterized in that said dasatinib is an anhydride and the particle size range is: D ( 0.1) = 3.0 to 10 m, D (0.5) = 15 to 60 μm, D (0.9) = 100 to 150 m.

The dasatinib tablet according to claim 10, which comprises: dasatinib and a filler, a binder, a disintegrator, and a lubricant.

The dasatinib tablet according to claim 1, which has the following composition prescription: dasatinib

Filler

Adhesive

Disintegrator

Lubricant

The dasatinib tablet according to claim 1, wherein the filler is any one or a mixture of two or more of microcrystalline cellulose, lactose, and pregelatinized starch.

The dasatinib tablet according to claim 1, wherein the binder is hydroxypropylmethylcellulose or starch.

The dasatinib tablet according to claim 1, wherein the disintegrant is crospovidone, croscarmellose sodium or sodium carboxymethyl starch.

16. The dasatinib tablet according to claim 1, wherein the dasatinib is obtained by the following chemical treatment:

a) adding dasatinib anhydrate to an organic solvent to obtain a slurry;

b) heating to reflux to obtain a clear solution;

d) cooling to room temperature after 5 to 15 hours;

e) Filtration, and the obtained solid was dried under vacuum at 40 to 60 °C.

The dasatinib tablet according to claim 16, wherein 1 gram of dasatinib anhydrate is added with 10 to 50 ml of an organic solvent.

The dasatinib tablet according to claim 16, wherein the organic solvent is any one of acetone, ethyl acetate, methanol, ethanol, isopropyl alcohol, and acetonitrile.

The dasatinib tablet according to any one of claims 10 to 18, wherein the dasatinib tablet is prepared by first wet granulation and then tableting or by direct powder tableting. Got it.