JP5589097B2 - Dasatinib polycrystal, preparation method thereof and drug composition - Google Patents

Description

  The present invention relates to a polycrystal of a drug compound, more specifically to a polycrystal of dasatinib, and the present invention further relates to a method for preparing the polycrystal and a drug composition thereof.

Dasatinib, trade name SPRYCEL ^™ is an orally administered tyrosine kinase inhibitor developed by BMS, used in adult chronic myelogenous leukemia (CML), for diseases such as Philadelphia chromosome positive acute lymphocytic leukemia Can also be used for treatment. Its chemical name is N- (2-chloro-6-methylphenyl) -2-({6- [4- (2-hydroxyethyl) piperazin-1-yl] -2-methylpyrimidin-4-yl} amino) 1,3-thiazole-5-carboxamide, the chemical structure is as follows.

  Bristol-Myers Squibb describes five crystal forms of dasatinib in a Chinese patent application-application number CN200580011916.6 (publication date 13 June 2007) and describes the preparation of the corresponding crystal forms Disclosed. The preparation method disclosed by the document is as follows.

  Monohydrate: 48 g dasatinib, 1056 ml (22 ml / g) ethanol and 144 ml water are added, heated to 75 ° C. to dissolve, purified, filtered and transferred to a receiving container. Rinse and dissolve the reactor and feed pipe with a mixture of 43 ml ethanol and 5 ml water. The solution is heated to 75-80 ° C to completely dissolve it, 384 ml water is heated and the solution temperature is maintained between 75-80 ° C. Cool to 75 ° C., add monohydrate crystal seeds (preferred), cool to 70 ° C. and keep warm for 1 h, cool to 5 ° C. in 2 h and keep warm between 0-5 ° C. for 2 h, filter slurry The filter cake is washed with a mixture of 96 ml ethanol and 96 ml water, and dried under reduced pressure at 50 ° C. or lower to obtain 41 g. Butanol solvate: Crystalline butanol solvate of dasatinib was prepared by dissolving dasatinib in 1-butanol under reflux (116-118 ° C.) at a concentration of about 1 g / 25 ml solvent. On cooling, the butanol solvate is crystallized from solution. Filter, wash with butanol and then dry. Ethanol solvate: To a 100 ml round bottom flask add 4 g (10.1 mmol) 5D, 6.6 g (50.7 mmol) 7B, 80 ml n-butyl alcohol and 2.61 g (20.2 mmol) DIPEA. The resulting slurry is heated to 120 ° C. and kept for 4.5 h, then cooled to 20 ° C. and stirred overnight. The crystals are filtered and the wet cake is washed with n-butyl alcohol (2 × 10 ml) to give a white crystalline product. The resulting wet cake is returned to the 100 ml reactor and 56 ml (12 ml / g) absolute ethanol (200 proof) is added. An additional 25 ml of ethanol is added at 80 ° C., and 10 ml of water is added to the mixture to quickly dissolve it. Stop heating and observe crystals at 75-77 ° C. The crystal slurry is further cooled to 20 ° C. and subsequently filtered. The wet cake is washed once with 10 ml ethanol: water (1: 1) and then once with 10 ml normal heptane. Drying at 60 ° C./30 in Hg for 17 h gives 3.55 g of material with a water content of 0.19%.

  Pure N-6: DIPEA (155 ml, 0. 15 ml) against a mixture of compound 5D (175.45 g, 0.445 mol) and hydroxyethylbiperazine (289.67 g, 2.225 mol) in NMP (1168 ml). 89 mmol) is added. The suspension is heated at 110 ° C. for 25 minutes to obtain a solution and then cooled to about 90 ° C. The obtained hot solution is added dropwise to hot water (80 ° C., 8010 ml) and stirred at 80 ° C. for 15 minutes, and then gradually cooled to room temperature. Collect the solid by vacuum filtration, wash with water (2 × 1600 ml) and dry in vacuo at 55-60 ° C. to give 192.45 g of compound.

  Pure T1H1-7 (pure and pharmaceutically acceptable carrier): obtained by heating dasatinib monohydrate at a temperature above the dehydration temperature.

  Dasatinib is almost insoluble in organic solvents such as water, methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol, amyl alcohol, etc. Dissolution is very difficult and disadvantageous for industrial mass production, and the method disclosed by the application document CN200580011916.6 reduces the related substances in the product in the process of crystal form preparation and effectively improves the quality of the product I can't.

  For the polycrystalline form of the drug, different polycrystalline forms can have different chemical and physical properties including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure and density. . These properties can directly affect the processing or production of the drug substance and the formulation and can affect the stability, solubility and bioavailability of the formulation. Therefore, the polycrystalline form of the drug has important significance for the quality, safety and efficacy of the drug formulation. With regard to dasatinib, there is a demand in this field for a new polycrystalline type that is suitable for industrial mass production and has excellent rationalization performance.

Chinese patent application No. 200580011916.6

  As a result of intensive studies, the inventors of the present invention surprisingly discovered a new dasatinib polycrystal and successfully solved the disadvantages existing in the prior art. The substance has advantages such as excellent chemical properties, good stability, and more suitable for industrial mass production.

  An object of the present invention is to provide a new dasatinib polycrystal.

  Another object of the present invention is to provide a method for preparing the new polycrystal.

  The third object of the present invention is to provide a drug composition containing the new polycrystal.

  Specifically, the present invention provides dasatinib polycrystal I containing one molecule of crystallization water and almost no other solvent. As shown in FIG.

  Dasatinib monohydrate polycrystal I provided by the present invention, which is 9.1 ± of 2θ expressed by intensity in an X-ray diffraction diagram (XRPD) measured using Cu-Kα ray It has diffraction peaks at 0.2 and 19.4 ± 0.2, and the dasatinib monohydrate polycrystal I is further 9.1 ± 0.2, 11.1 in the X-ray diffraction diagram. One or more of ± 0.2, 13.7 ± 0.2, 15.1 ± 0.2, 17.8 ± 0.2, 19.4 ± 0.2, 23.0 ± 0.2 FIG. 2 shows an example of an X-ray diffraction pattern of polycrystalline I of dasatinib monohydrate, which may have a diffraction peak (including two or more in a random combination).

  The XRPD diffraction peak of dasatinib polycrystalline I provided by the present invention is shown below.

  The dasatinib monohydrate polycrystal I provided by the present invention has a first endothermic peak between about 100-130 ° C, in particular at about 120 ° C, and 284-290 ° C in the differential scanning calorimetry (DSC) diagram. In particular, it may have a second endothermic peak, particularly a maximum endothermic peak, at about 286.50 ° C. Refer to FIG. 4 for an example of DSC spectrum of dasatinib monohydrate polycrystal I of the present invention, and thermogravimetric analysis (TGA) spectrum of dasatinib monohydrate polycrystal I of the present invention. The example shown is shown in FIG.

Moreover, the polycrystalline I of dasatinib monohydrate of the present invention has an infrared absorption spectrum (IR) measured by the KBr tableting method of about 3462.42 cm ⁻¹ , 3210.67 cm ⁻¹ , 3003.96 cm ^{−. 1} , 2954.14 cm ⁻¹ , 282.49 cm ⁻¹ , 1682.15 cm ⁻¹ , 1629.58 cm ⁻¹ , 1612.25 cm ⁻¹ , 1583.84 cm ⁻¹ , 1305.37 cm ⁻¹ , 1290.91 cm ⁻¹ , FIG. 3 shows an example of the infrared absorption spectrum of the dasatinib monohydrate polycrystal I which can have absorption peaks at 100.19 cm ⁻¹ and 1040.60 cm ⁻¹ .

The characteristic shift values in the solid ¹³ C-NMR spectrum of dasatinib monohydrate polycrystal I of the present invention are 16.75 ± 0.2 ppm, 24.92 ± 0.2 ppm, 41.72 ± 0.2 ppm. 43.23 ± 0.2 ppm, 44.28 ± 0.2 ppm, 54.01 ± 0.2 ppm, 55.48 ± 0.2 ppm, 57.53 ± 0.2 ppm, 58.70 ± 0.2 ppm, 62 .23 ± 0.2 ppm, 63.20 ± 0.2 ppm, 84.66 ± 0.2 ppm, 127.92 ± 0.2 ppm, 128.81 ± 0.2 ppm, 132.70 ± 0.2 ppm, 137.68 ± 0.2 ppm, 139.00 ± 0.2 ppm, 157.17 ± 0.2 ppm, 162.07 ± 0.2 ppm, 163.54 ± 0.2 ppm, 166.84 ± 0.2 ppm, 167.58 ± 0 .2p It may be a m, showing an illustrated example of the solid-state ^{13 C-NMR} spectrum of the polycrystalline body I of the dasatinib monohydrate in FIG.

  In an embodiment of the present invention, the present invention provides a method for preparing dasatinib monohydrate polycrystal I of the present invention, which method comprises the following steps.

  Step (1), dasatinib is added to a solution of dimethyl sulfoxide (DMSO) or dimethylformamide (DMF), and the volume and mass ratio of dimethylformamide to dasatinib is usually 1: 1 to 200: 1 (ml: g) Preferably, the volume and mass ratio of dimethylformamide to dasatinib is 2: 1 to 200: 1, and most preferably the volume and mass ratio of dimethylformamide to dasatinib is 3.5: 1 to 4: 1. It is. The volume and mass ratio of dimethyl sulfoxide and dasatinib may usually be 1: 1 to 200: 1, preferably the volume and mass ratio of dimethyl sulfoxide and dasatinib is 1.5: 1 to 200: 1, Most preferably, the volume and mass ratio of dimethyl sulfoxide to dasatinib is 2.5: 1 to 3: 1.

  Step (2), dissolved by heating under stirring. The heating temperature may be from room temperature to the reflux temperature of dimethyl sulfoxide (DMSO) or dimethylformamide (DMF), preferably the heating temperature may be 40 ° C. to 100 ° C., most preferably the heating temperature is 50 degreeC-80 degreeC may be sufficient.

  Step (3), a mixed solvent of pure water and an organic solvent is dropped, and the organic solvent is one or more mixed solvents in which dasatinib does not dissolve or slightly dissolves. Preferably, the temperature is 40 ° C. to 100 ° C., most preferably the temperature is 50 ° C. to 80 ° C., and the volume ratio of the mixed solvent of pure water and organic solvent to dimethylformamide or dimethyl sulfoxide is usually 1 : The volume ratio of the mixed solvent of water and the organic solvent and the volume ratio of dimethylformamide or dimethyl sulfoxide is preferably 2: 1 to 200: 1, and most preferably water and the organic solvent. The volume ratio of the mixed solvent to dimethylformamide or dimethyl sulfoxide is from 3: 1 to 200: 1. The organic solvent is one or more mixed solvents in which dasatinib is insoluble or slightly soluble, preferably acetonitrile, cyclohexane, 1,2-vinylidene chloride, 1,2-dimethoxyethane, dioxane, 2-ethoxyethanol, ethylene Glycol, normal hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, pyridine, tetralin, tetrahydrofuran, toluene, 1,1,2-trichloroethene, dimethylbenzene, acetone, anisole, n- Butyl alcohol, butyl alcohol, butyl acetate, tert-butyl methyl ether, isopropylbenzene, methanol, ethanol, propanol, acetate ester, diethyl ether, formate ester, nor Marheptane, isobutyl acetate, isopropyl acetate, methyl acetate, isopentyl alcohol, butanone, methyl isobutyl ketone, isobutyl alcohol, normal pentane, primary amyl alcohol, normal propyl alcohol, isopropyl alcohol, propyl acetate, 1,1-dimethoxypropane, Selected from 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, most preferably three or more organic solvents as defined by ICH, For example, acetone, anisole, n-butyl alcohol, butyl alcohol, butyl acetate, tert-butyl methyl ether, isopropylbenzene, ethanol, methanol Propanol, ethyl acetate, diethyl ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, isopentyl alcohol, butanone, methyl isobutyl ketone, isobutyl alcohol, normal pentane, primary amyl alcohol, normal propyl alcohol , Isopropyl alcohol, propyl acetate, 1,1-dimethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, etc. It is selected from seeds or more, and the mixed solvent is a two-component or two-component or more mixed system composed of water and an organic solvent. Of these, the weight ratio of water to the organic solvent is usually greater than 10%, preferably the weight ratio of water to the organic solvent is greater than 20%, most preferably the weight ratio of water to the organic solvent is 30%. Greater than%.

  Step (4), the dripping is stopped and the temperature is kept, and then the temperature is gradually lowered to 0 to 5 ° C. with stirring to completely precipitate the solid and form crystals, and the incubation time may be 10 minutes or more. The crystal formation time may be 10 minutes or longer, preferably 1 hour or longer, and most preferably 2 hours or longer.

  Step (5), collecting the solid by filtration, and drying, preferably, drying assistance with diphosphorus pentoxide, and vacuum drying at 50 ° C., −0.095 MPa for 12 hours or more under reduced pressure.

  In an embodiment of the present invention, the present invention provides another type of dasatinib organic solvent compound polycrystal II containing no water of crystallization, and is shown in FIGS. 14A and B.

  Dasatinib monohydrate polycrystal II provided by the present invention, in an X-ray diffractogram measured using Cu-Kα rays, 5.7 ± 0.2 of 2θ indicated by intensity And dasatinib polycrystal II has 5.7 ± 0.2, 11.5 ± 0.2, 12.2 in the X-ray diffraction pattern. 3 ± 0.2, 14.5 ± 0.2, 17.2 ± 0.2, 18.2 ± 0.2, 22.2 ± 0.2, 22.6 ± 0.2, 24.7 ± It may have one or more (including randomly combined, two or more) diffraction peaks at 0.2, 25.2 ± 0.2, see FIGS. 15-1 and 15-2. Here, the organic solvent is a mixture of dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) and one or more mixed solvents insoluble in dasatinib, and the solvent in which dasatinib is insoluble is preferably acetonitrile. , Trichloromethane, cyclohexane, 1,2-vinylidene chloride, dichloromethane, 1,2-dimethoxyethane, dioxane, 2-ethoxyethanol, ethylene glycol, normal hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, N -Methylpyrrolidone, pyridine, tetralin, tetrahydrofuran, toluene, 1,1,2-trichloroethene, dimethylbenzene, acetone, anisole, n-butyl alcohol, butyl alcohol, butyl acetate, ert-butyl methyl ether, isopropyl benzene, ethanol, ethyl acetate, diethyl ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, isopentyl alcohol, butanone, methyl isobutyl ketone, isobutyl alcohol, normal pentane, From monoamyl alcohol, normal propyl alcohol, isopropyl alcohol, propyl acetate, 1,1-dimethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether Most preferably, acetone, anisole, n-butyl alcohol, butyl alcohol, butyl acetate, tert-butylmethyl Ether, isopropylbenzene, ethanol, ethyl acetate, diethyl ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, isopentyl alcohol, butanone, methyl isobutyl ketone, isobutyl alcohol, normal pentane, primary amyl alcohol, 1 of normal propyl alcohol, isopropyl alcohol, propyl acetate, 1,1-dimethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, etc. It is selected from a seed or a mixed solvent of two or more kinds, more preferably, the organic solvent is a mixture of dimethyl sulfoxide and acetone or ethyl acetate There, or a mixture of dimethyl formamide and acetone or ethyl acetate.

  The XRPD diagram diffraction peak of dasatinib polycrystal II of the present invention is shown below.

  The dasatinib polycrystal II provided by the present invention, typically dimethylformamide / acetone solvate, may have two endothermic peaks between 160-210 ° C. in its DSC diagram, one of which The endothermic peak has a relatively large endothermic peak at about 193 ° C., and further has a third endothermic peak between 280-290 ° C., in particular at about 286.67 ° C., ie the maximum endothermic peak. An example of the DSC spectrum of the dasatinib polycrystal II of the present invention is shown in FIG. 17-1, and an example of the TGA spectrum is shown in FIG. 17-2.

The dasatinib polycrystal II provided by the present invention, typically its dimethylformamide / acetone solvate, has an infrared absorption spectrum measured by the KBr tableting method of about 3395.73 cm ⁻¹ , 3201.34 cm. ⁻¹ , 306.799 cm ⁻¹ , 2925.57 cm ⁻¹ , 2842.67 cm ⁻¹ , 2822.19 cm ⁻¹ , 1716.01 cm ⁻¹ , 1619.56 cm ⁻¹ , 1578.34 cm ⁻¹ , 1537.01 cm ^{−1 , 1315.41cm -1, 1293.55cm -1, 1006.06cm} -1, 984.74cm -1, obtained has an absorption peak at 1056.29cm ^-1, the infrared absorption spectrum of the dasatinib polycrystal II shows An example of this is shown in FIG.

The dasatinib polycrystal II provided by the present invention, typically its dimethylformamide / acetone solvate, has a characteristic shift value in the solid state ¹³ C-NMR spectrum of 18.80 ± 0.2 ppm, 26. 22 ± 0.2 ppm, 27.60 ± 0.2 ppm, 30.99 ± 0.2 ppm, 36.57 ± 0.2 ppm, 43.62 ± 0.2 ppm, 51.57 ± 0.2 ppm, 52.50 ± 0.2 ppm, 55.09 ± 0.2 ppm, 56.98 ± 0.2 ppm, 62.51 ± 0.2 ppm, 83.08 ± 0.2 ppm, 125.43 ± 0.2 ppm, 126.61 ± 0. 2 ppm, 128.44 ± 0.2 ppm, 129.33 ± 0.2 ppm, 132.65 ± 0.2 ppm, 139.50 ± 0.2 ppm, 156.34 ± 0.2 ppm, 161.15 0.2ppm, 162.96 ± 0.2ppm, 164.68 ± 0.2ppm, 165.47 ± 0.2ppm, may be a 203.49 ± 0.2ppm. An example of a solid ¹³ C-NMR spectrum of Dasatinib polycrystal II is shown in FIG.

  In an embodiment of the present invention, the present invention provides a method for preparing dasatinib polycrystal II, which method comprises the following steps.

  Step (1), dasatinib is added to dimethylformamide or anhydrous dimethylsulfoxide, and the volume and mass ratio of anhydrous dimethylformamide or anhydrous dimethylsulfoxide to dasatinib is usually 1: 1 to 200: 1, preferably anhydrous dimethylformamide or The volume and mass ratio of anhydrous dimethyl sulfoxide to dasatinib is 2: 1 to 200: 1, most preferably the volume and mass ratio of anhydrous dimethylformamide or anhydrous dimethyl sulfoxide to dasatinib is 3.5: 1 to 4: 1. Larger, dissolve with stirring and heating.

  In step (2), the solution is poured into an anhydrous organic solvent having a volume several times that of the solution, and the condition for selecting the organic solvent is an anhydrous organic solvent in which dasatinib does not dissolve or slightly dissolves. Here, the volume ratio of the organic solvent to dimethylformamide or dimethylsulfoxide is usually 1: 1 to 200: 1, preferably the volume ratio of the organic solvent to dimethylformamide or dimethylsulfoxide is larger than 3 to 200: 1. Most preferably, the volume ratio of organic solvent to dimethylformamide or dimethyl sulfoxide is from 5 to 200: 1. The organic solvent is one or more mixed solvents in which dasatinib is insoluble or slightly soluble, preferably acetonitrile, trichloromethane, cyclohexane, 1,2-vinylidene chloride, dichloromethane, 1,2-dimethoxyethane, dioxane, 2 -Ethoxyethanol, ethylene glycol, normal hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidone, pyridine, tetralin, tetrahydrofuran, toluene, 1,1,2-trichloroethene, dimethylbenzene, acetone , Anisole, n-butyl alcohol, butyl alcohol, butyl acetate, tert-butyl methyl ether, isopropyl benzene, ethanol, ethyl acetate, diethyl ether, ethyl formate, Normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, isopentyl alcohol, butanone, methyl isobutyl ketone, isobutyl alcohol, normal pentane, primary amyl alcohol, normal propyl alcohol, isopropyl alcohol, propyl acetate, 1,1-dimethoxypropane 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, most preferably acetone, anisole, n-butyl alcohol, butyl alcohol, butyl acetate , Tert-butyl methyl ether, isopropyl benzene, ethanol, ethyl acetate, diethyl ether, ethyl formate, normal heptane, vinegar Isobutyl, isopropyl acetate, methyl acetate, isopentyl alcohol, butanone, methyl isobutyl ketone, isobutyl alcohol, normal pentane, primary amyl alcohol, normal propyl alcohol, isopropyl alcohol, propyl acetate, 1,1-dimethoxypropane, 1,1 -It is selected from one or more mixed solvents of dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether and the like.

  Step (3), the organic solvent is gradually volatilized into a solution of dasatinib in dimethylformamide or dimethyl sulfoxide from room temperature to the reflux temperature of the organic solvent, where the volatilization time of the organic solvent is at least several hours and then several days. Preferably, it is 24 hours or more, and most preferably 72 hours or more.

  Step (4), collecting solids by filtration and drying, preferably drying assistance in the presence of niline pentoxide, and vacuum drying under reduced pressure at 50 ° C. and −0.095 MPa for 12 hours or more.

  In the present invention, the X-ray powder diffraction measurement apparatus and measurement conditions according to the present invention are as follows. Anode rotor target X-ray diffractometer D / max-2500 / PC type (Rigaku Corporation, Japan), copper target, graphite monochromator, voltage 40 kV, current 100 mA, diffusion slit and anti-scattering grid are both 1 °, incident Slit: 0.3 mm, scan speed 5 ° / min, scan range 3-40 °.

  The DSC measurement apparatus and measurement conditions according to the present invention are as follows. Heat from 25 ° C. to 300 ° C. at a rate of 10 ° C./min, US Perkin Elmer Diamond DSC.

  The TGA measurement apparatus and measurement conditions according to the present invention are as follows. Heat from 25 ° C. to 500 ° C. at a rate of 10 ° C./min, US Perkin Elmer Thermal Analysis Pyris 1 TGA, 10 ° C./min.

  The solid nuclear magnetic resonance measuring apparatus and measurement conditions according to the present invention are as follows.

  Apparatus: BRUKER AVANCE III 400 MHz wide hollow solid nuclear magnetic resonance apparatus.

  Measurement conditions: CP-MAS, method: rotational speed 14000 Hz, number of scans 1404, relaxation delay 40 s, contact time 2 ms, 13C frequency 100.62334936 MHz, 1H frequency 400.14143530 MHz.

  Measurement conditions and method of related substances according to the present invention (herein, the related substances refer to impurities other than dasatinib): Measured based on a high performance liquid chromatography method (Chinese Pharmaceuticals 2005 version, Part 2, Appendix VD).

Column conditions and system compatibility 0.05 mol / L potassium dihydrogen phosphate (0.2% triethylammonium, pH value adjusted to 2.5 with phosphoric acid) -methanol (45: 55) is the mobile phase. If the detection wavelength is 230 nm and the number of theoretical plates is calculated based on the peak of dasatinib, it should be 2000 or more, and the resolution between the peak of dasatinib and the adjacent impurity peak needs to satisfy the requirement.

  Measurement method Take a sample, dissolve by adding a moving layer, and prepare a solution of 0.5 mg / ml. Weigh 20 μl and inject each into high-performance liquid chromatography, 6 times the retention time of the main component peak Record the chromatogram until.

Properties of Dasatinib Monohydrate Polycrystal I I. Solubility: Tested based on the 2nd part legend of Chinese Pharmacy 2000 edition.

  Method: Accurately measure an appropriate amount of dasatinib monohydrate polycrystal I, gradually add a predetermined amount of solvent, shake vigorously for 30 seconds every 5 minutes, observe the dissolution for 30 minutes, Table 1 shows.

2. Stability 1. Light irradiation test Dasatinib monohydrate polycrystal I was uniformly dispensed into an open petri dish, the thickness was adjusted to 5 mm, the distance was adjusted, and the light irradiation intensity was adjusted to 4500 ± 500 Lx. A sample is taken and measured and compared with the results on day 0. The results are shown in Table 2. The X-ray diffraction pattern for 10 days is shown in FIG. FIG. 7 shows a DSC diagram of Dasatinib monohydrate polycrystal I on the 10th day of intense light irradiation.

2. High temperature test Dasatinib monohydrate polycrystal I raw material is put in a sealed clean glass bottle, left in a constant temperature drying apparatus at 60 ° C., and samples are taken on the 5th and 10th days, respectively. Compare with day results. The results are shown in Table 3. The X-ray diffraction pattern considered at 60 ° C. for 10 days is shown in FIG. The DSC diagram considered at 60 ° C. for 10 days is shown in FIG. 9-1, and the TGA diagram is shown in FIG. 9-2.

3. High-humidity test Dasatinib monohydrate polycrystal I raw material is uniformly dispensed into an open petri dish and placed in a constant temperature and humidity culture apparatus with a thickness ≤ 5 mm, room temperature (about 25 ° C), and relative humidity 75 ± 5%. Let it stand, take samples on the 5th and 10th day, make measurements and compare with the results on the 0th day. The results are shown in Table 4. The 10-day X-ray diffraction pattern at a relative humidity of 75 ± 5% is shown in FIG. 10, the DSC scanning chart is shown in FIG. 11-1, and the TGA chart is shown in 11-2.

4). Accelerated test Dasatinib monohydrate polycrystal I raw material is hermetically packaged in a plastic bag of polyethylene film, and left in a constant temperature and humidity culture apparatus at 40 ± 2 ° C. and relative humidity 75 ± 5% for 6 months. Samples are taken at the end of months 2, 3 and 6 and measured and compared to the results at 0 months. The results are shown in Table 5. The X-ray diffraction diagram for 6 months is shown in FIG. 12, the DSC scanning diagram is shown in FIG. 13-1, and the TGA diagram is shown in 13-2.

  As can be seen from the above experimental results, the dasatinib monohydrate polycrystal I obtained by the present invention slightly increased the content of the dasatinib polycrystal I related substance under light irradiation and the content decreased. In the high temperature test (60 ° C.), there was no significant change in appearance, but the content was slightly reduced. In the high humidity test, the polycrystalline I of the present invention has no significant change in appearance and content, and has low hygroscopicity. Therefore, the results of the acceleration experiment showed that its rationalized properties are relatively stable. .

  Polycrystalline I of the present invention showed no change in crystal form in a long-term reference product observation test, a slight increase in related substances, and a slight decrease in content. Tests have shown that the crystalline form of the polycrystalline I is stable and suitable for long-term storage.

  Moreover, the weight loss (water) process of polycrystal I occurred between 70 ° C. and 150 ° C., and the result calculated based on the TGA scanning diagram (FIG. 4-2) of polycrystal I of dasatinib monohydrate The weight loss is 3.60%, and the result measured for the compound is that the residual amount of the organic solvent is suitable for the limit requirement defined by ICH, and the moisture value by Karl Fischer moisture measurement is 3.59%. Based on the above experimental results, it was shown that the dasatinib polycrystal I of the present invention is a monohydrate.

  In further experiments, when the polycrystalline I of the present invention was placed in a strong dehydrating agent sealed environment (for example, discolored silica gel, niline pentoxide, etc.), water of crystallization could be gradually lost (partially or completely). However, it was found that the polycrystal I of the present invention gradually returned to the monohydrate state when the polycrystal lacking the crystal water was exposed to the atmosphere for a certain period of time.

Properties of Dasatinib Polycrystalline II 1. Solubility: Tested based on the Chinese Pharmacy 2000 edition 2 part legend.

  Method: Accurately measure an appropriate amount of dasatinib polycrystal II, gradually add a predetermined amount of solvent, shake vigorously for 30 seconds every 5 minutes, observe the degree of dissolution for 30 minutes, and the results are shown in Table 6 .

2. Stability 1. Light irradiation test Dasatinib polycrystal II is uniformly dispensed into an open petri dish, the thickness is adjusted to 5 mm, the distance is adjusted, and the light irradiation intensity is set to 4500 ± 500 Lx. And compare with the results on day 0. The results are shown in Table 7. The X-ray diffraction diagram on the 10th is shown in FIG. 19, and the DSC diagram on the 10th day of light irradiation is shown in FIG.

2. High temperature test Put dasatinib polycrystal II raw material in a sealed clean glass bottle and leave it in a constant temperature drying device at 60 ° C. Compare with The results are shown in Table 8. An X-ray diffraction diagram tested for 10 days at high temperature is shown in FIG. FIG. 22 shows the DSC diagram for 10 days test at high temperature.

3. High-humidity test Dasatinib polycrystal II material is uniformly dispensed into an open petri dish and left in a constant temperature and humidity culture apparatus with a thickness ≦ 5 mm, room temperature (about 25 ° C.), and relative humidity 75 ± 5%. Take a sample on day 10 and make a measurement and compare to the result on day 0. The results are shown in Table 9. FIG. 23 shows an X-ray diffraction diagram on the 10th day of the high humidity experiment, FIG. 24-1 shows a DSC diagram on the 10th day of the high humidity experiment, and 24-2 shows a TGA diagram on the 10th day of the high humidity experiment.

4). Accelerated test Dasatinib polycrystal II raw material is hermetically packaged in a plastic bag of polyethylene film and left in a constant temperature and humidity culture apparatus at 40 ± 2 ° C. and a relative humidity of 75 ± 5% for 6 months. 1, 2, 3, 6 Take a sample at the end of the month and make a measurement and compare it with the results at 0 months. The results are shown in Table 10. FIG. 25 shows an X-ray diffraction diagram of the sixth month of the 40 ° C. accelerated test, FIG. 26-1 shows a DSC diagram of the sixth month of the 40 ° C. accelerated test, and FIG. 26-2 shows a TGA diagram of the sixth month of the 40 ° C. accelerated test. Shown in

  As can be seen from the above results, the dasatinib polycrystal II obtained according to the present invention did not change significantly in appearance under light irradiation, the related substances increased to some extent, and the content decreased to some extent. In the high temperature test (60 ° C.), there was no significant change in appearance and content, indicating that the properties were relatively stable. Although the appearance and content of the product did not change significantly in the high humidity test, slight moisture absorption was observed. Accelerated experiments showed that the properties are relatively stable.

  In another embodiment of the invention, the present invention provides a drug composition, wherein the drug composition comprises one or two of the two dasatinib polycrystals I and II and a medicinal excipient. Containing a medicinal composition, preferably the drug composition contains 1 to 500 mg of dasatinib polycrystals, particularly preferably about 20, 50, 70, 100 mg of dasatinib polycrystals. The drug composition of the present invention can be prepared in various dosage forms, and an appropriate medicinal excipient can be selected. For example, based on the illness to be treated and the subject, the pharmaceutical composition of the invention can be administered orally, parenterally (eg, intramuscular, intraperitoneal, intravenous, ICV, intracerebral injection or perfusion, subcutaneous injection or perfusion), It can be administered by inhalation spray administration, nasal administration, genital administration, rectal administration, sublingual administration or topical administration, and is preferably an orally administered drug composition, particularly an oral administration tablet, capsule or granule. One skilled in the art can coat orally administered drug compositions based on the teachings of the prior art, for example, Chinese Patent Application CN 101170996A (Publication Date 30 April 2008).

  The present invention includes dasatinib polycrystal drug compositions and other therapeutic ingredients as needed, such as ixabepilone, paclitaxel, docetaxel, cisplatin, carboplatin, bevacizumab, bendamustine, erlotinib, nilotinib, Rituxima, dexamethasone, penalidomide, One or more of exemestane, letrozole, dacarbazine, vandetanib, Ipilimumab and the like can be further contained.

  The drug composition of the present invention is administered in one or more doses every day, and the daily dose is about 5-1000 mg / day, more preferably about 10-500 mg / day. Alternatively, about 10-250 mg / day is administered every other day.

  The dasatinib of the present invention can be used to treat diseases and symptoms. Examples include graft rejection, rheumatoid arthritis, multiple sclerosis, enteritis, lupus, graft-versus-host disease, T-cell mediated hypersensitivity, psoriasis, Hashimoto thyroiditis, cancer (chronic myeloid leukemia CML, Gastrointestinal stromal tumor GIST, small cell lung cancer SCLC, non-small cell lung cancer NSCLC, ovarian cancer, melanoma, mastocytosis, germ cell tumor, acute myeloid leukemia AML, child sarcoma, breast cancer, colorectal cancer, pancreas Cancer, prostate cancer, etc.), contact dermatitis, allergy, asthma, diabetic retinopathy, and chronic obstructive pulmonary disease, but are not limited thereto. In addition, under the teachings of the present invention, those skilled in the art can determine specific methods and dosages based on conventional techniques. For example, reference is made to International Publication Number WO2004085388A2.

  The beneficial technical effect of the present invention is that the CN200580011916.6 patent document of the prior art disclosed a dasatinib polycrystal and a method for preparing the same, but the method for preparing the dasatinib polycrystal provided in CN200580011916.6 has been tested. It has been found that the rotating crystallization method disclosed by the patent document is not suitable for industrial stable mass production.

  Prior art CN200580011916.6 patent document preparation method includes adding dasatinib to alcoholic organic solvent in which dasatinib hardly dissolves or a mixed solution of alcoholic organic solvent and water (for example, alcoholic solvent methanol, ethanol, butanol, etc.) and heating. After dissolution, the temperature is lowered to precipitate crystals.

  1. Dasatinib is hardly soluble in water or alcoholic organic solvents, and it is necessary to use a large amount of solvent even under heating conditions, so the rotary crystallization process is complicated, product quality controllability is poor, and industrial stable mass production Not suitable for.

  2. The rotating crystallization method described in patent document CN200580011916.6 significantly reduces the related substances of the original product, and thus cannot improve the quality of the product.

  3. It was proved by experiments that the stability of the crystal A prepared based on the conditions described in the patent document CN200580011916.6 is poorer than that of the crystal I prepared according to the present invention.

  In summary, the method for preparing dasatinib polycrystal disclosed in Patent Document CN200580011916.6 is not suitable for industrial stable mass production.

  On the other hand, the present invention provides two kinds of dasatinib polycrystals for industrial mass production and overcomes the problems in the prior art.

  The present invention is a simple and easy-to-implement preparation method for two new polycrystals of dasatinib, taking into account the characteristics that dasatinib does not dissolve in a large excess of solvent and is difficult to purify. adopt.

  1. The present invention has a simple preparation process, very easy operation, simple industrial production, good quality controllability and stable yield.

  2. The rotating crystal method removes strongly polar impurities very easily and significantly reduces related substances.

  3. The polycrystal obtained by the preparation process of the present invention can remarkably improve the appearance color problem of the product as compared with the polycrystal of the conventional method.

  4). The polycrystal obtained by the preparation process of the present invention has good stability and is suitable for long-term storage.

  5. The stability of the polycrystals I and II disclosed in the present invention in water is superior to that of the polycrystal A disclosed in the conventional patent CN200580011916.6 in the fracture test. After the dasatinib polycrystals I and II of the present invention were formulated by testing, the crystal form thereof was not substantially changed. It was proved to be applied by the use of a drug because it has excellent stability and does not increase the related substances of the drug substance contained in the preparation.

  6). The method for preparing a polycrystal according to the present invention can greatly reduce the amount of organic solvent used in rotating crystallization, thereby reducing the cost.

  7). The method of the present invention can prepare the polycrystal of the present invention by selecting and using a low toxicity type 3 organic solvent, and to some extent reduce the potential effect of the residual organic solvent on the human body. .

  The above advantages make the present invention useful for significant improvement in product quality and more suitable for industrial production.

1 is a photomicrograph of polycrystalline I of dasatinib monohydrate of the present invention. 1 is a typical XRPD diagram of polycrystalline I of dasatinib monohydrate of the present invention. FIG. FIG. 2 is an IR infrared absorption spectrum diagram of polycrystalline I of dasatinib monohydrate of the present invention. 1 is a DSC scanning diagram of polycrystalline I of dasatinib monohydrate of the present invention. FIG. 1 is a TGA scanning diagram of polycrystalline I of dasatinib monohydrate of the present invention. FIG. FIG. 3 is a solid state ¹³ C-NMR spectrum of polycrystalline I of dasatinib monohydrate of the present invention. FIG. 10 is an XRPD diagram of polycrystalline I of dasatinib monohydrate of the present invention on the 10th day of intense light irradiation. It is a DSC figure of the intense light irradiation 10th day of the polycrystalline I of dasatinib monohydrate of the present invention. FIG. 6 is an XRPD diagram of polycrystal I of dasatinib monohydrate of the present invention on the 10th day of 60 ° C. test. FIG. 6 is a DSC diagram of polycrystal I of dasatinib monohydrate of the present invention on the 10th day of 60 ° C. test. It is a TGA figure of the polycrystal I of this invention dasatinib monohydrate on the 10th day of a 60 degreeC test. It is a XRPD figure of the high humidity test 10th day of the polycrystalline I of dasatinib monohydrate of the present invention. It is a DSC figure on the 10th day of the high humidity test of the polycrystalline I of dasatinib monohydrate of the present invention. It is a TGA figure of the high humidity consideration 10th day of the polycrystal I of this invention dasatinib monohydrate. FIG. 4 is an XRPD diagram of a polycrystalline I of dasatinib monohydrate of the present invention after a 6-month test in a 40 ° C. environment. It is a DSC figure of the sixth month at 40 degreeC of the polycrystal I of this invention dasatinib monohydrate. FIG. 6 is a TGA scanning diagram of polycrystalline I of dasatinib monohydrate of the present invention at 40 ° C. at 6 months. 14A and 14B are photomicrographs of dasatinib polycrystal II of the present invention. FIG. 2 is a typical XRPD diagram of dasatinib (dimethylformamide / acetone) polycrystal II of the present invention. 1 is a typical XRPD diagram of Dasatinib (dimethyl sulfoxide / acetate) polycrystal II of the present invention. FIG. It is IR infrared absorption spectrum figure of this invention dasatinib polycrystal II. It is a DSC figure of this invention dasatinib polycrystal II. It is a TGA figure of this invention dasatinib polycrystal II. It is a solid-state ¹³ C-NMR spectrum figure of this invention dasatinib polycrystal II. It is a XRPD figure of light irradiation 10 days of this invention dasatinib polycrystal II. It is a DSC differential calorimetric scanning diagram of light irradiation 10 days of the dasatinib polycrystal II of the present invention. FIG. 6 is an XRPD diagram of dasatinib polycrystal II of the present invention on the 10th day at 60 ° C. It is a DSC figure of this invention dasatinib polycrystal II of 60 degreeC 10th day. It is a XRPD figure of the present invention dasatinib polycrystal II on the 10th day of high humidity. It is a DSC figure TGA figure of high humidity 10th day of this invention dasatinib polycrystal body II. It is a TGA figure of high humidity 10th day of this invention dasatinib polycrystal II. It is a XRPD figure of a reference product of 40 ° C. for 6 months of the dasatinib polycrystal II of the present invention. It is a DSC figure of the 6th month of 40 degreeC of this invention dasatinib polycrystal body II. It is a TGA figure of the 6th month of 40 degreeC of this invention dasatinib polycrystal body II. FIG. 3 is an XRPD comparison diagram of dasatinib polycrystalline bodies I and II of the present invention. FIG. 2 is an infrared contrast diagram of the dasatinib polycrystals I and II of the present invention. FIG. 3 is a DSC comparison diagram of dasatinib polycrystalline bodies I and II of the present invention. It is a solid state ¹³ C-NMR spectrum contrast diagram of the dasatinib polycrystals I and II of the present invention. It is an elution curve of capsule formulation 1 of the present invention dasatinib polycrystal I and II. It is an elution curve of capsule formulation 2 of the present invention dasatinib polycrystals I and II. It is an elution curve of the tablet formulation 1 of this invention dasatinib polycrystal I and II. It is an elution curve of the tablet formulation 2 of this invention dasatinib polycrystal I and II.

[Example 1]
Preparation of Polycrystal I A, 10 g of dasatinib and 40 ml of dimethyl sulfoxide were added to a reaction flask, the temperature was raised to 60-70 ° C. with stirring, and the mixture was dissolved and then kept warm and mixed with 120 ml of water and acetone ( 1: 1) is added and crystals are precipitated under stirring, and then the temperature is lowered to 0 ° C. to form crystals for 10 minutes. After vacuum filtration, the cake is washed with water, then washed with a mixture of water and acetone (1: 1) and vacuum dried. The cake was dried at about 50 ° C. under reduced pressure (−0.095 MPa) and assisted dried with diphosphorus pentoxide to obtain 7.7 g of a white solid, with a yield of 77%.

The following measurements were made on the product obtained by Method A: Microscope-Crystal type (see FIG. 1), XRPD measurement (see FIG. 2), IR measurement (see FIG. 3), DSC / TGA measurement ( 4-1 and 4-2), solid state ¹³ C-NMR spectrum measurement (see FIG. 5).

  B, 10 g of dasatinib and 40 ml of dimethyl sulfoxide were added to the reaction flask, the temperature was gradually raised to 60-70 ° C. while stirring and dissolved, and then 160 ml of a mixture of ethanol: water (1: 1) was added while keeping warm. In addition, crystals are precipitated under stirring, and then the temperature is lowered to 0 ° C. to form crystals for 10 minutes. After vacuum filtration, the cake is washed with water and then washed with a mixture of ethanol: water (1: 1). The cake is dried at about 50 ° C. under reduced pressure (−0.095 MPa) and assisted dried with diphosphorus pentoxide to obtain 8.7 g of a white solid. The yield is 87%.

[Example 2]
Preparation of Polycrystal II A, 10 g of dasatinib and 40 ml of dimethylformamide are added to a reaction flask, the temperature is raised to 60-70 ° C. and dissolved with stirring, and the dimethylformamide solution of dasatinib is dissolved in a 300 ml volume of acetone. Leave in a sealed environment. Acetone is volatilized into a solution of dasatinib in dimethylformamide from room temperature to reflux. After several hours and several days later, the deposited crystals are precipitated from the solution, and then left still for several hours and several days. Vacuum filter and wash the cake with acetone. The cake is dried under reduced pressure (−0.095 MPa) at about 50 ° C., and auxiliary dried with diphosphorus pentoxide to obtain 6.1 g of a white solid. The yield is 61%.

The following measurements were made on the product obtained by Method A: Microscope-Crystal type (see FIGS. 14A and B), XRPD measurement (see FIG. 15-1), IR measurement (see FIG. 16), DSC / TGA measurement (see FIGS. 17-1 and 17-2), solid ¹³ C-NMR spectrum measurement (see FIG. 18).

  B, 10 g of dasatinib and 40 ml of dimethyl sulfoxide are added to the reaction flask, the temperature is raised to 60-70 ° C. and dissolved with stirring, and the dimethyl sulfoxide solution of dasatinib is left in a sealed environment of 300 ml of ethyl acetate. . Ethyl acetate is volatilized into a dimethyl sulfoxide solution of dasatinib from room temperature to below reflux temperature. After several hours and several days later, the deposited crystals are precipitated from the solution, and then left still for several hours and several days. Vacuum-filter and dry the cake at about 50 ° C. under reduced pressure (−0.095 MPa) and auxiliary dry with diphosphorus pentoxide to obtain 8.1 g white solid, the yield is 81%.

[Example 3]
Formulation and preparation process of dasatinib capsules containing 50 mg of the dasatinib polycrystal I, II, or any proportion of I, II using multiple excipients based on the following method Prepare into a solid formulation.

  A method for producing a capsule containing dasatinib polycrystal I, II or a mixture of the above-mentioned two kinds of polycrystals in an arbitrary ratio is as follows. The former four of the excipients are uniformly mixed with dasatinib polycrystal I, II or a mixture of any two of the two polycrystals and added to the appropriate amount of water to prepare a soft material Then, the soft material is prepared into wet granules and then dried, and the dried granules are uniformly mixed with magnesium stearate and then filled into a capsule housing to obtain a dasatinib capsule.

The elution curve of capsule formulation 1 (lots 1 # to 6 #) is shown in FIG.

The elution curve of capsule formulation 2 (Lot 1 # -6 #) is shown in FIG.

[Example 4]
Formulation and preparation process of dasatinib tablets Tablets containing 50 mg of the dasatinib polycrystal I, II, or any proportion of I, II using multiple excipients based on the following method Prepare to.

A method for producing a tablet containing dasatinib polycrystal I, II or a mixture of the two kinds of polycrystals in an arbitrary ratio is as follows. The former four of the excipients are uniformly mixed with dasatinib polycrystal I, II or a mixture of any two of the two polycrystals and added to the appropriate amount of water to prepare a soft material After preparing the soft material into wet granules, drying is performed, the dried granules are uniformly mixed with magnesium stearate, and then compressed into tablets, and the resulting tablets are coated with OPADRY coating material To get dasatinib tablets.

The dissolution curve of tablet formulation 1 (Lot 1 # -6 #) is shown in FIG.

Capsules and tablets containing dasatinib 20 mg / 70 mg / 80 mg / 100 mg / 140 mg can be prepared in the same manner.

Stability contrast test The representative examples of dasatinib polycrystal A prepared by the method disclosed in CN200580011916.6 (hereinafter abbreviated as “916.6 polycrystal A”) are the polycrystals I and II of the present invention. The abbreviated “polycrystals I and II” are referred to below, and the stability consideration method and results of the fracture experiment are compared.

experimental method:
Oxidative destruction: Take 50 mg of sample, weigh accurately, put into a 100 ml volumetric flask, add 10 ml of 30% hydrogen peroxide, leave at room temperature for 2 hours, dilute to full scale with mobile phase, shake evenly, Measurement is performed by high performance liquid chromatography.

  Acid breakage: Take 50 mg of sample, weigh accurately, put in a 100 ml volumetric flask, add 10 ml of 1 mol / L hydrochloric acid solution, let stand at 40 ° C. for 1 hour, add 1 mol / L sodium hydroxide solution in equal volume Add, dilute to full scale with mobile phase, shake evenly, and measure by high performance liquid chromatography.

  Alkali destruction: Take 50 mg of sample, weigh accurately, put in a 100 ml volumetric flask, add 10 ml of 1 mol / L sodium hydroxide solution, leave it at 40 ° C. for 1 hour, and then add an equal amount of 1 mol / L hydrochloric acid solution. Add, dilute to full scale with mobile phase, shake evenly, and measure by high performance liquid chromatography.

  Photoirradiation disruption: Take 50 mg of sample, weigh accurately, place in a 100 ml volumetric flask, dissolve in mobile phase, and prepare a solution containing 0.5 mg dasatinib / ml and leave under irradiation with 4000 lx light for about 6 hours. Measurement is performed by high performance liquid chromatography.

  High-temperature fracture: Take 50 mg of sample, weigh accurately, put into a 100 ml volumetric flask, dissolve in mobile phase and prepare a solution containing 0.5 mg dasatinib / ml, leave in a constant temperature water bath at 60 ° C., about 4 hours later Remove and allow to cool. Measurement is performed by high performance liquid chromatography.

Method for Measuring Related Substances Conditions and System Compatibility of High Performance Liquid Chromatography 0.05 mol / L potassium dihydrogen phosphate (0.2% triethylammonium phosphate, pH value of 2 with phosphoric acid) Adjusted to 5) -methanol (45:55) as mobile phase. If the detection wavelength is 230 nm and the number of theoretical plates is calculated based on the peak of dasatinib, it should be 2000 or more. The resolution between the peak of dasatinib and the adjacent impurity peak needs to satisfy the required requirements.

  Measurement method: Take a sample, add mobile phase to dissolve, prepare to 0.5 mg / ml solution, weigh 20 ml, inject each into liquid chromatography, chromatograph up to 6 times the retention time of the main peak Record the gram. If there is an impurity peak in the chromatogram of the sample solution, the total impurity and a single impurity are calculated based on the peak area normalization method.

Stability of crystal form in the formulation XRPD of dasatinib polycrystal I prepared by Method A of Example 1 of the present invention by measuring X-ray diffractograms of the capsules and tablets prepared in Examples 3 and 4 of the present invention Comparison was made with characteristic peaks in the figure. It is shown as follows.

From the data of the comparison results in the comparison table, it was shown that the dasatinib polycrystal I of the present invention was almost unchanged after it was prepared into capsules or tablets by the formulation process.
In addition, the related substances of the capsules and tablets prepared in Examples 3 and 4 of the present invention were measured and compared with the related substance of dasatinib polycrystal I prepared by Method A of Example 1 of the present invention. . It is shown as follows.

  The data of the comparison results in the comparison table showed that the dasatinib polycrystal I of the present invention was stable after preparation into capsules or tablets in the formulation process and there was no significant change in related substances.

Industrial Applicability The present invention provides a new crystalline form of dasatinib, further provides a preparation method thereof, and a drug composition containing the new polycrystalline form of dasatinib. The dasatinib polycrystals provided by the present invention have excellent rationalization properties and good stability, are more suitable for industrial mass production, are also suitable for long-term storage, and can satisfy the requirements of the formulation process and long-term storage of the formulation. . The method for preparing dasatinib polycrystals provided by the present invention is simple in process, very easy to operate, convenient in industrial mass production, easy to control quality and stable in yield. In addition, the preparation method provided by the present invention greatly reduces the amount of organic solvent used in the rotation crystallization, and reduces the cost. In addition, since dasatinib polycrystals can be prepared by selecting and using class 3 organic solvents with low toxicity, the potential effects of poisoning by residual organic solvents on the human body can be mitigated to some extent.

Claims (7)

Dasatinib monohydrate polycrystal I, using Cu-Kα ray, and its X-ray diffraction pattern shows that 2θ indicated by intensity is 9.1 ± 0.2 , 11.1 ± 0.2 Dasatinib monohydrate with diffraction peaks at 13.7 ± 0.2, 15.1 ± 0.2, 17.8 ± 0.2, 19.4 ± 0.2, and 23.0 ± 0.2 Japanese polycrystalline I. The polycrystalline body I according to claim 1, wherein the XRPD diagram diffraction peaks are as follows.
  The polycrystal I according to claim 1 or 2, wherein the DSC diagram has a first endothermic peak between about 100-130 ° C and a second endothermic peak between 284-290 ° C. The infrared absorption spectrum measured by the KBr tableting method is characterized by about 3462.42 cm ⁻¹ , 3210.67 cm ⁻¹ , 3003.96 cm ⁻¹ , 2954.14 cm ⁻¹ , 282.49 cm ⁻¹ , 1682.15 cm. ^-1 , 1629.58 cm ⁻¹ , 161.25 cm ⁻¹ , 1583.84 cm ⁻¹ , 1305.47 cm ⁻¹ , 1290.91 cm ⁻¹ , 1000.19 cm ⁻¹ , 1040.60 cm ⁻¹ , The polycrystal I according to claim 1 or 2. The characteristic shift value of the solid ¹³ C-NMR spectrum is 16.75 ± 0.2 ppm, 24.92 ± 0.2 ppm, 41.72 ± 0.2 ppm, 43.23 ± 0.2 ppm, 44.28 ± 0. 2 ppm, 54.01 ± 0.2 ppm, 55.48 ± 0.2 ppm, 57.53 ± 0.2 ppm, 58.70 ± 0.2 ppm, 62.23 ± 0.2 ppm, 63.20 ± 0.2 ppm, 84.66 ± 0.2 ppm, 127.92 ± 0.2 ppm, 128.81 ± 0.2 ppm, 132.70 ± 0.2 ppm, 137.68 ± 0.2 ppm, 139.00 ± 0.2 ppm, 157. The polycrystal according to claim 1 or 2, which is 17 ± 0.2 ppm, 162.07 ± 0.2 ppm, 163.54 ± 0.2 ppm, 166.84 ± 0.2 ppm, or 167.58 ± 0.2 ppm. Body I Adding dasatinib to dimethylformamide or dimethyl sulfoxide (1);
Heating under stirring to dissolve it (2);
Dropping (3) a mixed solvent of water and an organic solvent that is one or more mixed solvents in which dasatinib is insoluble or slightly soluble;
Step (4) of stopping dripping, gradually lowering the temperature to 0 to 5 ° C. with stirring after heat retention to completely precipitate the solid, and growing crystals.
A method for preparing polycrystalline I according to any one of claims 1 to 5, comprising the step of collecting the solid by filtration and drying (5). A drug composition comprising the polycrystalline I of dasatinib according to any one of claims 1 to 5 .