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WO2011095059A1 - 达沙替尼多晶型物及其制备方法和药物组合物 - Google Patents

达沙替尼多晶型物及其制备方法和药物组合物 Download PDF

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WO2011095059A1
WO2011095059A1 PCT/CN2011/000185 CN2011000185W WO2011095059A1 WO 2011095059 A1 WO2011095059 A1 WO 2011095059A1 CN 2011000185 W CN2011000185 W CN 2011000185W WO 2011095059 A1 WO2011095059 A1 WO 2011095059A1
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polymorph
ppm
dasatinib
present
organic solvent
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PCT/CN2011/000185
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English (en)
French (fr)
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严荣
杨浩
许永翔
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南京卡文迪许生物工程技术有限公司
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Priority to AU2011213431A priority Critical patent/AU2011213431B2/en
Priority to US13/577,624 priority patent/US8884013B2/en
Priority to KR1020127022643A priority patent/KR101470715B1/ko
Priority to EP11739338.9A priority patent/EP2535339A4/en
Priority to JP2012551475A priority patent/JP5589097B2/ja
Publication of WO2011095059A1 publication Critical patent/WO2011095059A1/zh

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Definitions

  • the present invention relates to polymorphs of pharmaceutical compounds, and more particularly to polymorphs of dasatinib.
  • the present invention also relates to a process for the preparation of the polymorphs and pharmaceutical compositions thereof.
  • Dasatinib trade name SPRYCELTM, is an oral tyrosine kinase inhibitor developed by BMS for adult chronic myeloid leukemia (CML) and for the treatment of Philadelphia chromosome-positive acute lymphocytic Leukemia and other diseases.
  • CML chronic myeloid leukemia
  • SPRYCELTM an oral tyrosine kinase inhibitor developed by BMS for adult chronic myeloid leukemia (CML) and for the treatment of Philadelphia chromosome-positive acute lymphocytic Leukemia and other diseases.
  • Its chemical name is N-(2-chloro-6-mercaptophenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-mercapto-4- Pyrimidinyl]amino]-5-thiazolylamide, the chemical structure is as follows:
  • Monohydrate Add 48 g of dasatinib, 1056 ml (22 ml/g) of ethanol and 144 ml of water to 75 ° C to dissolve and purify the filter and transfer to the receiver.
  • the dissolution reactor and transfer line were rinsed with a mixture of 43 ml of ethanol and 5 ml of water. Heat the solution to 75 ⁇ 80 °C to completely dissolve it, heat 384ml of water and keep the solution temperature between 75 ⁇ 80 °C.
  • Butanol Solvate Dissolve dasatinib in 1-butanol at a concentration of about lg/25ml solvent under reflux (116 ⁇ 118 ° C) to prepare a crystalline butanol solvent for dasatinib Compound. When cooling The butanol solvate crystallizes from the solution. Filter, wash with butanol, and dry. Ethanol solvate: To a 100 ml round bottom flask was added 4 g (10. 1 mmol) of 5D, 6.6 g (50.7 mmol) of 7B, 80 ml of n-butanol and 2.61 g (20.2 mmol) of DIPEA.
  • the resulting slurry was washed with an alcohol (2 x 10 mL) to afford white crystals.
  • the resulting wet cake was returned to a 100 ml reactor and charged with 56 ml (12 ml/g) of 200 proof ethanol. An additional 25 ml of ethanol was added at 80 ° C, and 10 ml of water was added to the mixture to dissolve rapidly. The heat was removed and the crystals were observed at 75 to 77 °C.
  • the crystallization slurry was further cooled to 20 ° C and then filtered.
  • the wet cake was washed once with 10 ml of ethanol:water (1:1) and then once with 10 ml of n-heptane. Drying at 60 ° C / 30 in Hg for 17 hours gave 3.55 g of material containing only 0.19% water.
  • N-6 in pure form To a mixture of compound 5D (175.45, 0.445 mol) and hydroxyethylpiperazine (289.67 g, 2.225 mol) in NMP (1168 ml) was added DIPEA (155 ml, 0.89 ⁇ ol). The suspension was heated at 110 ° 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, 8010 ml) 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 ⁇ 1600ml), and dried in vacuo at 55 to 60 ° C to give 192.45 g of compound.
  • T1H1-7 Pure form of T1H1-7 (pure form and pharmaceutically acceptable carrier): Prepared by heating dasatinib monohydrate at a temperature above the dehydration temperature.
  • dasatinib is almost insoluble in water or an organic solvent such as sterol, ethanol, propanol, isopropanol, butanol or pentanol, it is necessary to use a large amount of solvent more than 100 times even if it is dissolved under heating. It is not conducive to industrial scale preparation; in addition, the method taught in the application document CN200580011916.6 cannot effectively reduce the related substances in the product during the crystal preparation process to improve the quality of the product.
  • polymorphic forms of the drug different polymorphs may 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 handling or production of the drug substance and formulation, and can affect the stability, solubility, and bioavailability of the formulation. Therefore, the polymorphic form of the drug is of great importance for the quality, safety and efficacy of the pharmaceutical formulation.
  • polymorphic form of the drug is of great importance for the quality, safety and efficacy of the pharmaceutical formulation.
  • dasatinib there is a need in the art for a new polymorph that is suitable for industrial scale production and excellent physical and chemical properties. Summary of the invention
  • the inventors of the present invention have surprisingly discovered a new dasatinib polymorph, and have successfully solved the shortcomings of the prior art, which have excellent physical and chemical properties, good stability, and better suitability.
  • Another object of the present invention is to provide a process for the preparation of the above novel polymorph.
  • a third object of the present invention is to provide a pharmaceutical composition comprising the above novel polymorph.
  • the present invention provides a crystalline form I of dasatinib containing one molecule of water of crystallization and containing no other organic solvent, as shown in FIG.
  • the polymorph I of dasatinib monohydrate provided by the present invention has an amplitude of 2 ⁇ at 9.1 ⁇ 0.2 and 19.4 in the X-ray powder diffraction (XRPD) chart measured by Cu-Ka radiation. A diffraction peak of ⁇ 0.2.
  • the polymorph I of the dasatinib monohydrate may also have 9.1 ⁇ 0.2, 11.1 ⁇ 0.2, 13.7 + 0.2, 15.1 ⁇ 0.2, 17.8 + 0.2, 19.4 in the X-ray powder diffraction pattern.
  • a diffraction peak of one or more of +0.2, and 23.0 ⁇ 0.2 in any combination, including two or more, or all).
  • An example of the X-ray powder diffraction pattern of the polymorph I of the dasatinib monohydrate is shown in FIG.
  • the XRPD pattern diffraction peaks of the dasatinib polymorph I provided by the present invention are as follows: Peak number 2 ⁇ Flex width d-value intensity L/LO
  • the polymorph I of dasatinib monohydrate provided by the present invention may have a difference between 100 and 130 ° C in a differential scanning calorimetry (DSC) chart, in particular The first endothermic peak at around 120 °C; and the second endothermic peak at between 284 and 290 °C, especially at about 286.50 °C, is the maximum endothermic transition.
  • DSC differential scanning calorimetry
  • An example of the DSC pattern of the polymorph I of dasatinib monohydrate of the present invention is shown in Figure 4-1.
  • An example of a thermogravimetric analysis (TGA) map of the polymorph I of dasatinib monohydrate of the present invention is shown in Figure 4-2.
  • the polymorph I of the dasatinib monohydrate of the present invention may have an infrared absorption (IR) spectrum measured by KBr tableting at about: 3462.42 cm” 1 , 3210.67 cm- 1 , 3003.96. Cm" 1 , 2954.14 cm 2823.49cm” 1 , 1682.15 cm 1629.58 cm 1612.25 cm 1583.84cm” 1 , 1305.47 cm” 1 , 1290.91cm- 1 , 1000.19cm- 1 , and 1040.60cm- 1 The absorption peak.
  • An example of an infrared absorption spectrum of polymorph I of hydrate is shown in FIG.
  • the characteristic shift of the polymorph I of the dasatinib monohydrate of the present invention in solid nuclear magnetic resonance carbon can be: 16.75 ⁇ 0.2ppm, 24.92 ⁇ 0.2ppm, 41.72 ⁇ 0.2ppm, 43.23 ⁇ 0.2ppm, 44.28 ⁇ 0.2ppm, 54.01 ⁇ 0.2ppm, 55.48 ⁇ 0.2ppm, 57.53 ⁇ 0.2ppm, 58.70 ⁇ 0.2ppm, 62.23 ⁇ 0.2ppm, 63.20 ⁇ 0.2ppm, 84.66 ⁇ 0.2ppm, 127.92 ⁇ 0.2ppm, 128.81 ⁇ 0.2ppm, 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, and 167.58 ⁇ 0.2 ppm.
  • the present invention provides a process for the preparation of the polymorph I of dasatinib monohydrate of the present invention, which comprises the steps of:
  • (ml: g) preferably, selected from the group consisting of: dimercaptocarboxamide and dasatinib in a volume to weight ratio of from 2:1 to 200:1; most preferably, selected from the group consisting of: dinonyl amide and dasha Tinier has a volume to weight ratio of 3.5:1 to 4:1.
  • the volume to weight ratio of dimercaptosulfoxide to dasatinib may be usually from 1:1 to 200:1; preferably, selected from the group consisting of: volume to weight ratio of dimercaptosulfoxide to dasatinib It is from 1.5:1 to 200:1; most preferably, it is selected from the group consisting of: dimercaptosulfoxide and dasatinib in a volume to weight ratio of from 2.5:1 to 3:1.
  • the heating temperature may be from room temperature to reflux temperature of dimercaptosulfoxide (DMSO) or dimercaptophthalamide (DMF); preferably selected from: heating temperature may be from 40 ° C to 100 ° C; most preferably selected From: The heating temperature can be from 50 ° C to 80 ° C.
  • DMSO dimercaptosulfoxide
  • DMF dimercaptophthalamide
  • a mixed solvent of pure water and an organic solvent is added dropwise; wherein the organic solvent is one or a mixture of two or more kinds of dasatinib insoluble or slightly soluble.
  • the temperature is from 40 ° C to 100 ° C; most preferably: from 50 ° C to 80 ° C: temperature.
  • the volume ratio of the volume of the mixed solvent of the pure water and the organic solvent to the dimercaptoamide or the dimercaptosulfoxide is usually from 1:1 to 200:1; preferably, it is selected from the group consisting of: mixing of water and an organic solvent.
  • the volume ratio of the volume of the solvent to the dimercaptoamide or the dimercaptosulfoxide is from 2:1 to 200:1; most preferably, it is selected from the group consisting of: a mixed solvent of water and an organic solvent.
  • the volume ratio of the product to the dinonyl amide or dimercapto sulfoxide is from 3:1 to 200:1.
  • the organic solvent is one or a mixture of two or more insoluble or slightly soluble in dasatinib, preferably selected from the group consisting of acetonitrile, cyclohexane, 1,2-dichloroethylene, 1,2-two Alkoxyethane, dioxane, 2-ethoxyethanol, ethylene glycol, n-hexane, 2-methoxyethanol, mercaptobutyl ketone, nonylcyclohexane, N-decylpyrrolidone, Pyridine, tetrahydronaphthalene, tetrahydrofuran, toluene, 1,1,2-trichloro-ethene, diterpene, acetone, decyloxybutoxide, n-butanol, sec-butanol, butyl acetate, tert-butyl fluorenyl Ether, isopropyl benzene, decyl alcohol, ethanol, propano
  • the weight ratio of water to the above organic solvent is usually more than 10%, preferably selected from: the weight ratio of water to the above organic solvent is more than 20%, optimally selected from: the weight ratio of water to the above organic solvent is more than 30% ;
  • the temperature is gradually lowered to 0 to 5 °C under stirring to precipitate the solid completely and crystallize.
  • the holding time may be 10 minutes or more, preferably 1 hour or more; most preferably 2 hours or more; the crystal growth time may be 10 minutes or more, preferably 1 hour or more; most preferably 2 hours or more;
  • the solid was collected by filtration and dried. Among them, preferably, it is dried with phosphorus pentoxide, and vacuum-dried at 50 ° C, -0.095 MPa under reduced pressure for 12 hours or more.
  • the present invention provides another dasatinib organic solvent polymorph II free of water of crystallization, as shown in Figures 14A and B.
  • the polymorph Form II of dasatinib provided by the present invention has a diffraction peak of 2 ⁇ at 5.7 ⁇ 0.2 and 14.5 ⁇ 0.2 in degrees in an X-ray powder diffraction pattern measured using Cu-Ka radiation. Said The polymorph Form II of dasatinib may also have 5.7 ⁇ 0.2, 11.5 + 0.2, 12.3 + 0.2, 14.5 + 0.2, 17.2 + 0.2, 18.2 + 0.2, 22.2+ in the X-ray powder diffraction pattern. A diffraction peak of one or more of 0.2, 22.6+0.2, 24.7+0.2, and 25.2 ⁇ 0.2 (in any combination, including two or more, or all).
  • the organic solvent is a mixture of one or two or more mixed solvents of dimercaptosulfoxide (DMSO) or dimercaptocarboxamide (DMF) and dasatinib insoluble or sparingly soluble solvent.
  • DMSO dimercaptosulfoxide
  • DMF dimercaptocarboxamide
  • the dasatinib insoluble or sparingly soluble solvent preferably selected from the group consisting of acetonitrile, trichlorodecane, cyclohexane, 1,2-dichloroethylene, dichlorodecane, 1,2-dioxane Ethylethane, dioxane, 2-ethoxyethanol, ethylene glycol, n-hexane, decyl alcohol, 2-methoxyethanol, mercaptobutyl ketone, nonylcyclohexane, N-decylpyrrolidone , pyridine, tetrahydronaphthalene, tetrahydrofuran, toluene, 1,1,2-trichloroethene, diterpene benzene, acetone, decyloxybenzene, n-butanol, sec-butanol, butyl acetate, tert-butyl fluorene Ether, isopropyl
  • the XRPD pattern diffraction peak of the dasatinib polymorph II of the present invention is as follows:
  • the polymorph Form II of dasatinib provided by the present invention may have a 160 to 210 ° C in the DSC chart.
  • the two endothermic peaks between them, one of the endothermic peaks is a large endothermic peak of about 193 ° C; also has a temperature of 280 ⁇ 290 ° C
  • the third endothermic peak at about 286.67 °C is the maximum endothermic peak.
  • An example of a DSC pattern of the polymorph II of dasatinib of the present invention is shown in Figure 17-1, and an example of a TGA map is shown in Figure 17-2.
  • the polymorph Form II of dasatinib provided by the present invention may have an optical absorption spectrum measured by KBr tableting at about 3359.73 cm. " 1 , 3201.34cm” 1 , 3067.99cm” 1 , 2925.57 cm” 1 , 2842.67cm” 1 , 2822.19cm- 1 , 1716.01cm- 1 , 1619.56 cm 1578.34 cm 1537.01cm- 1 , 1315.41cm- 1 , 1293.55 cm” 1, 1006.06 cm “1, 984.74cm " 1, and the absorption peak at 1056.29cm- 1.
  • An example of the infrared absorption spectrum of the polymorph II of dasatinib is shown in FIG.
  • the polymorph Form II of dasatinib of the present invention typically, its dimercaptocarboxamide/acetone solvate, the characteristic shift of carbon in solid nuclear magnetic resonance carbon can be: 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 ⁇ 0.2ppm, 125.43 ⁇ 0.2ppm, 126.61+0.2ppm, 128.44 ⁇ 0.2ppm, 129.33 ⁇ 0.2ppm, 132.65 ⁇ 0.2ppm, 139.50 ⁇ 0.2ppm, 156.34 ⁇ 0.2ppm, 161.15 ⁇ 0.2ppm, 162.96 ⁇ 0.2ppm, 164.68 ⁇ 0.2 ppm, 165.47 ⁇
  • the present invention provides a process for the preparation of the polymorph II of dasatinib of the present invention, the method comprising the steps of:
  • the weight ratio is usually from 1:1 to 200:1 (ml: g); preferably, it is selected from the group consisting of: anhydrous dimethyl hydrazide or anhydrous dimethyl sulfoxide and dasatinib in volume to weight ratio 2:1 to 200:1; most preferably, selected from the group consisting of: anhydrous dimercaptoamide or anhydrous dimercaptosulfoxide and dasatinib in a volume to weight ratio of 3.5:1 to 4:1; Stir and heat to dissolve.
  • the solution is placed in an anhydrous organic solvent environment several times the volume of the solution, wherein the organic solvent is one or a mixture of two or more solvents which are insoluble or slightly soluble in dasatinib.
  • the volume ratio of the organic solvent to the dimercaptoamide or the dimercapto sulfoxide is usually from 1 to 200:1; preferably, selected from The volume ratio of the organic solvent to the dimercaptoamide or the dimercapto sulfoxide is greater than 3 to 200:1, and most preferably, the ratio of the organic solvent to the dimercaptoamide or the dimercapto sulfoxide is 5 to 200:1. .
  • the organic solvent is one or a mixture of two or more of dasatinib insoluble, preferably selected from the group consisting of acetonitrile, trichlorodecane, cyclohexane, 1,2-dichloroethylene, dichloro Decane, 1,2-dimethoxyethane, dioxane, 2-ethoxyethanol, ethylene glycol, n-hexane, decyl alcohol, 2-methoxyethanol, mercaptobutyl ketone, hydrazine Cyclohexane, N-decylpyrrolidone, pyridine, tetrahydronaphthalene, tetrahydrofuran, toluene, 1,1,2-trichloroethylene, diphenylbenzene, acetone, decyloxybenzene, n-butanol, sec-butanol , butyl acetate, tert-butyl decyl ether, isopropyl
  • organic solvent slowly volatilizes to the dadecyl amide or dimercapto sulfoxide solution at room temperature to the reflux temperature of the organic solvent.
  • the organic solvent can be volatilized for at least several hours or even several times. Day; preferably selected from above 24 hours; most preferably selected from above 72 hours.
  • the solid was recovered by filtration and dried. Among them, it is preferably dried in the presence of phosphorus pentoxide, and dried under reduced pressure of 50 ° C and -0.095 MPa for 12 hours or more.
  • the X-ray powder diffraction test apparatus and test conditions of the present invention are: anode-target X-ray powder diffractometer D/max-2 5 00/PC type (Japanese science); copper target, graphite
  • the monochromator, tube voltage 40 kV, tube current 100 mA, divergence slit and anti-scatter slit are all 1.
  • the receiving slit is 0.3mm, the scanning speed is 5 min, and the scanning range is 3 to 40°.
  • the DSC test apparatus and test conditions involved in the present invention are: Perkin Elmer Diamond DSC, USA; heating at a rate of 10 ° C/min, from 25 ° C to 300 ° C.
  • the TGA test instrument and test conditions of the present invention are: Perkin Elmer Thermal, USA Analysis Pyris 1 TGA; heated at 10 °C / min, from 25 °C to 500 °C.
  • the solid nuclear magnetic resonance test instrument and test conditions of the present invention are as follows:
  • Test conditions CP-MAS; Mode: Speed 14000Hz; Number of scans 1404 times; Relaxation delay: 40s; Contact time: 2ms; 13C Frequency: 100.6234936MHz; 1H Frequency: 400.1413530MHz
  • the relevant substances (the substances referred to herein refer to impurities other than dasatinib) and the detection conditions are as follows: According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix V D ).
  • octadecylsilane bonded silica as a filler; using 0.05 mol/L potassium dihydrogen phosphate (0.2% triethylamine, pH adjusted to 2.5 with phosphoric acid) - decyl alcohol (45:55) as mobile phase; detection The wavelength of 230 nm; the number of theoretical plates should be not less than 2000 according to the dasatinib peak. The degree of separation of dasatinib peak and adjacent impurity peaks should meet the requirements.
  • Solubility Refer to the Chinese Pharmacopoeia 2000 edition of the second edition of the test.
  • the polymorph I of dasatinib monohydrate was evenly distributed to the open culture sub-center, the thickness was ⁇ 5mm, the distance was adjusted, and the light intensity was 4500 ⁇ 500Lx, which was sampled and detected at 5, 10 days, respectively. The results of the day were compared. The results are shown in Table 2.
  • the 10-day X-ray powder diffraction pattern is shown in Fig. 6; the polymorphic form of dasatinib monohydrate I.
  • the DSC pattern of strong light irradiation for 10 days is shown in Fig. 7.
  • the polymorph I material of dasatinib monohydrate was placed in a sealed clean glass bottle, placed in a 60 ° C constant temperature oven, sampled at 5, 10 days, and compared with the results of 0 days. .
  • the results are shown in Table 3.
  • the 10-day X-ray powder diffraction pattern at 60 °C is shown in Fig. 8; the 10 day DSC chart at 60 °C is shown in Fig. 9-1, and the TGA pattern is shown in Fig. 9-2.
  • the polymorph I material of dasatinib monohydrate was hooked up to the open culture sub-center, thickness ⁇ 5mm, placed at room temperature (about 25 °C), constant humidity and humidity of 75 ⁇ 5 % relative humidity In the incubator, samples were taken at 5 and 10 days, respectively, and compared with the results of 0 days. The results are shown in Table 4.
  • the X-ray powder diffraction pattern with a relative humidity of 75 ⁇ 5 % and a high humidity of 10 days is shown in Figure 10; the DSC is shown in Figure 11-1; and the TGA is shown in Figure 11-2.
  • the raw material of the polymorph I of dasatinib monohydrate is sealed and packaged in a polyethylene film plastic bag, placed in a constant temperature and humidity incubator at 40 ⁇ 2° C. and a relative humidity of 75 ⁇ 5 %, and placed in six In the month, samples were taken at the end of 1, 2, 3, and 6 months, and compared with the results of 0 months.
  • the results are shown in Table 5.
  • the 6-month X-ray powder diffraction pattern is shown in Figure 12; the DSC chart is shown in Figure 13-1; and the TGA pattern is shown in Figure 13-2.
  • the experimental results show that the polymorph I of the dasatinib monohydrate obtained by the invention has a small increase in the content of the polymorph I in the light condition, and the content is decreased.
  • the high temperature test 60 °C
  • the appearance did not change significantly but the content decreased in a small amount
  • the polymorph I of the present invention showed no significant change in appearance and content in the high-humidity test, and the hygroscopicity was small
  • the experimental results show that the physical and chemical properties are relatively stable.
  • the long-term retention observation test of the polymorph I of the present invention no change in the crystal form was observed; the related substances had a small increase, and the content decreased in a small amount. Tests have shown that the crystalline form of the polymorph I is stable and suitable for long-term storage.
  • the weight loss (water) process of polymorph I occurs between 70 ° C and 150 ° C, and the weight loss is calculated from the TGA map of polymorph I of dasatinib monohydrate ( Figure 4-2). 3.60%; and the compound has been tested to determine the residual amount of the organic solvent in accordance with the limits specified by the ICH; the moisture value determined by the Karl Fischer method is 3.59%; and the analysis of the above experimental results shows that the dasatinib polymorph I of the present invention It is indeed a monohydrate.
  • the polymorph I of the present invention gradually loses (partially to all) of the crystal water in a closed environment (such as discoloration silica gel, phosphorus pentoxide, etc.) placed in a strong dehydrating agent, but
  • the polymorphic substance which loses part of the crystal water is gradually returned to the state of a crystal water of the polymorph I of the present invention after being left in an air environment for a while.
  • Solubility Refer to the Chinese Pharmacopoeia 2000 edition of the second edition of the test.
  • the Dasatinib Polymorph ⁇ raw materials are allocated to the hook open culture jnr thickness ⁇ 5mm, adjusting the distance the light intensity was 4500 ⁇ 500Lx, 5 respectively, 10 days sample testing, and the results at day 0 with Control.
  • the results are shown in Table 7.
  • the X-ray powder diffraction pattern for 10 days of illumination is shown in Figure 19, and the DSC pattern for 10 days of illumination is shown in Figure 20.
  • the dasatinib polymorph II material was placed in a sealed clean glass bottle, placed in a constant temperature drying oven at 60 ° C, and sampled at 5, 10 days, respectively, and compared with the results of 0 days. The results are shown in Table 8.
  • the X-ray powder diffraction pattern at high temperature for 10 days is shown in Figure 21; the DSC pattern at high temperature for 10 days is shown in Figure 22.
  • the dasatinib polymorph ⁇ raw materials are all branched into open culture jnr, thickness mm, placed at room temperature (about 25 ° C), relative humidity of 75 ⁇ 5% in a constant temperature and humidity incubator, respectively Samples were taken at 5, 10 days for comparison and compared to the results for 0 days. The results are shown in Table 9.
  • the 10-day X-ray powder diffraction pattern of the high-humidity experiment is shown in Fig. 23.
  • the 10-day DSC chart of the high-humidity experiment is shown in Figure 24-1, and the 10-day TGA chart of the high-humidity experiment is shown in Figure 24-2.
  • the dasatinib polymorph II material was sealed in a polyethylene film plastic bag and placed in a constant temperature and humidity incubator at 40 ⁇ 2 ° C and a relative humidity of 75 ⁇ 5 % for six months. Samples were taken at 1, 2, 3, and 6 months and compared with the results for 0 months. The results are shown in Table 10.
  • the X-ray powder diffraction pattern accelerated at 40 °C for 6 months is shown in Figure 25.
  • the DSC pattern at 40 °C for 6 months is shown in Figure 26-1, and the TGA pattern at 40 °C for 6 months is shown in Figure 26-2.
  • the dasatinib crystal form II obtained by the present invention has no significant change in the appearance of the light test, and the related substances have increased, and the content has decreased in the high temperature (60 ° C) test, appearance and content. There is no major change, indicating that its properties are relatively stable. The appearance and content of this product have not changed significantly in the high-humidity test, but it shows that the small hygroscopic acceleration experiment shows that its properties are relatively stable.
  • the present invention provides a pharmaceutical composition comprising one or both of the above two dasatinib polymorphs I and II and a drug Use an excipient.
  • the pharmaceutical composition contains from 1 to 500 mg of the dasatinib polymorph, particularly preferably from about 20, 50, 70, or 100 mg of the dasatinib polymorph of the present invention.
  • the pharmaceutical compositions of the present invention can be formulated into a variety of dosage forms and selected suitable pharmaceutical excipients.
  • the pharmaceutical composition of the present invention may be administered orally, parenterally (for example, intramuscularly, a pharmaceutical composition for intraperitoneal, intravenous, ICV, intracisternal injection or perfusion, subcutaneous injection or perfusion), inhalation spray, nasal, vaginal, rectal, sublingual or topical route of administration; preferably, an oral pharmaceutical combination
  • parenterally for example, intramuscularly, a pharmaceutical composition for intraperitoneal, intravenous, ICV, intracisternal injection or perfusion, subcutaneous injection or perfusion), inhalation spray, nasal, vaginal, rectal, sublingual or topical route of administration
  • an oral pharmaceutical combination In particular, oral tablets, capsules or granules.
  • Oral pharmaceutical compositions can be coated by one of ordinary skill in the art in accordance with the teachings of the prior art, for example, Chinese Patent Application CN 101170996A (published on Apr. 30, 2008).
  • the pharmaceutical composition comprising the dasatinib polymorph of the present invention may further contain other therapeutic ingredients, for example, ixabepilone, paclitaxel, docetaxel, cisplatin, carboplatin, bevacizumab, Bendamustine, erlotinib, nilotinib, Rituxima, dexamethasone, lenalidomide, capecitabine, exemestane, letrozole, dacarbazine, vandetanib and One or more of Ipilimumab and the like.
  • other therapeutic ingredients for example, ixabepilone, paclitaxel, docetaxel, cisplatin, carboplatin, bevacizumab, Bendamustine, erlotinib, nilotinib, Rituxima, dexamethasone, lenalidomide, capecitabine, exemestane, letrozole, dacarbazine, vande
  • the pharmaceutical composition of the present invention may be administered in one or more daily doses per day, and the daily dose is about 5 to 1000 mg / day, more preferably about 10 to 500 mg / day. Or, do it every other day, about 10 ⁇ 250 mg / day.
  • Examples of the dasatinib polymorph of the present invention for use in the treatment of diseases and conditions include, but are not limited to, graft rejection, rheumatoid arthritis, multiple sclerosis, enteritis, lupus, graft versus host disease, T - cell-mediated hypersensitivity disease, psoriasis, Hashimoto's sickle gland, cancer (including chronic myelogenous leukemia CML, gastrointestinal stromal tumor GIST, small cell lung cancer SCLC, non-small cell lung cancer NSCLC, ovarian cancer) , melanoma, mast cell proliferative disease, germ cell tumor, acute myeloid leukemia AML, pediatric sarcoma, breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, etc.), contact dermatitis, allergic disease, asthma, diabetic retina Lesions, as well as chronic obstructive pulmonary disease. Further, in the teachings of the present invention, those skilled in the art can determine specific methods and dosages according to the
  • the prior art CN200580011916.6 patent document is prepared by adding dasatinib to a mixture of an alcoholic organic solvent or an alcoholic organic solvent and water which is almost insoluble to satinib (eg, an alcohol solvent sterol, ethanol). , butanol, etc.), after heating and dissolving, crystals are precipitated under cooling.
  • an alcoholic organic solvent or an alcoholic organic solvent e.g., an alcohol solvent sterol, ethanol). , butanol, etc.
  • junction (transfer) method described in the patent document CN200580011916.6 does not significantly reduce the related substances of the original product, thereby improving the product quality;
  • the present invention provides two dasatinib polymorphs suitable for industrial production, overcoming the problems in the prior art.
  • the two novel polymorphs of dasatinib of the present invention have the crystallization conditions fully considered to be insoluble in the majority of solvents, and the purification is very difficult, and the preparation is simple and easy.
  • the preparation process of the invention is simple, very easy to operate, industrialized production is convenient to operate, quality is controllable, and the yield is parallel.
  • the crystal conversion scheme easily removes the highly polar impurities so that the related substances can be significantly reduced
  • the polymorph prepared by the preparation process of the present invention can significantly improve the appearance and color of the product compared to the polymorph of the original method;
  • the polymorph prepared by the preparation process of the invention has good stability and is suitable for long-term storage
  • the stability of the polymorphs I, II disclosed in the present invention in water is better than that of the polymorph A disclosed in the patent CN200580011916.6 in the destruction test, which makes the polymorph of the present invention It is more beneficial to the preparation process and the long-term preservation of the preparation; furthermore, it has been experimentally proved that the crystalline forms of the dasatinib polymorphs I and II of the present invention remain substantially unchanged after being formulated.
  • the stability is excellent, and the related substances of the drug substance contained in the test preparation are not increased, and are more suitable for use as a medicine.
  • the preparation method of the polymorph of the invention can greatly reduce the amount of organic solvent used in the crystal transformation, and reduce the cost; 7.
  • the method of the present invention can selectively use the three types of organic solvents having low toxicity to prepare the polymorph of the present invention, and to some extent reduce the potential influence of organic residues on human toxicity.
  • Figure 1 is a photomicrograph of a polymorph I of dasatinib monohydrate of the present invention.
  • Figure 2 is a typical XRPD pattern of the polymorph I of dasatinib monohydrate of the present invention.
  • Figure 3 is an infrared absorption spectrum (IR chart) of the polymorph I of dasatinib monohydrate of the present invention.
  • Figures 4-1 and 4-2 are respectively a DSC chart and a TGA chart of the polymorph I of dasatinib monohydrate of the present invention.
  • Figure 5 is a solid nuclear magnetic resonance carbon map of the polymorph I of dasatinib monohydrate of the present invention.
  • Figure 6 is an XRPD pattern of the polymorph I of the dasatinib monohydrate of the present invention exposed to strong light for 10 days.
  • Figure 7 is a 10-day DSC chart of the polymorph I of the dasatinib monohydrate of the present invention.
  • Figure 8 is a 10-day XRPD pattern of the polymorph I of dasatinib monohydrate of the present invention at 60 °C.
  • Figures 9-1 and 9-2 show the 10-day DSC and TGA plots of the polymorph I of the dasatinib monohydrate of the present invention at 60 °C, respectively.
  • Figure 10 is a 10 day XRPD pattern of the polymorph I of the dasatinib monohydrate of the present invention.
  • Fig. 11-1 and Fig. 11-2 are respectively a 10-day DSC chart and a TGA chart of the polymorph I of the dasatinib monohydrate of the present invention.
  • Fig. 12 is a view showing the June XRPD pattern of the polymorph I of the dasatinib monohydrate of the present invention in an environment of 40 °C.
  • Figure 13-1 and Figure 13-2 show the polymorph I of the dasatinib monohydrate of the present invention at 40 ° C, respectively.
  • Figures 14A and B are photomicrographs of the dasatinib polymorph II of the present invention.
  • Figure 15-1 is a typical XRPD pattern of the dasatinib (dimercaptoamide/acetone) polymorph II of the present invention.
  • Figure 15-2 is a typical XRPD pattern of the Dasatinib (dimercaptosulfoxide/ethyl acetate) polymorph II of the present invention.
  • Figure 16 is an infrared absorption spectrum (IR chart) of the dasatinib polymorph II of the present invention.
  • Figures 17-1 and 17-2 are DSC and TGA plots of dasatinib polymorph II of the present invention, respectively.
  • Figure 18 is a solid nuclear magnetic resonance carbon map of dasatinib polymorph II of the present invention.
  • Figure 19 is an XRPD pattern of the dashatinib polymorph II of the present invention for 10 days of light irradiation.
  • Figure 20 is a 10 day DSC chart of the light irradiation of dasatinib polymorph II of the present invention.
  • Figure 21 is a 10 day XRPD pattern of the dasatinib polymorph II of the present invention at 60 °C.
  • Figure 22 is a 10 day DSC chart of the dasatinib polymorph II of the present invention at 60 °C.
  • Figure 23 is an XRPD pattern of dasatinib polymorph II of the present invention for 10 days of high humidity.
  • Figures 24-1 and 24-2 are the 10-day DSC and TGA plots of the dasatinib polymorph II of the present invention, respectively.
  • Figure 25 is a graph showing the XRPD of the dasatinib polymorph II of the present invention placed at 40 ° C for 6 months.
  • Fig. 26-1 and Fig. 26-2 are DSC charts and TGA patterns of the dasatinib polymorph II of the present invention at 40 ° C for 6 months, respectively.
  • Figure 27 is a comparison of XRPD of dasatinib polymorphs I and II of the present invention.
  • Figure 28 is a comparison of infrared absorption gamma of dasatinib polymorphs I and II of the present invention.
  • Figure 29 is a comparison of DSC of dasatinib polymorphs I and II of the present invention.
  • Figure 30 is a solid nuclear magnetic resonance carbon contrast diagram of dasatinib polymorphs I and II of the present invention.
  • Figure 31 is a dissolution profile of the capsule formulation 1 of dasatinib polymorph I of the present invention.
  • Figure 32 is a dissolution profile of the capsule formulation 2 of dasatinib polymorph I of the present invention.
  • Figure 33 is a dissolution profile of Tablet Formulation 1 of Dasatinib Polymorph I of the present invention.
  • Figure 34 is a dissolution profile of Tablet Formulation 2 of Dasatinib Polymorph I of the present invention.
  • A Add 10 g of dasatinib and 40 ml of dimercaptosulfoxide to the reaction flask, and raise the temperature to 60-70 V with stirring. After mixing, add 120 ml of water and acetone (1:1) mixture under stirring. After the crystals were precipitated, the crystals were cooled to 0 ° C for 10 minutes. After suction filtration, the filter cake was rinsed with water, rinsed with water and acetone (1:1) and drained. The filter cake is dried at a reduced pressure (-0.095 MPa) at about 50 ° C, and assisted with phosphorus pentoxide.
  • Method A The product obtained in Method A was tested as follows: Microscope-crystal form (see Figure 1); XRPD test (see Figure 2); IR test (see Figure 3); DSC-TGA test (see Figure 4-1, 4-2); Solid-state nuclear magnetic resonance carbon spectrum detection (see Figure 5).
  • Method A The products obtained in Method A were tested as follows: Microscope-crystal form (see Figures 14A and B); XRPD test (see Figure 15-1); IR test (see Figure 16); DSC-TGA test (see drawing 17-1 and 17-2); solid nuclear magnetic resonance carbon detection (see Figure 18)
  • An anthraquinone containing a mixture of dasatinib polymorph I, II or any of the above two polymorphs in any ratio is prepared by the first four of the above excipients with dasatinib polycrystal Form I, II or a mixture of the above two polymorphs in any ratio is uniformly mixed, and water is added to prepare a soft material.
  • the soft material is made into wet granules and then dried, and the dried granules are uniformly mixed with magnesium stearate. After filling the capsule shell, a dasatinib capsule is obtained.
  • the dissolution profile of the capsule formulation 1 (1# to 6# batch) is shown in Figure 31.
  • a tablet comprising a mixture of dasatinib polymorphs I, II or any of the above two polymorphs in any ratio is prepared by the first four of the above excipients with dasatinib polymorph Mixtures of any ratio of the materials I, II or the above two polymorphs are mixed, and water is added to prepare a soft material.
  • the soft material is made into wet granules and then dried, and the dried granules are mixed with magnesium stearate.
  • the tablets were compressed after the hooking, and the obtained tablets were coated with the Opadry coating to obtain a dasatinib tablet.
  • dasatinib polymorph A The preparation of dasatinib polymorph A (hereinafter referred to as "916.6 polymorph A”) is represented by the method disclosed in CN200580011916.6, and the polymorphs I and II of the present invention (hereinafter referred to as “multiple” Crystallization I and II") Comparison of stability test methods and results:
  • Oxidative destruction Take 50mg of sample, accurately weigh it, place it in a 100ml volumetric flask, add 10ml of 30% hydrogen peroxide, leave it at room temperature for 2 hours, dilute to the mark with mobile phase, shake well, and measure by high performance liquid chromatography.
  • Acid destruction Take 50mg of sample, accurately weigh it, put it in a 100ml volumetric flask, add 10ml of 1mol/L hydrochloric acid solution, leave it at 40 °C for 1 hour, add an equal amount of 1mol/L sodium hydroxide solution to neutralize Dilute to the mark with mobile phase, shake well, and measure by high performance liquid chromatography.
  • Alkali destruction Take 50mg of sample, accurately weigh it, place it in a 100ml volumetric flask, add 10ml of 1mol/L sodium hydroxide solution, leave it at 40°C for 1 hour, add an equal amount of 1mol/L hydrochloric acid solution for neutralization. , then dilute to the mark with the mobile phase, shake well, and measure by high performance liquid chromatography.
  • Light damage Take 50mg of sample, accurately weigh it, place it in a 100ml volumetric flask, dissolve it with mobile phase and dilute and dilute to make a solution containing about 0.5mg of dasatinib per iml, and put it under 40001x light for about 6 hours. High performance liquid chromatography syntax detection.
  • High temperature destruction Take 50mg of sample, accurately weighed, placed in a 100ml volumetric flask, and dissolved with mobile The solution was diluted and diluted to prepare a solution containing about 0.5 mg of dasatinib per 1 ml, placed in a constant temperature water bath at 60 ° C, taken out after about 4 hours, and allowed to cool. High performance liquid chromatography.
  • the sample was taken, dissolved in a mobile phase and made into a solution containing 0.5 mg per 1 ml, and 20 ⁇ l was weighed and injected into a liquid chromatograph, and the chromatogram was recorded until the retention time of the main component peak was 6 times. If there are impurity peaks in the chromatogram of the test solution, the total impurity and individual impurities are calculated according to the peak area normalization method.
  • the comparative result data in the above comparison table indicates that the crystalline form of the dasatinib polymorph I of the present invention is substantially unchanged after being formed into a capsule or a tablet by a preparation process.
  • the comparative result data in the above comparison table indicates that the dasatinib polymorph I of the present invention is stabilized by the preparation process of the polymorph I, and the dashatinib polymorph I is stable, and the related substances are not obvious. Variety.
  • the present invention provides novel polymorphs of dasatinib, methods of making same, and pharmaceutical compositions comprising the novel polymorphs of dasatinib.
  • the dasatinib polymorph of the present invention has excellent physical and chemical properties and good stability, is more suitable for industrial scale preparation, and is suitable for long-term storage, and is more beneficial for meeting the preparation process and the long-term preservation of the preparation.
  • the preparation method of the dasatinib polymorph provided by the invention is simple in process, very easy to operate, convenient in industrial production, controllable in quality and parallel in yield.
  • the preparation method provided by the invention can greatly reduce the use amount of the organic solvent during the crystal transformation, and reduce the cost; and can also selectively use the three types of organic solvents with low toxicity to prepare the dasatinib polymorph, at a certain To a lesser extent, the potential impact of organic residues on human toxicity is reduced.

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Description

达沙替尼多晶型物及其制备方法和药物组合物 技术领域
本发明涉及药物化合物的多晶型物， 更具体地说， 涉及达沙替尼的多晶 型物， 另外， 本发明还涉及该多晶型物的制备方法及其药物组合物。
背景技术
达沙替尼， 商品名 SPRYCEL™, 是由 BMS公司研发的一种口服的酪氨 酸激酶抑制剂， 用于成人慢性髓性白血病 （CML ) , 还可用于治疗费城染色 体阳性的急性淋巴细胞性白血病等疾病。 其化学名称为 N-(2-氯 -6-曱基苯 基) -2-[[6-[4-(2-羟乙基) -1-哌嗪基 ]-2-曱基 -4-嘧啶基]氨基] -5-噻唑曱酰胺， 化学 结构如下：
Figure imgf000002_0001
布里斯托尔 -迈尔斯 ·斯奎布公司在中国专利申请 _申请号
CN200580011916.6文件（公开日为 2007年 6月 13日）中记载了达沙替尼的 五种晶态形式并披露了相应晶态形式的制备方法。 该文件中教导的制备方法 为：
一水合物： 加入 48g达沙替尼、 1056ml (22ml/g ) 乙醇及 144ml水加热到 75 °C溶解净化过滤转移到接收器中。用 43ml乙醇和 5ml水的混合物冲洗溶解 反应器和转移管线。 加热溶液到 75 ~ 80°C使其完全溶解， 加热 384ml水并使 溶液温度保持在 75 ~ 80°C之间。 冷却至 75°C加入一水合物晶种（优选）， 冷 却至 70°C保温 lh, 在 2h内冷却至 5°C并在 0 ~ 5°C之间保温 2h, 过滤淤浆， 用 96ml乙醇和 96ml水的混合物洗涤滤饼， ≤50°C减压干燥得 41g。
丁醇溶剂合物： 在回流（116 ~ 118°C ) 下， 在约 lg/25ml溶剂的浓度下 将达沙替尼溶解在 1-丁醇中， 制得达沙替尼的结晶丁醇溶剂合物。 当冷却时 该丁醇溶剂合物从溶液中结晶出来。 过滤， 用丁醇洗涤， 后干燥。 乙醇溶剂合物： 向 100ml 圓底烧瓶中加入 4g (lO.lmmol)的 5D, 6.6g (50.7mmol)的 7B, 80ml正丁醇和 2.61g (20.2mmol)的 DIPEA。 将所得淤浆加 醇 (2x10ml)洗涤，得白色结晶产物。将所得湿滤饼返回到 100ml反应器中， 装 入 56ml(12ml/g)的 200度（proof ) 乙醇。 在 80 °C再加入 25ml乙醇， 向此混合 物中加入 10ml水使其快速溶解。 除去加热， 在 75 ~ 77°C观察结晶。 将结晶 淤浆进一步冷却至 20°C接着过滤。 湿滤饼用 10ml乙醇:水 (1 :1)洗涤一次， 接 着用 10ml正庚烷洗涤一次。在 60 °C /30 in Hg下干燥 17小时得 3.55g仅含 0.19% 水的物质。
纯形式的 N-6: 向化合物 5D (175.45,0.445mol)和羟基乙基哌嗪 (289.67g, 2.225mol)在 NMP(1168ml)中的混合物中加入 DIPEA (155ml, 0.89匪 ol)。 将 悬浮液在 110°C加热 25min获得溶液， 然后冷却至约 90°C。 将所得热溶液滴 加到热水 (80°C,8010ml)中在 80°C保温搅拌 15分钟，后緩慢冷却至室温。真空 过滤收集固体，用水 (2x1600ml)洗涤，在 55 ~ 60 °C下真空中干燥，得到 192.45g 化合物。
纯形式的 T1H1-7 (纯形式及药学上可接受的载体）： 将达沙替尼一水合 物在高于脱水温度下进行加热而制得。
由于达沙替尼几乎不溶于水或曱醇、 乙醇、 丙醇、 异丙醇、 丁醇、 戊醇 等有机溶媒， 即使在加热情况下溶解也需要使用百倍以上的大量的溶媒， 溶 解十分困难， 不利于工业化规模制备； 另外， 申请文件 CN200580011916.6 教导的方法无法有效地在晶型制备过程中降低产品中的有关物质以提高产品 的质量。
对于药物的多晶型而言，不同的多晶型可以具有不同的化学和物理特性， 包括熔点、 化学稳定性、 表观溶解度、 溶解速率、 光学和机械性质、 蒸汽压 和密度。 这些性质可以直接影响原料药和制剂的处理或生产， 并且会影响制 剂的稳定性、 溶解度和生物利用度。 因此， 药物的多晶型对于药物制剂的质 量、 安全性和有效性具有重要的意义。 对于达沙替尼而言， 本领域存在着这 样的需求： 适于工业化规模生产、 理化性能优异的新多晶型。 发明内容
本发明的发明人经大量的研究， 令人惊奇地发现了新的达沙替尼多晶型 物， 成功地解决了现有技术存在的不足， 其具有理化性质优异、 稳定性好、 更适于工业化规模制备等优点。
本发明的目的是提供新的达沙替尼多晶型物。
本发明的另一个目的是提供上述新多晶型物的制备方法。
本发明的第三个目的是提供含有上述新多晶型物的药物组合物。
具体地说， 本发明提供了一种含一分子结晶水且不含其它有机溶剂的达 沙替尼多晶型物 I, 如图 1所示。
本发明所提供的达沙替尼一水合物的多晶型物 I, 在使用 Cu-Ka辐射测 得的 X-射线粉末衍射（ XRPD )图中具有以度表示的 2Θ在 9.1±0.2和 19.4±0.2 的衍射峰。 所述达沙替尼一水合物的多晶型物 I在所述 X-射线粉末衍射图中 还可以具有在 9.1±0.2、 11.1±0.2、 13.7+0.2, 15.1±0.2、 17.8+0.2, 19.4+0.2, 及 23.0±0.2中的一个或多个（以任意组合， 包括两个以上， 或者全部） 的衍 射峰。 所述达沙替尼一水合物的多晶型物 I的 X-射线粉末衍射图的示例如图 2所示。
本发明提供的达沙替尼多晶型物 I的 XRPD图衍射峰如下: 峰编号 2Θ Flex宽度 d-值 强度 L/LO
1 4.520 0.188 19.5333 2322 14
2 9.060 0.235 9.7527 9061 54
3 11.100 0.212 7.9645 8989 53
4 13.260 0.141 6.6716 2361 14
5 13.640 0.259 6.4865 16278 96
6 14.580 0.188 6.0704 1155 7
7 15.100 0.235 5.8625 9371 56
8 16.100 0.235 5.5005 2594 16
9 17.440 0.165 5.0808 1298 8 10 17.820 0.235 4.9733 5443 32
11 18.280 0.259 4.8492 1295 8
12 19.380 0.259 4.5764 17013 100
13 20.040 0.212 4.4271 1157 7
14 21.560 0.212 4.1183 1641 10
15 22.000 0.353 4.0369 1720 11
16 22.940 0.400 3.8736 5828 35
17 23.540 0.235 3.7762 4597 28
18 24.280 0.235 3.6628 1489 9
19 25.680 0.329 3.4662 2926 18
20 26.200 0.165 3.3985 1128 7
21 27.860 0.282 3.1997 3236 20
22 28.360 0.400 3.1444 3833 23
23 30.040 0.188 2.9723 1169 7
24 32.260 0.282 2.7726 1455 9
25 32.980 0.424 2.7137 1485 9
26 33.980 0.353 2.6361 1136 7
27 34.420 0.471 2.6034 1461 9
28 35.000 0.329 2.5616 2299 14
29 39.460 0.212 2.2817 1118 7 本发明所提供的达沙替尼一水合物的多晶型物 I在差示扫描量热（ DSC ) 图中， 可以具有约在 100 ~ 130°C之间， 特别是在 120 °C左右的第一个吸热峰； 以及在 284 ~ 290°C之间，特别是约在 286.50°C的第二吸热峰即最大吸热转变。 本发明的达沙替尼一水合物的多晶型物 I的 DSC图谱的例子见图 4-1。 本发 明的达沙替尼一水合物的多晶型物 I的热重分析（ TGA )图谱的示例如图 4-2 所示。
此外， 本发明的达沙替尼一水合物的多晶型物 I在用 KBr压片测得的红 外吸收（IR )图谱中，可以具有在约： 3462.42cm"1 , 3210.67cm-1 , 3003.96cm"1 , 2954.14 cm 2823.49cm"1 , 1682.15 cm 1629.58 cm 1612.25 cm 1583.84cm"1 , 1305.47 cm"1 , 1290.91cm-1 , 1000.19cm-1 , 及 1040.60cm-1处的吸 收峰。 所述达沙替尼一水合物的多晶型物 I的红外吸收图谱的示例如图 3所 示。
本发明的达沙替尼一水合物的多晶型物 I在固体核磁共振碳语中碳的特 征位移可以为： 16.75±0.2ppm、 24.92±0.2ppm、 41.72±0.2ppm、 43.23±0.2ppm、 44.28±0.2ppm、 54.01±0.2ppm、 55.48±0.2ppm、 57.53±0.2ppm、 58.70±0.2ppm、 62.23±0.2ppm、 63.20±0.2ppm、 84.66±0.2ppm、 127.92±0.2ppm、 128.81±0.2ppm、 132.70±0.2ppm 、 137.68±0.2ppm 、 139.00±0.2ppm 、 157.17±0.2ppm 、 162.07±0.2ppm、 163.54±0.2ppm、 166.84±0.2ppm、 及 167.58±0.2ppm。 所述达 沙替尼一水合物的多晶型物 I的固体核磁共振碳语的示例如图 5所示。
在本发明的实施方案中， 本发明提供了本发明的达沙替尼一水合物的多 晶型物 I的制备方法， 该方法包括如下步骤：
( 1 )将达沙替尼加入二曱基亚砜（DMSO )或者二曱基曱酰胺（DMF ) 中。 其中： 二曱基曱酰胺与达沙替尼的体积与重量比可以是通常 1 :1至 200:1
( ml: g ) ； 优选地， 选自： 二曱基曱酰胺与达沙替尼的体积与重量比 2:1至 200:1 ; 最优选地， 选自： 二曱基曱酰胺与达沙替尼的体积与重量比为 3.5:1 至 4:1。 其中： 二曱基亚砜与达沙替尼的体积与重量比可以是通常为 1 :1 至 200:1 ;优选地，选自：二曱基亚砜与达沙替尼的体积与重量比为 1.5:1至 200:1 ; 最优选地， 选自： 二曱基亚砜与达沙替尼的体积与重量比为 2.5:1至 3:1。
( 2 )在搅拌下加热使其溶解。 其中， 加热温度可为室温至二曱基亚砜 ( DMSO )或者二曱基曱酰胺（DMF ) 的回流温度； 优选地选自： 加热温度 可为 40°C至 100 °C ; 最优选地选自： 加热温度可为 50°C至 80°C。
( 3 )滴加纯水与有机溶媒的混合溶剂； 其中， 所述有机溶媒为达沙替尼 不溶或微溶的一种或两种以上混合溶剂。其中，优选地，温度在为 40°C至 100 °C下； 最优选地选自： 温度为 50°C至 80°C：。 其中， 纯水和有机溶媒的混合溶 剂体的体积与二曱基曱酰胺或二曱基亚砜的体积比通常为 1 :1至 200:1 ; 优选 地， 选自： 水和有机溶媒的混合溶剂体的体积与二曱基曱酰胺或二曱基亚砜 的体积比为 2： 1至 200： 1； 最优选地， 选自： 水和有机溶媒的混合溶剂体的体 积与二曱基曱酰胺或二曱基亚砜的体积比为 3:1至 200:1。 其中， 所述有机溶 媒为达沙替尼不溶或微溶的一种或两种以上混合的溶剂， 优选地， 选自乙腈、 环己烷、 1,2-二氯乙烯、 1,2-二曱氧基乙烷、 二氧六环、 2-乙氧基乙醇、 乙二 醇、 正己烷、 2-曱氧基乙醇、 曱基丁基酮、 曱基环己烷、 N-曱基吡咯烷酮、 吡啶、 四氢化萘、 四氢呋喃、 曱苯、 1,1,2-三氯乙婦、 二曱苯、 丙酮、 曱氧基 苯、 正丁醇、 仲丁醇、 乙酸丁酯、 叔丁基曱基醚、 异丙基苯、 曱醇、 乙醇、 丙醇、 乙酸乙酯、 乙醚、 曱酸乙酯、 正庚烷、 乙酸异丁酯、 乙酸异丙酯、 乙 酸曱酯、 3-曱基 -1-丁醇、 丁酮、 曱基异丁基酮、 异丁醇、 正戊烷、 正戊醇、 正丙醇、 异丙醇、 乙酸丙酯、 1,1-二乙氧基丙烷、 1,1-二曱氧基曱烷、 2,2-二 曱氧基丙烷、 异辛烷、 异丙醚、 曱基异丙基酮、 曱基四氢呋喃、 石油醚； 最 优选地， 选自 ICH规定的 3类或 3类以上的有机溶媒， 如： 丙酮、 曱氧基苯、 正丁醇、 仲丁醇、 乙酸丁酯、 叔丁基曱基醚、 异丙基苯、 乙醇、 曱醇、 丙醇、 乙酸乙酯、 乙醚、 曱酸乙酯、 正庚烷、 乙酸异丁酯、 乙酸异丙酯、 乙酸曱酯、 3-曱基 -1-丁醇、 丁酮、 曱基异丁基酮、 异丁醇、 正戊烷、 正戊醇、 正丙醇、 异丙醇、 乙酸丙酯、 1,1-二乙氧基丙烷、 1,1-二曱氧基曱烷、 2,2-二曱氧基丙 烷、 异辛烷、 异丙醚、 曱基异丙基酮、 曱基四氢呋喃、 石油醚等中的一种或 两种以上， 使得混合溶剂体系为由水和有机溶媒组成的二元或二元以上混合 体系。 其中水与上述有机溶媒的重量比例通常大于 10%, 优选地， 选自： 水 与上述有机溶媒的重量比例大于 20%, 最优地， 选自： 水与上述有机溶媒的 重量比例大于 30%;
( 4 ) 滴加完毕， 保温后在搅拌下緩緩降温至 0 ~ 5°C使固体析出完全并 养晶。 其中， 保温时间可在 10分钟以上， 优选 1小时以上； 最优选在 2小时 以上； 养晶时间可在 10分钟以上， 优选 1小时以上； 最优选在 2小时以上；
( 5 ) 过滤收集固体， 并干燥。 其中， 优选地， 用五氧化二磷助干， 在 50 °C , -0.095MPa减压真空干燥 12小时以上。 在本发明的实施方案中， 本发明提供了另一种不含结晶水的达沙替尼有 机溶媒化物多晶型物 II, 如图 14 A和 B所示。
本发明所提供的达沙替尼的多晶型物 II, 在使用 Cu - Ka辐射测得的 X- 射线粉末衍射图中具有以度表示的 2Θ在 5.7±0.2和 14.5±0.2的衍射峰。 所述 达沙替尼的多晶型物 II在所述 X-射线粉末衍射图中还可以具有在 5.7±0.2、 11.5+0.2, 12.3+0.2, 14.5+0.2, 17.2+0.2, 18.2+0.2, 22.2+0.2, 22.6+0.2, 24.7+0.2, 及 25.2±0.2中的一个或多个（以任意组合， 包括两个以上， 或者全部） 的衍 射峰。 所述达沙替尼的多晶型物 II的 X-射线粉末衍射图的示例如图 15-1和 15-2 所示。 这里， 所述的有机溶媒为二曱基亚砜（DMSO )或二曱基曱酰胺 ( DMF )与达沙替尼不溶的或微溶的溶剂一种或两种以上混合溶剂的混合物。 所述达沙替尼不溶的或微溶的溶剂， 优选地， 选自乙腈、 三氯曱烷、 环己烷、 1,2-二氯乙烯、 二氯曱烷、 1,2-二曱氧基乙烷、 二氧六环、 2-乙氧基乙醇、 乙 二醇、 正己烷、 曱醇、 2-曱氧基乙醇、 曱基丁基酮、 曱基环己烷、 N-曱基吡 咯烷酮、 吡啶、 四氢化萘、 四氢呋喃、 曱苯、 1,1,2-三氯乙婦、 二曱苯、 丙酮、 曱氧基苯、 正丁醇、 仲丁醇、 乙酸丁酯、 叔丁基曱基醚、 异丙基苯、 乙醇、 乙酸乙酯、 乙醚、 曱酸乙酯、 正庚烷、 乙酸异丁酯、 乙酸异丙酯、 乙酸曱酯、 3-曱基 -1-丁醇、 丁酮、 曱基异丁基酮、 异丁醇、 正戊烷、 正戊醇、 正丙醇、 异丙醇、 乙酸丙酯、 1,1-二乙氧基丙烷、 1,1-二曱氧基曱烷、 2,2-二曱氧基丙 烷、 异辛烷、 异丙醚、 曱基异丙基酮、 曱基四氢呋喃、 石油醚； 最优选地， 选自： 丙酮、 曱氧基苯、 正丁醇、 仲丁醇、 乙酸丁酯、 叔丁基曱基醚、 异丙 基苯、 乙醇、 乙酸乙酯、 乙醚、 曱酸乙酯、 正庚烷、 乙酸异丁酯、 乙酸异丙 酯、 乙酸曱酯、 3-曱基 -1-丁醇、 丁酮、 曱基异丁基酮、 异丁醇、 正戊烷、 正 戊醇、 正丙醇、 异丙醇、 乙酸丙酯、 1,1-二乙氧基丙烷、 1,1-二曱氧基曱烷、 2,2-二曱氧基丙烷、 异辛烷、 异丙醚、 曱基异丙基酮、 曱基四氢呋喃、 石油醚 等的一种溶剂或两种以上的混合溶剂； 更优选地， 所述的有机溶媒为二曱基 亚砜与丙酮或乙酸乙酯的混合物， 或者二曱基曱酰胺与丙酮或乙酸乙酯的混 合物。
本发明达沙替尼多晶型物 II的 XRPD图衍射峰如下：
Figure imgf000008_0001
5 14.860 0.165 5.9566 1571 7
6 15.940 0.282 5.5554 1821 8
7 17.240 0.259 5.1393 5961 26
8 18.200 0.235 4.8703 6730 29
9 18.980 0.235 4.6719 1476 7
10 20.440 0.235 4.3414 1527 7
11 21.180 0.212 4.1913 3249 14
12 22.160 0.235 4.0081 6002 26
13 22.560 0.212 3.9380 4970 22
14 23.140 0.235 3.8406 2388 11
15 24.120 0.235 3.6867 1177 5
16 24.740 0.259 3.5957 7961 34
17 25.240 0.235 3.5256 13052 56
18 25.600 0.188 3.4768 3701 16
19 26.320 0.235 3.3833 3072 13
20 26.940 0.165 3.3068 1379 6
21 27.180 0.188 3.2782 1469 7
22 27.520 0.188 3.2384 1659 8
23 27.940 0.329 3.1907 1668 8
24 28.560 0.282 3.1228 1194 6
25 29.300 0.235 3.0456 1665 8
26 33.340 0.235 2.6852 1437 7
27 35.120 0.282 2.5531 1248 6
28 38.000 0.329 2.3660 1202 6 本发明所提供的达沙替尼的多晶型物 II, 作为代表性地， 其二曱基曱酰 胺 /丙酮溶剂化物， 在 DSC图中可以具有在 160 ~ 210°C之间的两个吸热峰， 其中一个吸热峰是约在 193°C左右的较大的吸热峰； 还具有在 280 ~ 290°C之 间， 特别是约在 286.67 °C的第三个吸热峰即最大吸热峰。 本发明的达沙替尼 的多晶型物 II的 DSC图谱的示例如图 17-1所示， TGA图谱的示例如图 17-2 所示。
本发明所提供的达沙替尼的多晶型物 II, 代表性地， 其二曱基曱酰胺 /丙 酮溶剂化物， 在用 KBr 压片测得的红外吸收图谱中， 可以具有在约 3395.73cm"1 、 3201.34cm"1 、 3067.99cm"1 、 2925.57 cm"1 、 2842.67cm"1 、 2822.19cm-1、 1716.01cm-1、 1619.56 cm 1578.34 cm 1537.01cm-1、 1315.41cm-1 , 1293.55 cm"1 , 1006.06 cm"1 , 984.74cm"1 , 及 1056.29cm-1处的吸 收峰。 所述达沙替尼的多晶型物 II的红外吸收图谱的示例如图 16所示。
本发明的达沙替尼的多晶型物 II, 代表性地， 其二曱基曱酰胺 /丙酮溶剂 化物， 在固体核磁共振碳语中碳的特征位移可以为： 18.80±0.2ppm、 26.22±0.2ppm、 27.60±0.2ppm、 30.99±0.2ppm、 36.57±0.2ppm、 43.62±0.2ppm、 51.57±0.2ppm、 52.50±0.2ppm、 55.09±0.2ppm、 56.98±0.2ppm、 62.51+0.2ppm, 83.08±0.2ppm 、 125.43±0.2ppm 、 126.61+0.2ppm 、 128.44±0.2ppm 、 129.33±0.2ppm 、 132.65±0.2ppm 、 139.50±0.2ppm 、 156.34±0.2ppm 、 161.15±0.2ppm、 162.96±0.2ppm、 164.68±0.2ppm、 165.47±0.2ppm、 及 203.49 ±0.2ppm。 所述达沙替尼的多晶型物 II的固体核磁共振碳语的示例如图 18所 示。
在本发明的实施方案中， 本发明提供了本发明的达沙替尼的多晶型物 II 的制备方法， 该方法包括如下步骤：
( 1 )将达沙替尼加入无水二曱基曱酰胺或无水二曱基亚砜中， 其中： 无 水二曱基曱酰胺或无水二曱基亚砜与达沙替尼的体积与重量比通常为 1 :1 至 200: 1 ( ml: g )； 优选地， 选自： 无水二曱基曱酰胺或无水二曱基亚砜与达 沙替尼的体积与重量比为 2:1至 200: 1 ; 最优选地， 选自： 无水二曱基曱酰 胺或无水二曱基亚砜与达沙替尼的体积与重量比为 3.5:1至 4:1 ; 在搅拌加热 使其溶解。
( 2 )将上述溶液置于数倍于溶液体积的无水有机溶媒环境中， 其中， 所 述的有机溶媒为达沙替尼不溶或微溶的一种或两种以上混合溶剂。 这里， 有 机溶媒与二曱基曱酰胺或二曱基亚砜体积比通常为 1~200:1； 优选地， 选自有 机溶媒与二曱基曱酰胺或二曱基亚砜体积比大于 3~200:1 , 最优选地， 选自有 机溶媒与二曱基曱酰胺或二曱基亚砜体积比 5~200:1。 这里， 所述的有机溶媒 为达沙替尼不溶 ' 的一种或两种以上混合溶剂， 优选地， 选自乙腈、 三 氯曱烷、 环己烷、 1,2-二氯乙烯、 二氯曱烷、 1,2-二曱氧基乙烷、 二氧六环、 2-乙氧基乙醇、 乙二醇、 正己烷、 曱醇、 2-曱氧基乙醇、 曱基丁基酮、 曱基环 己烷、 N-曱基吡咯烷酮、 吡啶、 四氢化萘、 四氢呋喃、 曱苯、 1,1,2-三氯乙烯、 二曱苯、 丙酮、 曱氧基苯、 正丁醇、 仲丁醇、 乙酸丁酯、 叔丁基曱基醚、 异 丙基苯、 乙醇、 乙酸乙酯、 乙醚、 曱酸乙酯、 正庚烷、 乙酸异丁酯、 乙酸异 丙酯、 乙酸曱酯、 3-曱基 -1-丁醇、 丁酮、 曱基异丁基酮、 异丁醇、 正戊烷、 正戊醇、 正丙醇、 异丙醇、 乙酸丙酯、 1,1-二乙氧基丙烷、 1,1-二曱氧基曱烷、 2,2-二曱氧基丙烷、异辛烷、异丙醚、 曱基异丙基酮、 曱基四氢呋喃、石油醚； 最优选地， 选自： 丙酮、 曱氧基苯、 正丁醇、 仲丁醇、 乙酸丁酯、 叔丁基曱 基醚、 异丙基苯、 乙醇、 乙酸乙酯、 乙醚、 曱酸乙酯、 正庚烷、 乙酸异丁酯、 乙酸异丙酯、 乙酸曱酯、 3-曱基 -1-丁醇、 丁酮、 曱基异丁基酮、 异丁醇、 正 戊烷、 正戊醇、 正丙醇、 异丙醇、 乙酸丙酯、 1,1-二乙氧基丙烷、 1,1-二曱氧 基曱烷、 2,2-二曱氧基丙烷、异辛烷、异丙醚、 曱基异丙基酮、 曱基四氢呋喃、 石油醚等的一种溶剂或两种以上的混合溶剂。
( 3 M吏有机溶媒在室温至有机溶媒的回流温度下緩慢挥发至达沙替尼的 二曱基曱酰胺或二曱基亚砜溶液中。 这里， 有机溶媒挥发的时间可以至少为 数小时乃至数日； 优选地选自 24小时以上； 最优选地选自 72小时以上。
( 4 )过滤回收固体， 并干燥。 其中， 优选地， 在五氧化二磷存在条件下 助干， 50°C , -0.095MPa减压条件下干燥 12小时以上。
在本发明中， 本发明所涉及的 X-射线粉末衍射测试仪器及测试条件为： 阳极转靶 X-射线粉末衍射仪 D/max-2500/PC型（日本理学）； 铜靶、 石墨单色 器、 管电压 40kv、 管电流 100mA、 发散狭缝与防散射狭缝均为 1。、 接收狭缝 为 0.3mm、 扫描速度 5 min、 扫描范围 3 ~ 40°。
本发明所涉及的 DSC测试仪器及测试条件为：美国 Perkin Elmer Diamond DSC; 以 10 °C/min速度加热， 从 25 °C至 300 °C。
本发明所涉及的 TGA测试仪器及测试条件为：美国 Perkin Elmer Thermal Analysis Pyris 1 TGA; 以 10 °C /min速度加热， 从 25 °C至 500 °C。
本发明所涉及的固体核磁共振测试仪器及测试条件为：
仪器： BRUKER AVANCE III 400MHz宽腔固体核磁共振谱仪。
测试条件： CP-MAS; 方式： 转速 14000Hz; 扫描次数 1404次； 弛豫延 迟： 40s； 接触时间： 2ms； 13C 频率： 100.6234936MHz； 1H 频率： 400.1413530MHz
本发明所涉及的有关物质 （这里所述的有关物质是指除达沙替尼之外的 杂质）检测条件及方法为： 照高效液相色谱法（中国药典 2005年版二部附录 V D )测定。
色谱条件与系统适用性
用十八烷基硅烷键合硅胶为填充剂； 以 0.05mol/L磷酸二氢钾（ 0.2%三 乙胺， 用磷酸调节 pH值至 2.5 ) -曱醇（45:55 )为流动相； 检测波长 230nm; 理论塔板数按达沙替尼峰计算应不低于 2000。 达沙替尼峰与相邻杂质峰的分 离度应符合要求。
测定法 取样品， 加流动相溶解并制成每 1ml中含 0.5mg的溶液， 量取 20μ1, 分别注入液相色语仪， 记录色谱图至主成分峰保留时间的 6倍。 达沙替尼一水合物的多晶型物 I的特性
一、 溶解性： 参照中国药典 2000年版二部凡例进行试验。
方法： 精密称取达沙替尼一水合物的多晶型物 I适量， 緩慢加入一定量 的溶剂，每隔 5分钟强力振摇 30秒，观察 30分钟内的溶解情况，结果见表 1。
达沙替尼一水合物的多晶型物 I溶解度试验
Figure imgf000012_0001
O.lmol/LHCl溶液 0.0100 80 1:8000 完全溶解 极微溶解 乙腈 0.0106 100 1:9434 完全溶解 极微溶解 不能完全
甲醇 0.0106 120 1:11321 几乎不溶 溶解 二、 稳定性
1、 光照试验
将达沙替尼一水合物的多晶型物 I均匀分摊至敞口培养亚中，厚度≤5mm, 调节距离， 使光照强度为 4500±500Lx, 分别于 5, 10天取样检测， 并与 0天 的结果进行对照。 结果见表 2。 10天的 X-射线粉末衍射图见图 6; 达沙替尼 一水合物的多晶型物 I强光照射 10天的 DSC图见图 7。
光照试验 ( 4500±5001x )
Figure imgf000013_0001
注： 温度变化 23~26°C; 相对湿度变化 56%
2、 高温试马全
将达沙替尼一水合物的多晶型物 I原料放置于密封洁净玻璃瓶中， 置于 60°C恒温干燥箱中， 分别于 5, 10天取样检测， 并与 0天的结果进行对照。 结 果见表 3。 60°C考察 10天的 X-射线粉末衍射图见图 8; 60°C考察 10天的 DSC 图见图 9-1, TGA图见图 9-2。
表 3 高温试验 (60°C )
Figure imgf000013_0002
注： 相对湿度变化 54 % ~ 62% 3 、 高湿试验
将达沙替尼一水合物的多晶型物 I原料均勾分摊至敞口培养亚中， 厚度 <5mm, 置于室温（25 °C左右）， 相对湿度为 75±5 %的恒温恒湿培养箱中， 分 别于 5, 10天取样进行测定， 并与 0天的结果进行对照。 结果见表 4。 相对湿 度为 75±5 %高湿 10天的 X-射线粉末衍射图见图 10; DSC图见图 11-1 ; TGA 图见 11-2。
表 4 高湿试验（室温， 相对湿度、 75±5% )
Figure imgf000014_0001
注： 温度变化 23 ~ 26°C
4、 力口速试验
将达沙替尼一水合物的多晶型物 I的原料用聚乙烯薄膜塑料袋密封包装, 置于 40±2°C , 相对湿度为 75±5 %的恒温恒湿培养箱中， 放置六个月， 分别于 1, 2, 3, 6个月末取样检测， 并与 0 月的结果进行对照。 结果见表 5。 6个月的 X-射线粉末衍射图见图 12; DSC图见图 13-1 ; TGA图见图 13-2。
表 5 加速试验（40°C , 相对湿度 75% )
Figure imgf000014_0002
实验结果表明， 本发明得到的达沙替尼一水合物的多晶型物 I在光照条 件下多晶型物 I的有关物质会有少量增加，含量有所下降。在高温试验中（60 °C ), 外观无明显改变但含量有较少量的下降； 本发明多晶型物 I在高湿试验 中其外观和含量均没有明显变化， 吸湿性较小； 加速实验结果表明其理化性 质相对稳定。 本发明多晶型物 I在长期留样观察试验中， 没有观察到晶型发生变化； 有关物质有较少量的增加， 含量有较少量的下降。 试验表明此多晶型物 I的 结晶形态稳定， 适宜长期保存。
此外， 多晶型物 I的失重（水）过程发生在 70°C至 150°C之间， 根据达 沙替尼一水合物的多晶型物 I 的 TGA图 （图 4-2 )计算失重 3.60%; 且该化 合物经过检测有机溶媒残留量符合 ICH规定的限度要求； 卡氏水分法测定的 水分值为 3.59%; 综合上述实验结果分析表明本发明的达沙替尼多晶型物 I 确为一水合物。
通过进一步的实险发现， 本发明的多晶型物 I在置于强脱水剂的密闭环 境中 （如变色硅胶、 五氧化二磷等）会逐步失去（部分直至全部）结晶水， 但将该失去部分结晶水的多晶型物露置于空气环境中一段时间后又会逐步回 复至本发明多晶型物 I一个结晶水的状态。 达沙替尼多晶型物 II的特性：
一、 溶解性： 参照中国药典 2000年版二部凡例进行试验。
方法： 精密称取达沙替尼多晶型物 II适量， 緩慢加入一定量的溶剂， 每 隔 5分钟强力振摇 30秒， 观察 30分钟内的溶解情况， 结果见表 6。
表 6 达沙替尼多晶型物 II的溶解度试验
Figure imgf000015_0001
二、 稳定性 1、 光照试验
将达沙替尼多晶型 Π原料均勾分摊至敞口培养 jnr中，厚度≤5mm,调节距 离， 使光照强度为 4500±500Lx, 分别于 5, 10天取样检测， 并与 0天的结果 进行对照。 结果见表 7。 光照 10天的 X-射线粉末衍射图见图 19, 光照 10天 的 DSC图见图 20。
表 7 光照试验 ( 4500±5001x )
Figure imgf000016_0001
注： 温度变化 23 ~26°C; 相对湿度变化 56 % ~ 63%
2、 高温试马全
将达沙替尼多晶型物 II原料放置于密封洁净玻璃瓶中， 置于 60°C恒温干 燥箱中， 分别于 5, 10天取样检测， 并与 0天的结果进行对照。 结果见表 8。 高温 10天的 X-射线粉末衍射图见图 21; 高温 10天的 DSC图见图 22。
表 8 高温试验 (60°C )
Figure imgf000016_0002
注： 相对湿度变化 54 % ~ 62%
3、 高湿试验
将达沙替尼多晶型物 π原料均勾分摊至敞口培养 jnr中，厚度 mm,置于 室温（25°C左右）， 相对湿度为 75±5%的恒温恒湿培养箱中， 分别于 5, 10天 取样进行测定， 并与 0天的结果进行对照。 结果见表 9。 高湿实验 10天的 X- 射线粉末衍射图见图 23, 高湿实验 10天的 DSC图见图 24-1, 高湿实验 10 天的 TGA图见图 24-2。
表 9 高湿试验（室温， 相对湿度、 75±5%) 时间 考察项目
(天） 外观 水分（％ ) 含量 ( % ) 熔点分解（ V )
0 白色粉末 0.57 99.8 % 286.67°C
5 白色粉末 3.63 99.7 % 1
10 白色粉末 3.72 99.8 % 288.50°C
注： 温度变化 23 ~ 26°C
4、 力口速试验
将达沙替尼多晶型物 II原料用聚乙烯薄膜塑料袋密封包装， 置于 40±2 °C , 相对湿度为 75±5 %的恒温恒湿培养箱中， 放置六个月， 分别于 1, 2, 3, 6 个月末取样检测， 并与 0月的结果进行对照。 结果见表 10。 40°C加速 6个月 的 X-射线粉末衍射图见图 25, 40°C加速 6个月的 DSC图见图 26-1 , 40°C加 速 6个月的 TGA图见图 26-2。
表 10加速试验 ( 40°C , 相对湿度 75% )
Figure imgf000017_0001
由上述结果可知， 本发明得到的达沙替尼」 晶型物 II在光照试验外观无 较大改变， 有关物质有所增长， 含量有所下降 在高温（60°C )试验中， 外 观和含量均无较大改变， 说明其性质相对稳定 本品在高湿试验中其外观和 含量均没有明显变化， 但显示有较小的吸湿性 加速实验表明其性质相对稳 定。
在本发明的另一种实施方案中， 本发明提供了一种药物组合物， 所述药 物组合物含有上述二种达沙替尼多晶型物 I和 II中的一种或两种以及药用赋 形剂。优选地，该药物组合物含有达沙替尼多晶型物 1 ~ 500mg,特别优选地， 含有约 20、 50、 70、 或 100毫克的本发明的达沙替尼多晶型物。 本发明的药 物组合物可制成各种的剂型， 并选择适宜的药用赋形剂。 例如， 根据待治疗 疾病和对象， 本发明的药物组合物， 可以是通过口服、 肠胃外（例如肌肉内、 腹膜内、 静脉内、 ICV、 脑池内注射或灌注、 皮下注射或灌注）、 吸入喷雾、 鼻、 阴道、 直肠、 舌下或局部给药途径给药的药物组合物； 优选地， 为口服 药物组合物， 特别是， 口服片剂、 胶嚢或颗粒剂。 本领域的普通技术人员可 根据现有技术的教导对口服药物组合物进行包衣， 例如中国专利申请 CN 101170996A (公开日为 2008年 4月 30曰）。
本发明的包含达沙替尼多晶型物的药物组合物， 视需要还可含其它治疗 成分， 例如， 伊沙匹隆、 紫杉醇、 多烯紫杉醇、 顺铂、 卡铂、 贝伐单抗、 苯 达莫司汀、厄洛替尼、尼罗替尼、 Rituxima、地塞米松、 来那度胺、 卡培他滨、 依西美坦、 来曲唑、 达卡巴嗪、 凡德他尼和 Ipilimumab等其中的一种或者多 种。
本发明的药物组合物可以是每日一次或多次日剂量而给药的， 日剂量约 为 5 ~ 1000毫克 /天， 更优选为约 10 ~ 500毫克 /天。 或者， 隔天给药， 约 10 ~ 250毫克 /天。
本发明的达沙替尼多晶型物可用于治疗疾病和症状的例子包括但不限 于： 移植物排斥、 类风湿性关节炎、 多发性硬化症、 肠炎、 狼疮、 移植物抗 宿主病、 T-细胞介导的超敏性疾病、 牛皮癣、 桥本氏曱状腺肿、 癌症（包括 慢性髓性白血病 CML、 胃肠道间质瘤 GIST, 小细胞肺癌 SCLC、 非小细胞肺 癌 NSCLC、 卵巢癌、 黑素瘤、 肥大细胞增殖病、 生殖细胞瘤、 急性髓性白血 病 AML、 小儿肉瘤、 乳腺癌、 结肠直肠癌、 胰腺癌、 前列腺癌等）、 接触性 皮炎、 过敏性疾病、 哮喘、 糖尿病视网膜病变、 以及慢性阻塞性肺病等。 此 外， 在本发明的教导下， 本领域的技术人员根据现有技术， 可确定具体的方 法和剂量， 例如， 专利国际申请， 公布号 WO2004085388A2。
本发明的有益技术效果体现在：尽管现有技术 CN200580011916.6专利文 献的报导了达沙替尼多晶型物及其制备方法。但 CN200580011916.6提供的制 备达沙替尼的多晶型物制备方法通过试验得知该专利文献教导的转晶方法并 不适于规模化稳定生产。
现有技术 CN200580011916.6 专利文献其制备方法是将达沙替尼加入到 达沙替尼几乎不溶的醇类有机溶媒或醇类有机溶媒和水的混合液中 (如： 醇 类溶剂曱醇、 乙醇、 丁醇等）加热溶解后在降温下析出晶体。 1、 由于达沙替尼几乎不溶于水或醇类有机溶剂中， 即使在加热情况下也 需要使用大量的溶剂， 所以转晶工艺繁瑣， 产品质量可控性差， 不适合规模 化稳定生产。
2、 以专利文件 CN200580011916.6中所述的结 （转） 晶方法不能使原产 品的有关物质显著降低， 从而提高产品质量；
3、 在专利文件 CN200580011916.6中按其条件所制备的晶型 A稳定性通 过实验得知相比于本发明制备的晶型物 I的稳定性表现差；
总之，专利文件 CN200580011916.6中教导的达沙替尼多晶型物的制备方 法不适于规模化稳定生产。
然而， 本发明提供了适于工业化生产的二种达沙替尼多晶型物， 克服了 现有技术中存在的问题。
本发明对达沙替尼的二种新的多晶型物， 其结晶条件充分考虑到达沙替 尼在绝大部分的溶剂中不溶解， 提纯十分困难的特点， 釆用了简便易行的制 备方法：
1、 本发明制备工艺简单， 十分易于操作， 工业化生产操作方便， 质量可 控， 收率平行。
2、 转晶方案很容易地去处了强极性的杂质使得有关物质可显著降低；
3、本发明制备工艺所制得的多晶型物相比于原方法的多晶型物可显著地 改善了产品的外观色泽的问题；
4、 本发明制备工艺所制得的多晶型物稳定性好， 适于长期贮放；
5、 本发明所公开的多晶型 I、 II 在水中的稳定性相比于专利 CN200580011916.6中公开的多晶型 A在破坏试验中的稳定性好，这使得本发 明的多晶型物更加有益于制剂工艺以及制剂长期保存的要求； 此外， 经实验 证明， 本发明的达沙替尼多晶型物 I、 II在制成制剂后， 其晶型基本上保持不 变， 晶型的稳定性优秀， 且检测制剂中所含的原料药的有关物质没有增长， 更适于用作药物。
6、本发明的多晶型的制备方法可大大降低转晶时有机溶剂使用量， 降底 了成本； 7、本发明的方法可选择性使用毒性低的 3类有机溶剂类制备本发明的多 晶型物， 在一定程度上降低了有机残留对人体的毒害的潜在影响作用。
以上的优点使本发明有益于对产品的质量的显著提高并且更适宜于工业 化生产。 附图概述
图 1 是本发明达沙替尼一水合物的多晶型物 I的显微镜照片图。
图 2 是本发明达沙替尼一水合物的多晶型物 I的典型的 XRPD图。
图 3 是本发明达沙替尼一水合物的多晶型物 I 的红外吸收光谱图 （IR 图）。
图 4-1和图 4-2分别是本发明达沙替尼一水合物的多晶型物 I的 DSC图 和 TGA图。
图 5 是本发明达沙替尼一水合物的多晶型物 I的固体核磁共振碳语图。 图 6 是本发明达沙替尼一水合物的多晶型物 I强光照射 10天的 XRPD 图。
图 7 是本发明达沙替尼一水合物的多晶型物 I强光照射 10天 DSC图。 图 8 是本发明达沙替尼一水合物的多晶型物 I的 60°C考察 10天 XRPD 图。
图 9-1和图 9-2分别是本发明达沙替尼一水合物的多晶型物 I的 60 °C考察 10天 DSC图和 TGA图。
图 10是本发明达沙替尼一水合物的多晶型物 I高湿考察 10天的 XRPD 图。
图 11-1和图 11-2分别是本发明达沙替尼一水合物的多晶型物 I高湿考察 10天 DSC图和 TGA图。
图 12是本发明达沙替尼一水合物的多晶型物 I置 40°C环境中考察 6月 XRPD图。
图 13-1和图 13-2分别是本发明达沙替尼一水合物的多晶型物 I置 40°C 6 月的 DSC图和 TGA图。
图 14 A和 B是本发明达沙替尼多晶型物 II的显微镜照片图。
图 15-1 是本发明达沙替尼（二曱基曱酰胺 /丙酮） 多晶型物 II的典型的 XRPD图。
图 15-2是本发明达沙替尼（二曱基亚砜 /乙酸乙酯） 多晶型物 II的典型 的 XRPD图。
图 16是本发明达沙替尼多晶型物 II的红外吸收光谱图 （ IR图）。
图 17-1和图 17-2分别是本发明达沙替尼多晶型物 II的 DSC图和 TGA 图。
图 18是本发明达沙替尼多晶型物 II的固体核磁共振碳语图。
图 19是本发明达沙替尼多晶型物 II光照射 10天的 XRPD图。
图 20是本发明达沙替尼多晶型物 II光照射 10天 DSC图。
图 21是本发明达沙替尼多晶型物 II的 60 °C 10天 XRPD图。
图 22是本发明达沙替尼多晶型物 II的 60 °C 10天 DSC图。
图 23是本发明达沙替尼多晶型物 II高湿 10天的 XRPD图。
图 24-1和图 24-2分别是本发明达沙替尼多晶型物 II高湿 10天 DSC图和 TGA图。
图 25是本发明达沙替尼多晶型物 II置 40°C6月留样 XRPD图。
图 26-1和图 26-2分别是本发明达沙替尼多晶型物 II置 40°C6月的 DSC 图和 TGA图。
图 27是本发明达沙替尼多晶型物 I和 II的 XRPD对比图。
图 28是本发明达沙替尼多晶型物 I和 II的红外吸收光语对比图。
图 29是本发明达沙替尼多晶型物 I和 II的 DSC对比图。
图 30是本发明达沙替尼多晶型物 I和 II的固体核磁共振碳语对比图。 图 31是本发明达沙替尼多晶型物 I的胶嚢配方 1的溶出曲线。
图 32是本发明达沙替尼多晶型物 I的胶嚢配方 2的溶出曲线。 图 33是本发明达沙替尼多晶型物 I的片剂配方 1的溶出曲线。 图 34是本发明达沙替尼多晶型物 I的片剂配方 2的溶出曲线。 本发明的较佳实施方式
实施例 1
多晶型物 I的制备：
A、在反应瓶中加入达沙替尼 10g,二曱基亚砜 40ml,搅拌下升温至 60~70 V , 待溶解后保温下加入 120ml水和丙酮 （1:1 ) 的混合液， 搅拌下析出晶体 后降温至 0°C养晶 10分钟。 抽滤， 滤饼用水淋洗后用水和丙酮（1:1 )的混合 液淋洗并抽干。 滤饼于 50°C左右减压 （-0.095MPa )干燥， 用五氧化二磷助
Figure imgf000022_0001
Figure imgf000022_0002
对方法 A所得产品进行了如下检测： 显微镜 -晶形 （见附图 1 ); XRPD 检测 （见附图 2 ); IR检测 （见附图 3 ); DSC-TGA检测 （见附图 4-1,4-2 ); 固体核磁共振碳谱检测 （见附图 5 )。
B、在反应瓶中加入达沙替尼 10g, 二曱基亚砜 40ml, 搅拌下緩慢升温至 60-70 °C , 溶解后在保温下加入乙醇:水 (1:1)的混合液 160ml, 搅拌下析出晶体 后降温至 0°C养晶 10分钟。 抽滤， 滤饼用乙醇:水 (1:1)的混合液淋洗。 滤饼于 50°C左右减压 （-0.095MPa )干燥， 用五氧化二磷助干。 得 8.7g 白色固体。 收率： 87%。
Figure imgf000022_0003
Figure imgf000023_0001
实施例 2
多晶型物 II的制备：
A、 在反应瓶中加入达沙替尼 10g, 二曱基曱酰胺 40ml, 升温至 60~70 °C搅拌下溶解； 将上述达沙替尼的二曱基曱酰胺溶液置于丙酮的密闭体系环 境中， 丙酮的体积为 300ml。 让丙酮在室温至回流温度下挥发入达沙替尼的 二曱基曱酰胺溶液中。 历时数小时乃至数日后溶液中析出堆积状晶体后再静 置数小时乃至数日。 抽滤， 滤饼用丙酮淋洗。 滤饼于 50°C左右 （-0.095MPa ) 减压干燥， 用五氧化二磷助干。 得 6.1g白色固体。 收率： 61%。
Figure imgf000023_0003
对方法 A所得产品进行了如下检测： 显微镜 -晶形 （见附图 14A及 B ); XRPD检测 （见附图 15-1 ); IR检测 （见附图 16 ); DSC-TGA检测 （见附图 17-1及 17-2 ); 固体核磁共振碳语检测 （见附图 18 )
B、 在反应瓶中加入达沙替尼 10g, 二曱基亚砜 40ml, 升温至 60~70°C搅 拌下溶解； 将上述达沙替尼的二曱基亚砜溶液置于乙酸乙酯的密闭体系环境 中， 乙酸乙酯的体积为 300ml。 让乙酸乙酯在室温至回流温度下挥发入达沙 替尼的二曱基亚砜溶液中。 历时数小时乃至数日后溶液中析出堆积状晶体后 再静置数小时乃至数日。 抽滤， 滤饼于 50°C左右 （-0.095MPa )减压干燥，
Figure imgf000023_0002
Figure imgf000023_0004
TGA失重 I I I 对方法 B所得产品进行了如下检测： XRPD检测 （见附图 15-2 ) 实施例 3
达沙替尼胶嚢剂的处方及制备工艺：
按下述方法用几种赋形剂将上述达沙替尼多晶型物 I、 II, 或 I、 II的任 意比例混合物制成含 50mg的固体制剂。
Figure imgf000024_0001
含达沙替尼多晶型物 I、 II 或上述二种多晶型物的任意比例的混合物的 胶嚢剂的制造方法是将上述赋形剂中的前四种与达沙替尼多晶型物 I、 II或 上述二种多晶型物的任意比例的混合物混合均匀， 加水适量制得软材， 将软 材制成湿颗粒后进行干燥， 干燥后的颗粒与硬脂酸镁混合均匀后填入胶嚢壳 即得到达沙替尼胶嚢剂。
溶出曲线：
胶嚢配方 1 (多晶型物 I )
Figure imgf000024_0002
胶嚢配方 1 ( 1#至6#批次）溶出曲线见图 31。
胶嚢配方 2 (多晶型物 I ) 时间 1# 2# 3# 4# 5# 6# 平均％ SD %
0 0 0 0 0 0 0 0.00 0.00
5 59.9 62.7 58.1 63.5 65.2 57.7 61.2 3.07
10 86.9 89.5 86.1 84.2 83.3 88.7 86.5 2.44
20 93.4 96.7 94.8 96.5 95.6 91.2 94.7 2.10
30 99.5 97.6 98.1 97.3 98.8 99.7 98.5 0.99
45 98.6 97.2 97.6 96.4 97.5 98.8 97.7 0.90
60 98.1 96.3 96.7 95.9 96.6 97.4 96.8 0.79 胶嚢配方 2 ( 1#至 6#批次）溶出曲线见图 32。
实施例 4
达沙替尼片剂的处方及制备工艺：
按下述方法用几种赋形剂将上述达沙替尼多晶型物 I或 II, 或 I、 II 的任 意比例混合物制成含 50mg的片剂。
Figure imgf000025_0001
含达沙替尼多晶型物 I、 II或上述二种多晶型物的任意比例的混合物的片 剂的制造方法是将上述赋形剂中的前四种与达沙替尼多晶型物 I、 II或上述二 种多晶型物的任意比例的混合物混合均勾， 加水适量制得软材， 将软材制成 湿颗粒后进行干燥， 干燥后的颗粒与硬脂酸镁混合均勾后压制片剂， 所得片 剂用欧巴代包衣料包裹薄膜衣即得到达沙替尼片剂。
溶出曲线：
片剂配方 1 (多晶型物 I )
Figure imgf000025_0002
10 75.9 78.8 74.2 79.4 77.3 76.8 77.1 1.91
20 88.9 86.4 88.2 87.1 87.7 91.7 88.3 1.86
30 95.5 94.1 93.3 94.9 96.7 97.8 95.4 1.66
45 98.7 97.9 97.4 96.9 98.3 99.4 98.1 0.90
60 97.1 97.2 96.8 96.7 97.5 98.2 97.3 0.55 片剂配方 1 ( 1#至6#批次）溶出曲线见图 33。
片剂配方 2 (多晶型物 I )
时间 1# 2# 3# 4# 5# 6# 平均％ SD %
0 0 0 0 0 0 0 0.00 0.00
5 40.8 38.6 39.4 37.2 42.9 45.9 40.80 3.17
10 72.5 70.3 68.4 71.6 67.8 72.3 70.48 2.01
20 85.1 86.7 82.2 80.5 83.9 84.5 83.82 2.19
30 92.6 93.8 91.2 95.7 92.4 91.1 92.80 1.74
45 96.3 97.9 96.7 99.5 98.1 97.2 97.62 1.15
60 96.0 97.3 95.8 98.2 97.4 96.6 97.60 0.92 同法可以制备含达沙替尼 20mg/70mg/80mg /100mg/140mg的胶嚢及片剂。 稳定性对比试验：
以 CN200580011916.6所公开方法制备达沙替尼多晶型物 A(以下简称为 "916.6多晶型物 A" )为代表， 与本发明的多晶型物 I和 II (以下简称为"多晶 型物 I和 II" )对比破坏实验的稳定性考察方法及结果：
表 16 "916.6多晶型物 A"与多
Figure imgf000026_0001
总杂: 0.06% 总杂: 0.06% 总杂: 0.06% lmol/L tR3.580 0.01% tR4.102 0.02% tR4.101 0.01% 酸破坏 tR4.106 0.02% tR4.987 0.01% tR4.993 0.01%
tR5.001 0.02% tR5.603 0.02% tR5.604 0.02% 总杂: 0.11% 总杂: 0.08% 总杂: 0.08%
tR4.107 0.01% tR4.130 0.02% tR3.580 0.01% lmol/L tR5.007 0.03% tR5.089 0.01% tR4.131 0.02% 碱破坏 tR5.351 0.03% tR5.501 0.02% tR5.092 0.01%
tR8.943 0.01% tR5.512 0.02%
tR9.424 0.01% 总杂: 1.89% 总杂: 1.28% 总杂: 1.36%
tR2.456 0.30% tR2.199 0.04% tR2.197 0.05% tR3.732 0.14% tR2.527 0.06% tR2.526 0.05% tR4.589 0.11% tR2.911 0.33% tR2.910 0.02% tR5.088 0.06% tR3.734 0.11% tR3.733 0.11% 光照破坏 tR5.503 0.19% tR4.119 0.04% tR4.116 0.04%
tR10.095 0.82% tR4.585 0.08% tR4.582 0.07%
tR5.089 0.03% tR5.084 0.02% tR5.502 0.14% tR5.496 0.15% tR5.996 0.08% tR5.990 0.06% tR10.096 0.66% tR10.084 0.78% 总杂: 0.08% 总杂: 0.05% 总杂: 0.06%
tR4.118 0.02% tR3.569 0.01% tR3.567 0.01% 面温破坏 tR5.081 0.03% tR4.120 0.02% tR4.117 0.01%
tR5.502 0.03% tR5.088 0.01% tR5.085 0.01%
tR5.520 0.02% tR5.507 0.02% 实验方法:
氧化破坏： 取样品 50mg, 精密称定， 置于 100ml量瓶中， 加入 30%双 氧水 10ml, 室温放置 2小时后， 用流动相稀释至刻度， 摇匀， 高效液相色谱 法检测。
酸破坏： 取样品 50mg, 精密称定， 置于 100ml量瓶中， 加 lmol/L的盐 酸溶液 10ml, 于 40°C放置 1小时后， 加入等量的 lmol/L的氢氧化钠溶液中 和， 再用流动相稀释至刻度， 摇匀， 高效液相色谱法检测。
碱破坏： 取样品 50mg, 精密称定， 置于 100ml量瓶中， 加 lmol/L的氢 氧化钠溶液 10ml, 于 40°C放置 1小时后， 加入等量的 lmol/L的盐酸溶液中 和， 再用流动相稀释至刻度， 摇匀， 高效液相色谱法检测
光照破坏： 取样品 50mg, 精密称定， 置于 100ml量瓶中， 用流动相溶 解并稀释稀释制成每 iml约含达沙替尼 0.5mg的溶液， 置 40001x光照下约 6 小时。 高效液相色语法检测。
高温破坏： 取样品 50mg, 精密称定， 置于 100ml量瓶中， 用流动相溶 解并稀释稀释制成每 1ml约含达沙替尼 0.5mg的溶液， 置 60 °C恒温水浴中 , 约 4小时后取出， 放冷。 高效液相色谱法检测。
有关物质测定检测方法：
色谱条件与系统适用性 用十八烷基硅烷键合硅胶为填充剂； 以 0.05mol/L磷酸二氢钾 ( 0.2%三乙胺， 用碑酸调节 pH值至 2.5 ) -曱醇（45:55 ) 为流动相； 检测波长 230nm; 理论塔板数按达沙替尼峰计算应不低于 2000。 达沙替尼峰与相邻杂质峰的分离度应符合要求。
测定法 取样品， 加流动相溶解并制成每 1ml中含 0.5mg的溶液， 量取 20μ1, 分别注入液相色语仪， 记录色谱图至主成分峰保留时间的 6倍。 供试 品溶液色谱图中如有杂质峰， 按峰面积归一化法计算总杂及单个杂质。
晶型在制剂中的稳定性
检测本发明实施例 3和 4中制备的胶嚢及片剂的 X-射线衍射图， 与本发 明实施例 1方法 Α制备的达沙替尼多晶型物 I的 XRPD特征峰进行对比， 列 表如下：
Figure imgf000028_0001
上述对比表中的对比结果数据表明， 本发明的达沙替尼多晶型物 I经制 剂工艺制成胶嚢或片剂后， 其晶型基本保持不变。
此外， 检测本发明实施例 3和 4中制备的胶嚢及片剂的有关物质， 与本 发明实施例 1方法 A制备的达沙替尼多晶型物 I的有关物质进行对比， 列表 下：
Figure imgf000029_0001
上述对比表中的对比结果数据表明， 本发明的达沙替尼多晶型物 I经制 剂工艺制成胶嚢或片剂后， 达沙替尼多晶型物 I稳定， 有关物质无明显的变 化。
工业实用性
本发明提供了达沙替尼的新多晶型物， 还提供了其制备方法， 以及包含 该达沙替尼的新多晶型物的药物组合物。 本发明所提供的达沙替尼多晶型物 理化性质优异且稳定性好， 更适于工业化规模制备， 并且适于长期贮放， 更 有益于满足制剂工艺以及制剂长期保存的要求。 本发明所提供的达沙替尼多 晶型物的制备方法工艺简单、 十分易于操作、 工业化生产操作方便， 质量可 控且收率平行。 此外， 本发明所提供的制备方法可大大降低转晶时有机溶剂 使用量， 降底了成本； 还可选择性使用毒性低的 3类有机溶剂类制备达沙替 尼多晶型物， 在一定程度上降低了有机残留对人体的毒害的潜在影响作用。

Claims

权 利 要 求 书
1. 一种达沙替尼一水合物的多晶型物 I, 其在使用 Cu-Ka辐射测得的 X- 射线粉末衍射图中， 具有以度表示的 2Θ在 9.1±0.2和 19.4±0.2的衍射峰。
2. 根据权利要求 1所述的多晶型物 I, 其中， 所述多晶型物 I在所述 X- 射线粉末衍射图中， 还具有以度表示的 2Θ在 11.1±0.2、 13.7+0.2, 15.1±0.2、 17.8+0.2, 及 23.0±0.2中的一个或多个的衍射峰。
3. 根据权利要求 1或 2所述的多晶型物 I,所述多晶型物 I在差示扫描量 热图中，具有约在 100~130°C之间的第一吸热峰以及在 284~290°C之间的第二 吸热峰。
4. 根据权利要求 1或 2所述的多晶型物 I, 所述多晶型物 I在用 KBr压 片测得的红外吸收图语中， 具有在约 3462.42cm-1、 3210.67cm-1 , 3003.96cm"1 , 2954.14cm-1、 2823.49cm-1、 1682.15cm-1、 1629.58cm"1 , 1612.25cm-1、 1583.84cm"1 , 1305.47cm-1 , 1290.91cm-1 , 1000.19cm-1 , 及 1040.60cm-1处的吸收峰。
5. 根据权利要求 1或 2所述的多晶型物 I,所述多晶型物 I在固体核磁共 振碳谱图中碳的特征位移为： 16.75±0.2ppm、 24.92±0.2ppm、 41.72±0.2ppm、 43.23±0.2ppm、 44.28±0.2ppm、 54.01±0.2ppm、 55.48±0.2ppm、 57.53±0.2ppm、 58.70±0.2ppm、 62.23±0.2ppm、 63.20±0.2ppm、 84.66±0.2ppm、 127.92±0.2ppm、 128.81±0.2ppm 、 132.70±0.2ppm 、 137.68±0.2ppm 、 139.00±0.2ppm 、 157.17±0.2ppm 、 162.07±0.2ppm 、 163.54±0.2ppm 、 166.84±0.2ppm、 及 167.58±0.2ppm。
6. 一种达沙替尼的多晶型物 II,其在使用 Cu-Ka辐射测得的 X-射线粉末 衍射图中， 具有以度表示的 2Θ在 5.7±0.2和 14.5±0.2的衍射峰。
7. 根据权利要求 6所述的多晶型物 II,所述多晶型物 II在所述 X-射线粉 末衍射图谱中，还具有以度表示的 2Θ在 11.5±0.2、 12.3+0.2, 17.2+0.2, 18.2+0.2, 22.2+0.2, 22.6+0.2, 24.7+0.2, 及 25.2±0.2中的一个或多个的衍射峰。
8. 根据权利要求 6或 7所述的多晶型物 II, 所述多晶型物 II在差示扫描 量热图中具有在 160~210°C之间的两个吸热峰， 其中一个吸热峰是约在 193 °〇左右的较大的吸热峰； 还具有在 280~290°C之间的第三个吸热峰即最大吸 热峰。
9. 根据权利要求 6或 7所述的多晶型物 II,所述多晶型物 II在用 KBr压 片测得的红外吸收图语中， 具有在约 3395.73cm-1、 3201.34cm-1 , 3067.99cm-1 , 2925.57cm-1 2842.67cm-1、2822.19cm-1、 1716.01cm-1、 1619.56cm-1、 1578.34cm-1、 1537.01cm"1、 1315.41cm"1、 1293.55cm"1、 1006.06cm"1、 984.74cm"1、及 1056.29cm-1 处的吸收峰。
10. 根据权利要求 6或 7所述的多晶型物 II, 所述多晶型物 II在固体核 磁共振碳语图 中碳的特征位移为： 18.80±0.2ppm、 26.22+0.2ppm、 27.60±0.2ppm、 30.99±0.2ppm、 36.57±0.2ppm、 43.62±0.2ppm、 51.57±0.2ppm、 52.50±0.2ppm、 55.09±0.2ppm、 56.98±0.2ppm、 62.51±0.2ppm、 83.08±0.2ppm、 125.43±0.2ppm 、 126.61+0.2ppm 、 128.44±0.2ppm 、 129.33±0.2ppm 、 132.65±0.2ppm 、 139.50±0.2ppm 、 156.34±0.2ppm 、 161.15±0.2ppm 、 162.96±0.2ppm、 164.68±0.2ppm、 165.47±0.2ppm、 及 203.49 ±0.2ppm。
11. 权利要求 1至 5中任一项权利要求所述的多晶型物 I的制备方法，所 述方法包括如下步骤：
( 1 )将达沙替尼加入二曱基曱酰胺或者二曱基亚砜中；
( 2 )在搅拌下加热使其溶解；
( 3 )滴加水与有机溶媒的混合溶剂体系； 其中， 所述有机溶媒为达沙替 尼不溶或微溶的一种或两种以上混合溶剂；
( 4 )滴加完毕， 保温后在搅拌下緩緩降温至 0~5°C使固体析出完全并养 曰曰 ,
( 5 )过滤收集固体， 并干燥。
12. 权利要求 6至 10中任一项权利要求所述的多晶型物 II的制备方法， 所述方法包括如下步骤：
( 1 )将达沙替尼加入无水二曱基曱酰胺或二曱基亚砜中， 搅拌加热使其 溶解；
( 2 )将步骤（1 ) 所得到的溶液置于无水有机溶媒环境中， 其中， 所述 的有机溶媒为达沙替尼不溶或微溶的一种或两种以上混合溶剂； ( 3 M吏有机溶媒在室温至有机溶媒的回流温度下緩慢挥发至达沙替尼的 二曱基曱酰胺或二曱基亚砜溶液中；
( 4 )过滤回收固体， 并干燥。
13. 一种药物组合物， 其包含权利要求 1至 5中任一项所述的达沙替尼 一水合物的多晶型物 I和权利要求 6至 10中任一项所述的达沙替尼的多晶型 物 II中的一种或两种。
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WO2014086326A1 (en) 2012-12-06 2014-06-12 Zentiva, K.S. A method for the preparation and purification of new and known polymorphs and solvates of dasatinib
CN104515813A (zh) * 2013-09-29 2015-04-15 山东新时代药业有限公司 一种达沙替尼中间体的分析检测方法
WO2017108605A1 (en) 2015-12-22 2017-06-29 Synthon B.V. Pharmaceutical composition comprising amorphous dasatinib

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AU2011213431A1 (en) 2012-09-06
US8884013B2 (en) 2014-11-11
CN101891738A (zh) 2010-11-24
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AU2011213431B2 (en) 2014-12-11
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