CN105503715A - Sorafenib semi-tosylate polymorphism and preparing method thereof - Google Patents
Sorafenib semi-tosylate polymorphism and preparing method thereof Download PDFInfo
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- CN105503715A CN105503715A CN201610027864.1A CN201610027864A CN105503715A CN 105503715 A CN105503715 A CN 105503715A CN 201610027864 A CN201610027864 A CN 201610027864A CN 105503715 A CN105503715 A CN 105503715A
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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Abstract
The invention relates to a sorafenib semi-tosylate monohydrate, a crystallization form and preparing method of the sorafenib semi-tosylate monohydrate, a medicine composition containing the sorafenib semi-tosylate monohydrate and application of the sorafenib semi-tosylate monohydrate in anti-cancer drugs.
Description
Technical field
The present invention relates to novel 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) is amino] phenoxy group } compound and crystallized form and preparation method thereof of-N-picoline-2-methane amide half tosylate monohydrate cancer therapy drug, belong to field of pharmaceutical chemistry technology.
Background technology
WO2000/42012A discloses diphenyl urea compounds 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) the is amino] phenoxy group that a class ω-carboxyl aryl replaces }-N-picoline-2-methane amide, i.e. Xarelto, its structural formula is such as formula shown in (I):
WO2000/42012A also discloses this compound and salt thereof, such as tosilate, i.e. Sorafenib Tosylate, and as structural formula (II), it can be used for suppressing the mediated cancerous cell growth of Raf kinases institute.
WO2003/068228A particularly relates to the application of formula (II) compound in the disease (such as tumour) for the treatment of VEGF signal transduction pathway mediation, can be used for abnormal vascular and generates or hypertonicity illness.WO2003/0475979A discloses formula (II) compound and combines with cell toxicant or cytostatic compound and be used for the treatment of the kinase mediated disease of Raf, such as cancer, as lung cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, intestinal cancer or growth of cancer cells.
The method preparation that formula (I) compound or its salt can describe in WO2000/42012A or WO2000/41698.
WO2006/034797A discloses 3 kinds of non-solvent compounds (being called polymorphic I, II, III), 2 kinds of solvates (Methanol Solvate, an alcohol solvent compound) of formula (II) compound, wherein: polymorphic I is thermodynamically metastable sizing, decompose in 223 ~ 231 DEG C of fusings, and polymorphic I is even by being still storage-stable after suspension process; Polymorphic II metastable state, has the transition point of 194 DEG C; Polymorphic III, in 187 ~ 190 DEG C of thawings.WO2009092070A relates to 2 kinds of solvates of formula (II) compound, i.e. DMSO solvate polymorph b, nmp solvent compound polymorphic C.WO2009/106825A relates to unformed formula (I) and (II) compound.WO2010/142678A relates to the unformed of formula (II) compound, formula (I) compound hydrochloride of crystallization or its hydrate, mesylate, benzene sulfonate, half benzene sulfonate monohydrate eutectic and maleate.WO2010/079498A relates to the non-solvent compound (polymorphic II) of formula (II) compound, its PXRD collection of illustrative plates has diffraction peak in 9.7,11.2,13.1,17.7,18.4,21.4,22.7 and 24.6 ± 2theta place, DSC collection of illustrative plates shows it to start to melt at 181.25 DEG C, has endotherm(ic)peak at 184.61 DEG C of places.WO2014/138905A relates to half DMSO solvate of formula (II) compound.CN104761492A relates to 2 kinds of non-solvent compounds (polymorph b, C) of formula (II) compound, and wherein, polymorphic C has exothermic peak at 169.78 DEG C ~ 179.94 DEG C, has endotherm(ic)peak at 232.95 DEG C ~ 238.66 DEG C.WO2009/092070A also relates to a kind of Xarelto half toluenesulphonic acids (1:0.5) and polymorphic (polymorphic A) thereof, wherein, the PXRD collection of illustrative plates of described polymorphic A 6.6,9.0,9.6,13.4,14.0,17.2,18.3,20.4,22.8,24.9,27.1 ± 0.2theta place has diffraction peak.
WO2006/034797A relates to polymorphic I, the polymorphic II, polymorphic III and preparation method thereof of formula (II) compound, in order to obtain stable crystal formation, need high temperature or long-time stirring to turn brilliant preparation, and gained crystal formation degree of crystallinity is not high, is difficult to the requirement meeting industrialized production.The polymorphic A of WO2009/092070A turns brilliant by the polymorphic III of formula (II) compound in aqueous suspension, or obtained by recrystallization after the salt-forming reaction of formula (I) compound, wherein the latter needs to use Virahol (or propyl alcohol or acetone), 1-butyl methyl ether solvents, can cause larger organic solvent residual.Therefore, need to develop a kind of good stability, security high, be suitable for producing, and there is the new crystal of the Xarelto salt of good patent medicine prospect.
Summary of the invention
The invention provides the compound that one has structural formula (III), i.e. Xarelto half tosylate monohydrate,
Present invention also offers the crystallized form of the compound of a kind of structural formula (III), be called polymorphic S.The X-ray powder diffraction of Xarelto half tosylate monohydrate polymorphic S of the present invention is that 13.6 ± 0.2 °, 17.4 ± 0.2 °, 20.6 ± 0.2 °, 23.9 ± 0.2 °, 27.3 ± 0.2 ° places have characteristic peak at diffraction angle 2 θ.Further, it is that 13.6 ± 0.2 °, 14.1 ± 0.2 °, 17.4 ± 0.2 °, 20.6 ± 0.2 °, 21.6 ± 0.2 °, 23.9 ± 0.2 °, 27.3 ± 0.2 ° places have characteristic peak at diffraction angle 2 θ.Again further, its X-ray powder diffraction as shown in Figure 1.
Further, the X-ray powder diffraction of Xarelto half tosylate monohydrate polymorphic S of the present invention as shown in Figure 1.
Again further, the DSC collection of illustrative plates of Xarelto half tosylate monohydrate polymorphic S of the present invention is that 133.8 ~ 146.2 DEG C of places have endotherm(ic)peak in temperature.
Again further, the DSC collection of illustrative plates of Xarelto half tosylate monohydrate polymorphic S of the present invention as shown in Figure 2.
Present invention also offers a kind of method preparing Xarelto half tosylate monohydrate polymorphic S, it comprises the steps: Xarelto to suspend in ethanol, stir, drip the ethanolic soln of tosic acid monohydrate, stir, be heated to and be warming up to 25 ~ 100 DEG C, drip water, cooling crystallization, to obtain final product.In some embodiments of the present invention, the preferred 75-80 DEG C of described warming temperature.In other embodiments of the present invention, described in, it is 0 ~ 80 DEG C that the temperature that the ethanolic soln of described tosic acid monohydrate drips controls, preferably 10 ~ 60, and more preferably 20 ~ 30 DEG C.
Present invention also offers a kind of method preparing Xarelto half tosylate monohydrate polymorphic S, it comprises the steps: Sorafenib Tosylate I crystal to be suspended in ethanol or methyl alcohol, stirs, be warming up to 25 ~ 100 DEG C, temperature control drips water, Quan Rong, cooling crystallization, to obtain final product.In some embodiments of the present invention, suspension etoh solvent can substitute with methyl alcohol.In some embodiments of the present invention, the preferred 75-80 DEG C of described warming temperature, more preferably 80 DEG C.
Present invention also offers a kind of pharmaceutical composition, it contains Xarelto half tosylate monohydrate or its polymorphic S of dose therapeutically effective, and pharmaceutically acceptable auxiliary material.
The present invention also provides Xarelto half tosylate monohydrate or the application of its polymorphic S in the medicine preparing the generation for the treatment of abnormal vascular or hyperpermeability processes associated conditions or cancer, wherein, described cancer is selected from the growth of leukemia, lung cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, intestinal cancer or cancer cells.
Present invention also offers a kind of combination medicine, comprise Xarelto half tosylate monohydrate or its polymorphic and one or more other drugs, one or more other drugs wherein said are cell toxicity medicament, signal transduction inhibitor, anticarcinogen or antiemetic.
The crystal stability of Xarelto half tosylate monohydrate polymorphic S of the present invention is good, purity is high, degree of crystallinity is high, the not easily feature such as moisture absorption, is suitable for producing, has good patent medicine characteristic.
Accompanying drawing explanation
Fig. 1 is the PXRD collection of illustrative plates of Xarelto half tosylate monohydrate polymorphic S of the present invention.
Fig. 2 is the TG-DSC collection of illustrative plates of Xarelto half tosylate monohydrate polymorphic S of the present invention.
Fig. 3 is Xarelto half tosylate monohydrate polymorphic S's of the present invention
1h-NMR collection of illustrative plates.
Fig. 4 is Xarelto half tosylate monohydrate polymorphic S's of the present invention
13c-NMR collection of illustrative plates.
Fig. 5 is influence factor 10 days (placing 10 days for 92.5%, 25 DEG C) PXRD collection of illustrative plates of Xarelto half tosylate monohydrate polymorphic S of the present invention.
Fig. 6 is influence factor 10 days TG-DSC collection of illustrative plates of Xarelto half tosylate monohydrate polymorphic S of the present invention.
Fig. 7 is the solubility curve of Xarelto half tosylate monohydrate polymorphic S and I of the present invention in medium 0.1N hydrochloric acid+0.15% tween 80.
Fig. 8 is the solubility curve of Xarelto half tosylate monohydrate polymorphic S and I of the present invention in medium pH4.5 phosphate buffered saline buffer+1% tween 80.
Fig. 9 is the solubility curve of Xarelto half tosylate monohydrate polymorphic S and I of the present invention in medium pH6.8 phosphate buffered saline buffer+1% tween 80.
Figure 10 is that Xarelto half tosylate monohydrate polymorphic S and S of the present invention be not containing the solubility curve of crystal water in medium 0.1N hydrochloric acid+0.3% tween 80.
Figure 11 is that Xarelto half tosylate monohydrate polymorphic S and S of the present invention be not containing the solubility curve of crystal water in pH4.5 phosphate buffered saline buffer+1.5% tween 80.
Figure 12 is that Xarelto half tosylate monohydrate polymorphic S and S of the present invention be not containing the solubility curve of crystal water in pH6.8 phosphate buffered saline buffer+1.5% tween 80.
Specific embodiments
Explain further below by example and the present invention is described, but not limiting the present invention in any form.Any type of equivalent substituting all falls into protection scope of the present invention.
characterizing method
The testing tool of X-ray powder diffraction (PXRD) collection of illustrative plates is BrukerD8ADVANCE type X-ray diffractometer, test condition is Cu target, K α line, 40kV, 40mA, step-length is 0.02 °, and sweep velocity is 8 °/min, and sweep limit is 3 ° ~ 45 °.
The testing tool of thermogravimetric (TG-DSC) collection of illustrative plates is synchronous solving, numbering: Q20SB-432, content measurement: DSC and TGA, and test condition is intensification from room temperature 25 DEG C, speed 5 DEG C/min, Range of measuring temp 25 DEG C ~ 250 DEG C.
1h-NMR,
13the determining instrument of C-NMR collection of illustrative plates is Bruker400MHZAdvance nuclear magnetic resonance analyser.
The preparation of embodiment 1 Xarelto half tosylate monohydrate polymorphic S
In 250ml there-necked flask, by 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) is amino] phenoxy group }-N-picoline-2-methane amide (5g, 135.8mmol) be suspended in ethanol (15ml), stir, tosic acid monohydrate (2.5g) is dissolved in 7.5ml ethanol, in temperature control 10 ~ 15 DEG C of instillation reaction flasks.Stirring reaction 30min, is heated to 80 DEG C by this suspension.Drip 8ml purified water.Treat complete molten Temperature fall crystallization 4 ~ 5h, leach product.Solid washing with alcohol twice (each 10ml), 50 DEG C of drying under reduced pressure, obtain 5.14g finished product, are pale yellow crystals.
structural characterization
PXRD, the TG-DSC of the product of testing example 1,
1h-NMR and
13c-NMR collection of illustrative plates, is shown in Fig. 1, Fig. 2, Fig. 3 and Fig. 4 respectively.Its TG-DSC shows, Xarelto half tosylate monohydrate polymorphic S has endotherm(ic)peak temperature 133.8 ~ 146.2 DEG C, peak value is 146.2 DEG C, and (TGA collection of illustrative plates) has obvious weightless step at 102 ~ 143.4 DEG C, weightlessness 3.05%, illustrates that polymorphic S is 1 molecular water compound herein.
Table 1X-ray powder diffraction result
The preparation of embodiment 2 Xarelto half tosylate monohydrate polymorphic S
In 250ml there-necked flask, by 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) is amino] phenoxy group }-N-picoline-2-methane amide (5g, 135.8mmol) be suspended in ethanol (15ml), stir, tosic acid monohydrate (2.5g) is dissolved in 7.5ml ethanol, in temperature control 5 ~ 10 DEG C of instillation reaction flasks.Stirring reaction 30min, is heated to 80 DEG C by this suspension.Drip 8ml purified water.Treat complete molten Temperature fall crystallization 4 ~ 5h, leach product.Solid washing with alcohol twice (each 10ml), 50 DEG C of drying under reduced pressure, obtain 4.21g finished product, are pale yellow crystals.
It has the DSC collection of illustrative plates shown in PXRD, the Fig. 2 shown in Fig. 1.
The preparation of embodiment 3 Xarelto half tosylate monohydrate polymorphic S
In 250ml there-necked flask, by 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) is amino] phenoxy group }-N-picoline-2-methane amide (5g, 135.8mmol) be suspended in ethanol (15ml), stir, tosic acid monohydrate (2.5g) is dissolved in 7.5ml ethanol, in temperature control 20 ~ 30 DEG C of instillation reaction flasks.Stirring reaction 30min, is heated to 80 DEG C by this suspension.Drip 8ml purified water.Treat complete molten Temperature fall crystallization 4 ~ 5h, leach product.Solid washing with alcohol twice (each 10ml), 50 DEG C of drying under reduced pressure, obtain 5.34g finished product, are pale yellow crystals.
It has the DSC collection of illustrative plates shown in PXRD, the Fig. 2 shown in Fig. 1.
The preparation of embodiment 4 Xarelto half tosylate monohydrate polymorphic S
In 250ml there-necked flask, by 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) is amino] phenoxy group }-N-picoline-2-methane amide (5g, 135.8mmol) be suspended in ethanol (15ml), stir, tosic acid monohydrate (2.5g) is dissolved in 7.5ml ethanol, in temperature control 60 ~ 74 DEG C of instillation reaction flasks.Stirring reaction 30min, is heated to 80 DEG C by this suspension.Drip 8ml purified water.Treat complete molten Temperature fall crystallization 4 ~ 5h, leach product.Solid washing with alcohol twice (each 10ml), 50 DEG C of drying under reduced pressure, obtain 5.21g finished product, are pale yellow crystals.
It has the DSC collection of illustrative plates shown in PXRD, the Fig. 2 shown in Fig. 1.
The preparation of embodiment 5 half tosylate monohydrate polymorphic S
Sorafenib Tosylate polymorphic I is prepared according to the method for CN101065360A (patent families of WO2006/034797A).
By 6.3g4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] amino } carbonyl) is amino] phenoxy group }-N-picoline-2-methane amide is suspended in ethanol and stirs, add 0.91g tosic acid monohydrate, under stirring, reaction solution is warming up to 74 DEG C, by other a part of 2.2g tosic acid monohydrate with after having dissolve with ethanol, be added dropwise in above-mentioned solution, after dropwising, temperature control reacts 2 hours, preferably 2 hours.Be cooled to 3 ± 2 DEG C at 2 hours, then temperature control continue stirring 1 hour, suction filtration, forced air drying obtains 8.08g Sorafenib Tosylate polymorphic I.
5g Sorafenib Tosylate polymorphic I is suspended in 25ml ethanol, 80 DEG C are heated under stirring, again 8g purified water is slowly added dropwise in above-mentioned suspension, treat entirely molten, stir lower Temperature fall crystallization 5 hours, separate out a large amount of solid, suction filtration obtains faint yellow solid, 50 DEG C of forced air dryings 2 hours, obtain 4.19g product.
It has the DSC collection of illustrative plates shown in PXRD, the Fig. 2 shown in Fig. 1.
The preparation of embodiment 6 Xarelto half tosylate monohydrate crystal form S
5g Sorafenib Tosylate polymorphic I is suspended in 25ml methyl alcohol, 80 DEG C are heated under stirring, again 8g purified water is slowly added dropwise in above-mentioned suspension, treat entirely molten, stir lower Temperature fall crystallization 5 hours, separate out a large amount of solid, suction filtration obtains faint yellow solid, 50 DEG C of forced air dryings 2 hours, obtain 4.03g product.
It has the DSC collection of illustrative plates shown in PXRD, the Fig. 2 shown in Fig. 1.
simultaneous test
According to the method Xarelto half tosylate anhydrate (polymorphic A) of WO2009/092070A embodiment 9.
In 100ml there-necked flask, by 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) is amino] phenoxy group }-N-picoline-2-methane amide (450mg), dissolve with Virahol (20mL) at 40 DEG C, be cooled to room temperature (25 DEG C), drip tosic acid monohydrate (225mg) water (0.6mL) solution, after reacting completely, gained solution is cooled to 0.5 DEG C, place 2 days, filter, washed with isopropyl alcohol, dry, to obtain final product.
1, stability experiment
Get above-mentioned Sorafenib Tosylate polymorphic I, Xarelto half tosylate monohydrate (polymorphic S) is appropriate, it is placed 10 days respectively at temperature is 60 DEG C, relative humidity be 92.5%, temperature be 25 DEG C at place 10 days, or under illumination (4500lx ± 500lx) place 10 days.
Being taken at relative humidity is that 92.5%, 25 DEG C of samples placed 10 days carry out XRD, TG-DCS analysis, sees Fig. 5 and Fig. 6.Separately being taken at temperature is place the sample of 10 days at 60 DEG C and under illumination (4500lx ± 500lx), place the sample of 10 days, and detect, it all has XRD figure spectrum, the TG-DCS shown in Fig. 6 shown in Fig. 5.
Get the sample after above-mentioned process, carry out HPLC test with reference to the method described in Chinese Pharmacopoeia 2015 editions four governing principles 9001.
The liquid-phase condition that HPLC analyzes: detecting instrument is ThermoU3000 high performance liquid chromatograph, chromatographic column is WatersXbridgeC18 (250*4.6mm, 5um), column temperature is 30 DEG C, and determined wavelength is 235nm, and flow velocity is 1ml/min, sample size is 5ul, moving phase is pH2.4 phosphate buffer soln is mobile phase A, and acetonitrile-ethanol (60:40) is Mobile phase B, carries out table 2 gradient elution.Stability test the results are shown in Table 3.
Table 2HPLC condition determination
Table 3 stability test result
Result shows: the polymorphic S that the method for the invention obtains has good thermostability, high humidity stability and light durability.
2, water absorbability experiment
Measure with reference to the method described in Chinese Pharmacopoeia 2015 editions four governing principles 9001, the water absorbability of test products under the condition of relative humidity 92.5%, result is as shown in table 4 below.
Water absorbability when table 4 relative humidity is 92.5%
Result shows: the polymorphic S that the method for the invention obtains does not have obvious water absorbability.
3, equilibrium solubility test
In pH1 (0.1M hydrochloric acid)+0.15% tween 80, pH4.5 (McIlvaine damping fluid)+1% tween 80 and pH6.8 (McIlvaine damping fluid)+1% tween 80 medium, add excessive Sorafenib Tosylate polymorphic I, Xarelto half tosylate monohydrate (polymorphic S) is made into saturated solution in stripping rotor, in 10,20,30,45,60,90,120 minutes point samplings, filter, measure.The results are shown in Figure 7, Fig. 8 and Fig. 9.
In pH1 (0.1M hydrochloric acid)+0.3% tween 80, pH4.5 (McIlvaine damping fluid)+1.5% tween 80 and pH6.8 (McIlvaine damping fluid)+1.5% tween 80 medium, add excessive Xarelto half tosylate anhydrate (polymorphic A), Xarelto half tosylate monohydrate (polymorphic S) is made into saturated solution in stripping rotor, in 10,20,30,45,60,90,120 minutes point samplings, filter, measure.The results are shown in Figure 10, Figure 11 and Figure 12.
Claims (12)
1. there is the compound of structural formula (III),
2. the crystallized form of the compound of a structural formula (III), it is characterized in that, its X-ray powder diffraction is that 13.6 ± 0.2 °, 17.4 ± 0.2 °, 20.6 ± 0.2 °, 23.9 ± 0.2 °, 27.3 ± 0.2 ° places have characteristic peak at diffraction angle 2 θ.
3. crystallized form according to claim 2, it is characterized in that, its X-ray powder diffraction is that 13.6 ± 0.2 °, 14.1 ± 0.2 °, 17.4 ± 0.2 °, 20.6 ± 0.2 °, 21.6 ± 0.2 °, 23.9 ± 0.2 °, 27.3 ± 0.2 ° places have characteristic peak at diffraction angle 2 θ.
4. crystallized form according to claim 2, is characterized in that, its X-ray powder diffraction as shown in Figure 1.
5. crystallized form according to claim 2, is characterized in that, its DSC collection of illustrative plates is that 133.8 ~ 146.2 DEG C of places have endotherm(ic)peak in temperature.
6. crystallized form according to claim 2, is characterized in that, its DSC collection of illustrative plates as shown in Figure 2.
7. prepare the method for crystallized form according to claim 2 for one kind, it is characterized in that, comprise the steps: Xarelto to suspend in ethanol, stir, drip the ethanolic soln of tosic acid monohydrate, stir, be heated to and be warming up to 25 ~ 100 DEG C, preferred 75-80 DEG C, drip water, cooling crystallization, to obtain final product.
8. preparation method according to claim 7, is characterized in that, it is 0 ~ 80 DEG C that the temperature that the ethanolic soln of described tosic acid monohydrate drips controls, preferably 10 ~ 60, and more preferably 20 ~ 30 DEG C.
9. prepare the method for crystallized form according to claim 2 for one kind, it is characterized in that, comprise the steps: Sorafenib Tosylate I crystal to be suspended in ethanol or ethanol, stir, be warming up to 25 ~ 100 DEG C, preferred 75-80 DEG C, more preferably 80 DEG C, temperature control drips water, Quan Rong, cooling crystallization, to obtain final product.
10. a pharmaceutical composition, is characterized in that, the compound of the claim 1 containing dose therapeutically effective or the crystallized form of claim 2, and pharmaceutically acceptable auxiliary material.
The compound of 11. claims 1 or the application of the crystallized form of claim 2 in the medicine preparing the generation for the treatment of abnormal vascular or hyperpermeability processes associated conditions or cancer, wherein, described cancer is selected from the growth of leukemia, lung cancer, carcinoma of the pancreas, thyroid carcinoma, kidney, intestinal cancer or cancer cells.
12. 1 kinds of combination medicines, comprise crystallized form and one or more other drugs of the compound of the claim 1 of claim 1 or claim 2, one or more other drugs wherein said are cell toxicity medicament, signal transduction inhibitor, anticarcinogen or antiemetic.
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| CN106226421A (en) * | 2016-07-14 | 2016-12-14 | 合肥华方医药科技有限公司 | A kind of Sorafenib Tosylate has the detection method of related substance |
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| WO2017101548A1 (en) * | 2015-12-14 | 2017-06-22 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof |
| CN108368052A (en) * | 2015-12-14 | 2018-08-03 | 正大天晴药业集团股份有限公司 | Half Sorafenib Tosylate hydrate crystallization and preparation method thereof |
| CN106226421A (en) * | 2016-07-14 | 2016-12-14 | 合肥华方医药科技有限公司 | A kind of Sorafenib Tosylate has the detection method of related substance |
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