10/22/2020
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`CN104592184A - Scutellarin aglycone crystal forms and preparation method thereof - Google Patents
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`Scutellarin aglycone crystal forms and preparation method thereof
`
`Abstract
`
`Belonging to the eld of pharmaceutical chemical engineering, the invention in particular relates to a
`variety of scutellarin aglycone crystal forms and a preparation method thereof. The invention also
`relates to application of the scutellarin aglycone crystal forms in preparation of drugs preventing
`and/or treating cardiovascular and cerebrovascular diseases, rheumatism arthritis, stroke sequelae
`and the like. The scutellarin aglycone crystal forms provided by the invention have good stability, and
`can overcome the poor oral absorption and low bioavailability problems of scutellarin.
`
`Classications
`
`CN104592184A
`China
`
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` Find Prior Art
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`Other languages: Chinese
`
`Inventor: 王泽人, 徐俊, 王明辉, 朱兆云, 王京昆, 梅双喜, 孙文强, 崔
`涛
`
` A61K31/352 Heterocyclic compounds having oxygen as the only ring hetero atom, e.g.
`fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed
`with carbocyclic rings, e.g. cannabinols, methantheline
`
`Worldwide applications
`
`2014 CN CN 2015 US WO
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`View 12 more classications
`
`Application CN201410764911.1A events
`
`2014-12-15
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`Application led by 云南省药物研究所, 深圳市华
`力康生物医药有限公司
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`2014-12-15
`
`Priority to CN201410764911.1A
`
`2015-05-06
`
`Publication of CN104592184A
`
`2017-09-29
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`Application granted
`
`2017-09-29
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`Publication of CN104592184B
`
`Info: Patent citations (9), Non-patent citations (2), Cited by (6),
`Legal events, Similar documents, Priority and Related
`Applications
`
`External links: Espacenet, Global Dossier, Discuss
`
`Claims (45)
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`Hide Dependent
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`1. Scutellarein crystal form A, it is characterized in that described crystal form A is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, at
`least there is the principal character absorption peak being about following position: 14.5 ± 0.2 °, 16.9 ± 0.2 °, 22.0 ± 0.2 °, 26.7 ± 0.2 ° and 27.4 ± 0.2 °.
`
`2. the crystal form A of claim 1, it is characterized in that in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, what also have in the
`charateristic avsorption band being selected from and being about following position is one or more: 11.2 ± 0.2 °, 13.8 ± 0.2 °, 20.4 ± 0.2 °, 24.8 ± 0.2 °, 28.7 ± 0.2 ° and
`30.4 ± 0.2 ° etc.
`
`3. the crystal form A of claim 1 or 2, it utilizes the fusing point of determine with dsc method to be about 366.1 ± 3.0 DEG C.
`
`4. the crystal form A of any one of claim 1-3, its purity >=90%, preferably >=95%.
`
`5. the preparation method of the crystal form A of any one of claim 1-4, it comprises the following steps:
`
`(1) get lamp-dish ower acetic and add the organic solvent (such as propylene glycol or ethylene glycol) miscible with water that reux temperature is 120 DEG C to 220
`DEG C (such as 180 DEG C), reux, makes lamp-dish ower acetic all dissolve;
`
`(2) in solution, slowly acid solution is dripped; Continue backow 6-16 hour;
`
`(3) solution cooling, separate out precipitation, lter, lter cake is respectively with the reux solvent (such as propylene glycol or ethylene glycol) described in step (1),
`water washing, and optional drying, pulverizing step, obtain Scutellarein crystal form A;
`
`(4) optionally, also crystal form A can be obtained from scutellarin solid (comprising crystal form A, unformed or other crystal formation) by one or more in the stirring
`that suspends, slow cooling, anti-solvent interpolation, oppositely anti-solvent interpolation, liquid-solid gas-phase permeation, ionic liquid induced crystallization,
`humidity induction and wet grinding.
`
`6. Scutellarein crystal formation D, it is characterized in that described crystal formation D is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ
`angles, at least there is the principal character absorption peak being about following position: 14.1 ± 0.2 °, 15.8 ± 0.2 °, 24.1 ± 0.2 °, 26.1 ± 0.2 °, 28.0 ± 0.2 °.
`
`7. the crystal formation D of claim 6, it is characterized in that in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, what also have
`in the charateristic avsorption band being selected from and being about following position is one or more: 10.0 ± 0.2 °, 11.2 ± 0.2 °, 18.0 ± 0.2 °, 24.6 ± 0.2 °, 25.6 ± 0.2 °,
`29.5 ± 0.2 ° and 29.8 ± 0.2 °.
`
`8. the crystal formation D of claim 6 or 7, it utilizes the fusing point of determine with dsc method to be about 363.2 ± 3.0 DEG C.
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`EISAI EXHIBIT 1029
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`10/22/2020
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`CN104592184A - Scutellarin aglycone crystal forms and preparation method thereof - Google Patents
`9. the crystal formation D of any one of claim 6-8, its purity >=90%, preferably >=95%.
`
`10. the preparation method of the crystal formation D of any one of claim 6-9, it is selected from the one in following seven kinds of methods:
`
`(1) Scutellarein solid (such as crystal form A) is got, add pyridine-acetone (volume ratio is as being 3:1) or pyridine-heptane (volume ratio is as being 3:1) mixed solvent,
`sample is dissolved completely and obtains settled solution, slowly volatilize at ambient temperature, the solid obtained after volatilizing solvent is Scutellarein crystal
`formation D;
`
`(2) get Scutellarein solid (such as crystal form A), add pyridine, solid is dissolved completely, then slowly adds ethanol, the solid obtained after the precipitation of
`precipitation or at ambient temperature volatilization is Scutellarein crystal formation D; Or using dimethyl formamide as solvent, tetrahydrofuran (THF) also can obtain
`similar results as anti-solvent.
`
`(3) Scutellarein solid (such as crystal form A) is got, add N-Methyl pyrrolidone, solid is dissolved completely, is then slowly added in acetonitrile by this settled solution,
`the solid obtained after the precipitation of precipitation or at ambient temperature volatilization is Scutellarein crystal formation D; Using pyridine as solvent, ethanol as
`anti-solvent or using dimethyl formamide as solvent, tetrahydrofuran (THF) also can obtain similar results as anti-solvent.
`
`(4) Scutellarein solid (such as crystal form A) is got, add DMF/MEK (volume ratio is as being 1:1) mixed solvent, obtain settled solution, add mixed polymer in settled
`solution, gained solution slowly volatilizees at ambient temperature, namely obtains Scutellarein crystal formation D.
`
`(5) get Scutellarein solid (such as crystal form A), being dissolved in pyridine/ethyl acetate (volume ratio is as being 3:1), in the uncovered volatilization of room
`temperature, namely obtaining Scutellarein crystal formation D.
`
`(6) Scutellarein solid (such as crystal form A) is got, add acetone or acetonitrile obtains suspension, stir 4-8 days (such as 6 days) under room temperature (RT) and 40-
`60 DEG C of (such as 50 DEG C) condition, centrifugation solid obtains the mixture of crystal formation D and crystal form A.
`
`(7) Scutellarein solid (such as crystal form A) is got, add dimethyl formamide, solid is dissolved completely, then slowly adds water, the solid obtained after the
`precipitation of precipitation or at room temperature volatilization is the mixture of crystal formation D and crystal form A.
`
`11. Scutellarein crystal formation E, is characterized in that described crystal formation E is in use Cu-K α radiation,
`
`In the X-ray powder diffraction pattern represented with 2 θ angles, at least there is the principal character absorption peak being about following position: 9.6 ± 0.2 °, 14.0 ± 0.2
`°, 15.3 ± 0.2 °, 17.8 ± 0.2 ° and 26.6 ± 0.2 °.
`
`The crystal formation E of 12. claims 11, it is characterized in that in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, what also
`have in the charateristic avsorption band being selected from and being about following position is one or more: 10.2 ± 0.2 °, 10.9 ± 0.2 °, 16.1 ± 0.2 °, 19.3 ± 0.2 °, 21.2 ±
`0.2 °, 28.5 ± 0.2 °, 29.8 ± 0.2 ° and 31.1 ± 0.2 ° etc.
`
`The crystal formation E of 13. claims 11 or 12, it utilizes the fusing point of determine with dsc method to be about 364.0 ± 3.0 DEG C.
`
`The preparation method of the crystal formation E of 14. any one of claim 11-13, it comprises the following steps:
`
`Get Scutellarein solid (such as crystal form A) to be heated to 250-350 DEG C (such as 300 DEG C), after being then naturally down to room temperature, namely obtain
`Scutellarein crystal formation E.
`
`15. Scutellarein ammonium salt crystal formations, it is characterized in that described ammonium salt crystal formation is in use Cu-K α radiation, in the X-ray powder
`diffraction pattern represented with 2 θ angles, at least there is the principal character absorption peak being about following position: 9.0 ± 0.2 °, 10.5 ± 0.2 °, 14.9 ± 0.2 °, 23.6 ±
`0.2 ° and 26.6 ° ± 0.2 °.
`
`The ammonium salt crystal formation of 16. claims 15, it is characterized in that in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ
`angles, what also have in the charateristic avsorption band being selected from and being about following position is one or more: 6.4 ± 0.2 °, 12.8 ± 0.2 °, 13.8 ± 0.2 °,
`14.9 ± 0.2 °, 15.3 ± 0.2 °, 22.7 ± 0.2 °, 25.7 ± 0.2 °, 27.7 ± 0.2 °, 29.1 ± 0.2 ° and 32.0 ± 0.2 ° etc.
`
`The ammonium salt crystal formation of 17. claims 15 or 16, it is hydrate.
`
`The preparation method of the ammonium salt crystal formation of 18. any one of claim 15-17, it is method (1) or (2):
`
`(1) Scutellarein solid (such as crystal form A) is got, add the ammoniacal liquor of certain volume, stir at ambient temperature, add ammoniacal liquor to original volume
`when ammoniacal liquor volume reduces to continue to stir, after 13-17 days (such as 15 days), namely obtain Scutellarein ammonium salt crystal formation;
`
`(2) Scutellarein solid (such as crystal form A) is got, add ammoniacal liquor, and add acetone and obtain suspension, stir 4-8 days (such as 6 days) at ambient
`temperature, centrifugation solid obtains the mixture of Scutellarein ammonium salt crystal formation and Scutellarein crystal form A.
`
`19. Scutellarein crystal form Bs, it is characterized in that described crystal form B is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles,
`at least there is the principal character absorption peak being about following position: 7.2 ± 0.2 °, 9.9 ± 0.2 °, 14.6 ± 0.2 °, 15.7 ± 0.2 ° and 26.2 ± 0.2 °.
`
`The crystal form B of 20. claims 19, it is characterized in that in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, what also have in
`the charateristic avsorption band being selected from and being about following position is one or more: 11.2 ± 0.2 °, 14.1 ± 0.2 °, 18.9 ± 0.2 °, 20.8 ± 0.2 °, 25.0 ± 0.2 °
`and 28.0 ± 0.2 ° etc.
`
`The crystal form B of 21. claims 19 or 20, it utilizes the fusing point of determine with dsc method to be about 361.6 ± 3.0 DEG C.
`
`The preparation method of the crystal form B of 22. any one of claim 19-21, it is method (1) or (2) or (3):
`
`(1) Scutellarein solid (such as crystal form A) is got, add in pyridine-water (volume ratio is as being 3:1) mixed solvent, sample is dissolved completely and obtains settled
`solution, gained solution slowly volatilizees at ambient temperature, namely obtains Scutellarein crystal form B after volatilizing solvent;
`
`(2) Scutellarein solid (such as crystal form A) is got, add in pyridine-acetonitrile (volume ratio is as being 3:1) mixed solvent, sample is dissolved completely and obtains
`settled solution, gained solution slowly volatilizees at ambient temperature, namely obtains Scutellarein crystal form B after volatilizing solvent.
`
`(3) Scutellarein solid (such as crystal form A) is got, add in pyridine-heptane (volume ratio is as being 3:1) mixed solvent, sample is dissolved completely and obtains
`settled solution, gained solution slowly volatilizees at ambient temperature, namely obtains Scutellarein crystal form B after volatilizing solvent.
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`23. Scutellarein crystal Cs, it is characterized in that described crystal C is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, at least
`there is the principal character absorption peak being about following position: 7.2 ± 0.2 °, 14.6 ± 0.2 °, 19.5 ± 0.2 °, 20.7 ± 0.2 ° and 25.0 ± 0.2 °.
`
`The crystal C of 24. claims 23, it is characterized in that in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, what also have in the
`charateristic avsorption band being selected from and being about following position is one or more: 9.2 ± 0.2 °, 16.4 ± 0.2 °, 16.9 ± 0.2 °, 17.7 ± 0.2 °, 18.2 ± 0.2 °, 18.9 ±
`0.2 °, 21.5 ± 0.2 °, 22.0 ± 0.2 °, 22.8 ± 0.2 °, 25.7 ± 0.2 °, 27.0 ± 0.2 °, 27.7 ± 0.2 °, 28.7 ± 0.2 °, 29.3 ± 0.2 ° and 32.4 ± 0.2 ° etc.
`
`The crystal C of 25. claims 23 or 24, it utilizes the fusing point of determine with dsc method to be about 363.2 ± 3.0 DEG C.
`
`The preparation method of the crystal C of 26. any one of claim 23-25, it is method (1) or (2):
`
`(1) get Scutellarein solid (such as crystal form A), add pyridine, solid is dissolved completely, then slowly adds heptane, the solid obtained after the precipitation of
`precipitation or at room temperature volatilization is Scutellarein crystal C;
`
`(2) get Scutellarein solid (such as crystal form A), add pyridine, solid is dissolved completely, then slowly join in heptane, the solid obtained after the precipitation of
`precipitation or at room temperature volatilization is Scutellarein crystal C.
`
`27. Scutellarein crystal formation F, it is characterized in that described crystal formation F is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ
`angles, at least there is the charateristic avsorption band being about following position: 18.1 ± 0.2 °, 31.7 ± 0.2 ° and 37.3 ± 0.2 °.
`
`The crystal formation F of 28. claims 27, it utilizes the fusing point of determine with dsc method to be about 328.4 ± 3.0 DEG C.
`
`The preparation method of the crystal formation F of 29. claims 27 or 28, it comprises the following steps:
`
`Get Scutellarein solid (such as crystal form A), add normal hexane or toluene obtains suspension, stir 4-8 days (such as 6 days) under room temperature (RT) and 40-60
`DEG C of (such as 50 DEG C) condition, centrifugation solid obtains the mixture of crystal formation F and crystal form A.
`
`30. Scutellarein crystal formation G, it is characterized in that described crystal formation G is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ
`angles, at least there is the principal character absorption peak being about following position: 8.3 ± 0.2 °, 14.3 ± 0.2 °, 18.2 ± 0.2 °, 20.7 ± 0.2 ° and 23.6 ± 0.2 °.
`
`The crystal formation G of 31. claims 23, it is characterized in that in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, what also
`have in the charateristic avsorption band being selected from and being about following position is one or more: 7.2 ± 0.2 °, 10.9 ± 0.2 °, 15.8 ± 0.2 °, 16.7 ± 0.2 °, 22.4 ±
`0.2 °, 24.8 ± 0.2 °, 25.7 ± 0.2 ° and 27.7 ± 0.2 ° etc.
`
`The crystal formation G of 32. claims 30 or 31, it utilizes the fusing point of determine with dsc method to be about 358.8 ± 3.0 DEG C.
`
`The preparation method of the crystal formation G of 33. any one of claim 30-32, it is method (1) or (2):
`
`(1) Scutellarein solid (such as crystal form A) is got, add pyridine/heptane mixed solvent, obtain settled solution, add mixed polymer in settled solution, gained solution
`slowly volatilizees at ambient temperature, obtains Scutellarein crystal formation G.
`
`(2) Scutellarein solid (such as crystal form A) is got, add pyridine or pyridine/methyl alcohol or pyridine/1,4-dioxane or pyridine/methyl tertiary butyl ether or pyridine/2-
`methyltetrahydrofuran or pyridine/toluene (volume ratio is as being 3:1) mixed solvent, sample is dissolved completely and obtains settled solution, slowly volatilize at
`ambient temperature, the solid obtained after volatilizing solvent is Scutellarein crystal formation G.
`
`34. Scutellarein crystal formation H, it is characterized in that described crystal formation H is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2
`θ angles, at least there is the principal character absorption peak being about following position: 7.4 ± 0.2 °, 14.8 ± 0.2 °, 19.1 ± 0.2 °, 21.0 ± 0.2 ° and 25.0 ± 0.2 °.
`
`The crystal formation H of 35. claims 34, it is characterized in that in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, what also
`have in the charateristic avsorption band being selected from and being about following position is one or more: 10.1 ± 0.2 °, 10.9 ± 0.2 °, 11.5 ± 0.2 °, 16.2 ± 0.2 °, 19.8 ±
`0.2 °, 22.2 ± 0.2 °, 23.2 ± 0.2 °, 27.7 ± 0.2 ° and 29.0 ± 0.2 ° etc.
`
`The crystal formation H of 36. claims 34 or 35, it utilizes the fusing point of determine with dsc method to be about 364.4 ± 3.0 DEG C.
`
`The preparation method of the crystal formation H of 37. any one of claim 34-36, it comprises the following steps:
`
`Get Scutellarein solid (such as crystal form A), be dissolved in pyridine/ethyl acetate mixed solvent, room temperature is volatilized, and obtains crystal formation D; Be
`dissolved in pyridine/ethyl acetate by the crystal formation D obtained, room temperature is volatilized, and obtains crystal formation H.
`
`38. Scutellarein crystal formation I, it is characterized in that described crystal formation I is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ
`angles, at least there is the principal character absorption peak being about following position: 6.9 ± 0.2 °, 15.6 ± 0.2 °, 19.9 ± 0.2 °, 22.3 ± 0.2 ° and 26.8 ± 0.2 °.
`
`The crystal formation I of 39. claims 38, it is characterized in that described crystal formation I is in use Cu-K α radiation, in the X-ray powder diffraction pattern
`represented with 2 θ angles, what also have in the charateristic avsorption band being selected from and being about following position is one or more: 21.0 ± 0.2 °, 25.8
`± 0.2 ° and 26.3 ± 0.2 ° etc.
`
`The crystal formation I of 40. claims 38 or 39, it utilizes the fusing point of determine with dsc method to be about 362.1 ± 3.0 DEG C.
`
`The preparation method of the crystal formation I of 41. any one of claim 38-40, it comprises the following steps:
`
`Get Scutellarein solid (such as crystal form A), be dissolved in pyridine/ethyl acetate mixed solvent, room temperature is volatilized, and obtains crystal formation I.
`
`The crystal formation E of the crystal form A of 42. any one of claim 1-4, the crystal formation D of any one of claim 6-9, any one of claim 11-13, the crystal formation F of
`claim 27 or 28, it is anhydride.
`
`The crystal formation G of the crystal form B of 43. any one of claim 19-21, the crystal C of any one of claim 23-25, any one of claim 30-32, the crystal formation H of any
`one of claim 34-36, the crystal formation I of any one of claim 38-40, it is solvate, such as, be pyrroles's compound.
`
`44. pharmaceutical compositions, it contains the crystal form A being selected from any one of claim 1-4, the crystal formation D of any one of claim 6-9, the crystal
`formation E of any one of claim 11-13, the ammonium salt hydrate crystal forms of any one of claim 15-17, the crystal form B of any one of claim 19-21, the crystal C of
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`CN104592184A - Scutellarin aglycone crystal forms and preparation method thereof - Google Patents
`any one of claim 23-25, the crystal formation F of claim 27 or 28, the crystal formation G of any one of claim 30-32, at least one in the crystal formation H of any one of
`claim 34-36 or the crystal formation I of any one of claim 38-40, and pharmaceutically acceptable carrier or vehicle.
`
`The crystal form A of 45. any one of claim 1-4, the crystal formation D of any one of claim 6-9, the crystal formation E of any one of claim 11-13, the ammonium salt
`hydrate crystal forms of any one of claim 15-17, the crystal form B of any one of claim 19-21, the crystal C of any one of claim 23-25, the crystal formation F of claim 27
`or 28, the crystal formation G of any one of claim 30-32, the crystal formation H of any one of claim 34-36 or the crystal formation I of any one of claim 38-40 prevents
`and/or treats cardiovascular and cerebrovascular diseases in preparation and (loses paralysis after caused by the such as occlusive cerebrovascular, coronary heart
`disease, stenocardia), rheumatic arthritis, apoplexy sequela, nephrotic syndrome, diabetic nephropathy, the kidney diseases such as chronic glomerulonephritis, the liver
`injury of antitubercular agent physical property, acute icterohepatitisshock, chronic hepatitis, the hepatic diseases such as Refractory ascites resulted from
`hepatocirrhosis, acute exacerbation of chronic obstructive pulmonary disease merges hypoxemia, diabetic peripheral neuropathy, the chronic complicating diseases of
`diabetes such as diabetic foot, retina owmetry, ischemic optic neuropathy, the ophthalmic diseasess such as eye central serous retinopathy, purposes in the medicine of
`the disease such as sudden deafness or FGR.
`Description
`
`Scutellarein crystal formation and preparation method thereof
`
`Technical eld
`
`The invention belongs to eld of medicine and chemical technology, be specically related to multiple Scutellarein crystal formation and preparation method thereof.The
`invention still further relates to Scutellarein crystal formation and prepare the purposes prevented and/or treated in the medicine of cardiovascular and cerebrovascular
`diseases, rheumatic arthritis or apoplexy sequela etc.
`
`Background technology
`
`Scutellarin (also claiming scutellarin, English Scutellarin by name) has and improves brain circulation of blood, increases cerebral blood ow (CBF), reduces the effect
`such as blood viscosity and anti-platelet aggregation.Scutellarin clinical application is extensive, is mainly used in cardiovascular and cerebrovascular diseases, loses
`paralysis, coronary heart diseases and angina pectoris etc. after caused by the occlusive cerebrovascular.Scutellarin has signicant curative effect (Tang Yuping in
`treatment cardiovascular and cerebrovascular diseases, rheumatic arthritis and apoplexy sequela etc., Li Nianguang, the golden storehouse for grain, etc. of section.
`scutellarin aglycone derivative and preparation method thereof and its application [P]. Jiangsu: CN101891728A, 2010-11-24.).In addition, Breviscarpine also can be used
`for treating nephrotic syndrome clinically, diabetic nephropathy, the kidney diseases such as chronic glomerulonephritis, the liver injury of antitubercular agent physical
`property, acute icterohepatitisshock, chronic hepatitis, the hepatic diseases such as Refractory ascites resulted from hepatocirrhosis and acute exacerbation of chronic
`obstructive pulmonary disease merge hypoxemia, diabetic peripheral neuropathy, the chronic complicating diseases of diabetes such as diabetic foot, retina owmetry,
`ischemic optic neuropathy, the ophthalmic diseasess such as eye central serous retinopathy, and (the Sun Hua such as sudden deafness and FGR, Song Yi. the clinical
`expansive approach [J] of Breviscarpine. Asia-Pacic traditional medicine, 2013, 05:63-64.).
`
`Due to purifying process imperfection in the early time, the treatment adopting Breviscarpines to carry out clinical disease as bulk drug more.Breviscarpine administration
`Problems existing is, Breviscarpine is originally as scutellarin, scutellarin isomers-different scutellarin and other mixture thereof, and complicated component, exists
`some problems in quality control.And scutellarin is the principal constituent in Breviscarpine, be the result that technology advances, but scutellarin oral absorption is
`poor, Oral availability is not high.
`
`Scutellarein is the hydrolysate (Liu Jianming of scutellarin, Xiong Yuqing. the progress [J] of scutellarin and aglycon Pharmacokinetic Characteristics thereof. CHINA
`JOURNAL OF CHINESE MATERIA MEDICA, 2009,24:3165-3168.), have another name called scutellarin, English Scutellarein, CAS NO.529-53-3 by name, molecular formula
`is C 15h 10o 6, molecular weight is 286.2.
`
`Along with the development of puries and separates technology and detection technique, in conjunction with nding the research of scutellarin and aglycon at present,
`Scutellarein has higher perviousness compared with B prime at gi tract, and oral absorption is about 3 times of scutellarin.Che Qingming etc. study rat oral gavage and
`give equivalent Scutellarein and scutellarin, show that oral being easy to of Scutellarein absorbs, compared with scutellarin, internal metabolism is stablized, and its
`relative bioavailability is 301.8% (Che Qingming, Chen Ying, Pan Liyi, He Hong. the rat pharmacokinetics of breviscapine B aglycone different dosing dosage compares [J].
`Chinese Journal of New Drugs, 2006,18:1557-1561.).Che Qingming etc. also nd, the effective constituent scutellarin of Herba Erigerontis injection is converted mainly in
`vivo after Scutellarein oral administration, the situation of the distribution of its blood medicine and Herba Erigerontis injection is comparatively close to (Che Qingming,
`Pan Liyi, Chen Ying, He Hong. the pharmacokinetic studies [J] of breviscapine B aglycone. Chinese Pharmaceutical Journal, 2007,18:1418-1421.).In other words,
`Scutellarein has the pharmacologically active being almost equal to scutellarin.Lu etc. utilize cerebral tissue to carry out the dynamics research of scutellarin liposome,
`show scutellarin by hemato encephalic barrier at cerebral tissue distribution (Int J Pharm.2005Dec8 in conjunction with existing result of study; 306 (1-2): 99-
`106.Distribution of liposomal breviscapine in brain following intravenous injection in rats.Lv W1, Guo J, Li J, Huang L, Ping Q.).Aglycon oral administration, when dosage is
`200mg/kg, Scutellarein and scutellarin can be measured in rat plasma, and when dosage is 20mg/kg, scutellarin can only be measured, can't detect original shape
`medicine (Che Qingming, Chen Ying, Pan Liyi, He Hong. bile excretion research [J] of breviscapine B aglycone. CHINA JOURNAL OF CHINESE MATERIA MEDICA,
`2006,20:1710-1712.).Occupy Wen Zheng etc. and determine scutellarin Plasma Concentration and Clinical pharmacokinetics, experimenter's oral administration 360mg
`scutellarin, hematometry scutellarin concentration is got at 1,3,5,8 hour, only littlely measure 20ng/ml constantly 5, and in blood plasma and urine, record a large amount
`of aglycons, prompting scutellarin may be hydrolyzed to aglycon at colon and absorb and (occupy civilian political affairs, Chu Jihong, Tan Renxiang, the peaceful .UPLC-
`MS/MS of bear joins usage analysis lamp-dish ower acetic at GI metabolite [J]. Chinese Clinical pharmacology and therapeutics, 2006,03:292-295.).
`
`Because scutellarin oral absorption is poor, Oral availability is not high, and Scutellarein can be converted into scutellarin in vivo, and its oral absorption is better than
`scutellarin, if the crystal formation that Scutellarein has certain stability can be obtained, will more be conducive to drug development and suitability for industrialized
`production.
`
`Summary of the invention
`
`The present invention prepares the polymorphic of Scutellarein and the ammonium salt hydrate crystal forms of aglycon by the method such as crystallization of slowly
`volatilizing, the stirring that suspends, slow cooling, anti-solvent interpolation, oppositely anti-solvent interpolation, liquid-solid gas-phase permeation, liquid-liquid-vapor
`inltration, ionic liquid induced crystallization, polymkeric substance induced crystallization, humidity induction, wet grinding, heating induction, this completes the
`present invention.
`
`First aspect present invention relates to Scutellarein crystal form A, it is characterized in that described crystal form A is in use Cu-K α radiation, in the X-ray powder
`diffraction pattern represented with 2 θ angles, at least there is the principal character absorption peak being about following position: 14.5 ± 0.2 °, 16.9 ± 0.2 °, 22.0 ± 0.2
`°, 26.7 ± 0.2 ° and 27.4 ± 0.2 °.
`
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`CN104592184A - Scutellarin aglycone crystal forms and preparation method thereof - Google Patents
`10/22/2020
`In one embodiment of the invention, described crystal form A is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles, what also
`have in the charateristic avsorption band being selected from and being about following position is one or more: 11.2 ± 0.2 °, 13.8 ± 0.2 °, 20.4 ± 0.2 °, 24.8 ± 0.2 °, 28.7 ±
`0.2 ° and 30.4 ± 0.2 ° etc.
`
`In a specic embodiments of the present invention, described crystal form A is in use Cu-K α radiation, in the X-ray powder diffraction pattern represented with 2 θ angles,
`there is the charateristic avsorption band being about following position: 7.2 ± 0.2 °, 11.2 ± 0.2 °, 13.8 ± 0.2 °, 14.5 ± 0.2 °, 16.9 ± 0.2 °, 20.4 ± 0.2 °, 21.3 ± 0.2 °, 22.0 ± 0.2 °,
`23.0 ± 0.2 °, 24.4 ± 0.2 °, 24.8 ± 0.2 °, 26.7 ± 0.2 °, 27.4 ± 0.2 °, 28.7 ± 0.2 °, 30.4 ± 0.2 °, 31.1 ± 0.2 °, 32.3 ± 0.2 °, 33.1 ± 0.2 °, 33.8 ± 0.2 °, 34.8 ± 0.2 ° and 37.3 ± 0.2 °.
`
`In specic embodiment of the invention scheme, its typical X-ray powder diffraction pattern as shown in Figure 1.
`
`According to the crystal form A of any one of the present invention, it utilizes the fusing point of determine with dsc method (onset temperature) scope to be 366.1 ± 3.0
`DEG C.
`
`In specic embodiment of the invention scheme, it utilizes the fusing point of determine with dsc method to be about 366.1 DEG C.
`
`In specic embodiment of the invention scheme, its typical DSC gure as shown in Figure 2.
`
`According to the crystal form A of any one of the present invention, its purity >=90%, preferably >=95%.
`
`The invention still further relates to the preparation method of the crystal form A of any one of the present invention, it comprises the following steps:
`
`(1) get scutellarin and add the organic solvent (such as propylene glycol or ethylene glycol) miscible with water that reux temperature is 120 DEG C to 220 DEG C (such
`as 180 DEG C), reux, makes lamp-dish ower acetic all dissolve;
`
`(2) in solution, slowly drip acid (such as dilute hydrochloric acid or dilute sulphuric acid) solution; Continue backow 6-16 hour;
`
`(3) solution cooling, separate out precipitation, lter, lter cake is respectively with the reux solvent (such as propylene glycol or ethylene glycol) described in step (1),
`water washing, and optional drying, pulverizing step, obtain Scutellarein crystal form A;
`
`(4) optionally, also crystal form A can be obtained from scutellarin solid (comprising crystal form A, unformed or other crystal formation) by one or more in the stirring
`that suspends, slow cooling, anti-solvent interpolation, oppositely anti-solvent interpolation, liquid-solid gas-phase permeation, ionic liquid induced crystallization,
`humidity induction and wet grinding.
`
`In embodiments of the invention, the method in above-mentioned steps (4) is selected from one or more in following eight kinds of methods:
`
`(1) Scutellarein solid (such as crystal form A) is got, add water or ethanol or or acetic acid or acetonitrile or acetone or methyl iso-butyl ketone (MIBK) or tetrahydrofuran
`(THF) or Iso Butyl Acetate or methyl tertiary butyl ether or 1, 4-dioxane or normal hexane or toluene or glycol/water mixed solvent or propylene glycol/water mixed solvent
`or PEG400/ heptane mixed solvent or N-Methyl pyrrolidone/water mixed solvent or methyl-sulphoxide/water mixed solvent or dimethyl formamide/water mixed solvent
`obtain suspension, stir 4-8 days (such as 6 days) under room temperature (RT) or 40-60 DEG C of (such as 50 DEG C) condition, centrifugation solid obtains crystal form
`A,
`
`(2) Scutellarein solid (such as crystal form A) is got, add methyl-sulphoxide/alcohol mixed solvent or methyl-sulphoxide/tetrahydrofuran (THF) mixed solvent or N-Methyl
`pyrrolidone/methyl tertiary butyl ether mixed solvent or N-Methyl pyrrolidone/ethyl acetate mixed solvent or dimethyl formamide/acetone mixed solvent or or dimethyl
`formamide/acetonitrile mixed solvent, 40-60 DEG C (such as 50 DEG C) ba