CN112679428A - New crystal form of roxasistat and preparation method thereof - Google Patents
New crystal form of roxasistat and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000001757 thermogravimetry curve Methods 0.000 claims description 18
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 10
- 229960000672 rosuvastatin Drugs 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 9
- 230000004580 weight loss Effects 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 208000007502 anemia Diseases 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 229910002483 Cu Ka Inorganic materials 0.000 abstract description 4
- DOUMFZQKYFQNTF-WUTVXBCWSA-N (R)-rosmarinic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-WUTVXBCWSA-N 0.000 description 28
- ZZAFFYPNLYCDEP-HNNXBMFYSA-N Rosmarinsaeure Natural products OC(=O)[C@H](Cc1cccc(O)c1O)OC(=O)C=Cc2ccc(O)c(O)c2 ZZAFFYPNLYCDEP-HNNXBMFYSA-N 0.000 description 14
- DOUMFZQKYFQNTF-MRXNPFEDSA-N rosemarinic acid Natural products C([C@H](C(=O)O)OC(=O)C=CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-MRXNPFEDSA-N 0.000 description 14
- TVHVQJFBWRLYOD-UHFFFAOYSA-N rosmarinic acid Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=Cc2ccc(O)c(O)c2)C=O TVHVQJFBWRLYOD-UHFFFAOYSA-N 0.000 description 14
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- 238000004458 analytical method Methods 0.000 description 6
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- 239000012453 solvate Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 2
- 229960000245 rasagiline Drugs 0.000 description 2
- YOZBGTLTNGAVFU-UHFFFAOYSA-N roxadustat Chemical compound C1=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=C1OC1=CC=CC=C1 YOZBGTLTNGAVFU-UHFFFAOYSA-N 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- YHIRCCBZPIUJMZ-UHFFFAOYSA-N 1,2,2,3,3,3-hexafluoropropane-1,1-diol Chemical compound OC(O)(F)C(F)(F)C(F)(F)F YHIRCCBZPIUJMZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 125000002059 L-arginyl group Chemical class O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
- 125000001176 L-lysyl group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])C(N([H])[H])([H])[H] 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010058116 Nephrogenic anaemia Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
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- 238000002844 melting Methods 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229950008113 roxadustat Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel crystal form of roxasistat and a preparation method thereof. Specifically, the X-ray powder diffraction pattern of the new crystalline form II of the present invention, measured using Cu-ka, has characteristic diffraction peaks at the following 2 θ angles: 16.3 +/-0.2 degrees, 28.3 +/-0.2 degrees and 33.8 +/-0.2 degrees. The X-ray powder diffraction pattern of the new crystalline form III of the roxasistat of the invention measured by using Cu-Ka has characteristic diffraction peaks at the following 2theta angles: 5.0 +/-0.2 degrees, 24.9 +/-0.2 degrees and 27.4 +/-0.2 degrees. The crystal form of the invention has low water content, good solubility and high product stability.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of roxasistat and a preparation method thereof.
Background
Rasagiltat, having the english name Roxadustat and the trade name: kebomei, molecular formula: c19H16N2O5The molecular weight is: 352.11, CAS number: 808118-40-3, the structural formula is:
the drug is developed by FibroGen company, applies for the treatment of renal anemia at 11 months in 2017, is in phase III clinical use in the United states and Europe, and submits NDA application in the United states in the next half year in 2018.
The original crystal form patent WO2014014835 reports crystalline form a, crystalline form B, crystalline form C, crystalline form D, amorphous, sodium salt, L-arginine salt, L-lysine salt, ethanolamine salt, diethanolamine salt, tromethamine salt, potassium salt, hydrochloride, sulfate, methanesulfonate, bistetraethylamine salt, hemicalcium salt, and semispherical salt of roxasistat.
In this patent specification, it is described that form a is an anhydrate, and this form, although having good stability, has a problem of poor solubility. The patent specification describes that form B is a hemihydrate, which is poorly stable and completely converts to form a after storage for 1 month at 25 ℃. Form C is described in the patent specification as a hexafluoropropanediol solvate, which is a metastable solvate at ambient conditions and converts to form a. It is described in this patent specification that form D is a co-solvate of DMSO and water, which is very easily converted to form a when dried at ambient temperature. The amorphous form described in this patent specification, prepared by rotary evaporation or freeze drying, is readily converted to form a upon standing at ambient conditions.
Prior art WO2013013609 discloses crystalline forms of roxasistat Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII. Wherein example 1 discloses the synthetic route of the compound, there is a substantial technical error in the conversion reaction from intermediate 4 to intermediate 5, and thus the disclosed crystalline form is not crystalline form of rosxastat.
Prior art CN109369525A discloses crystal form ARZ-A, crystal form ARZ-B, crystal form ARZ-C, crystal form ARZ-D, crystal form ARZ-E, crystal form ARZ-F, crystal form ARZ-G, crystal form ARZ-H, crystal form ARZ-J, crystal form ARZ-K. Form ARZ-A isA monohydrate and form ARZ-B isA hemihydrate. Wherein the crystal form ARZ-B is prepared by volatilization of an anisole mixed solvent, a TG picture shows that the crystal form is easy to dehydrate at 30-90 ℃, and the crystal form is unstable. Most of the other disclosed crystal forms are solvates, and are not suitable for industrial production.
WO2019030711A discloses crystalline form γ, crystalline form δ, eutectic L-proline, nicotinamide, urea. Wherein the crystal form gamma isA formic acid-water cosolvent, the crystal form delta is the same asA diffraction spectrum of crystal form ARZ-A powder in CN109369525A, and the crystal form delta is obtained by crystal transformation of the crystal form gamma, so that the risk of overproof formic acid exists. Meanwhile, TGA of the monohydrate crystal form shows that moisture is easily lost at 40 ℃, DSC shows that the TGA becomes a crystal form A after the moisture is lost, and the crystal form is unstable. As can be seen from the above prior art: although the roxasistat has a plurality of crystal forms, most of the crystal forms have the problems of poor stability, poor solubility or unsuitability for industrial production and the like.
In view of the above, there is a need in the art for a new crystalline form of rasagiline with excellent solubility and stability, which is suitable for the industrial preparation of formulations and meets various performance requirements of the formulations.
Disclosure of Invention
The object of the present invention is to provide a new crystalline form of rasagiline having both excellent solubility and excellent stability.
The invention provides a crystalline form I of roxasistat, which is characterized in that an X-ray powder diffraction pattern of the crystalline form I has characteristic diffraction peaks at the following 2theta angles: 6.3 +/-0.2 degrees, 12.6 +/-0.2 degrees and 18.9 +/-0.2 degrees.
In some embodiments of the invention, the crystalline form i of rosmarinic acid has an X-ray powder diffraction pattern, measured using Cu-ka, with characteristic diffraction peaks at 5 or more 2 Θ angles selected from the group consisting of: 6.3 +/-0.2 degrees, 9.5 +/-0.2 degrees, 12.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.0 +/-0.2 degrees, 22.2 +/-0.2 degrees, 25.3 +/-0.2 degrees, 25.9 +/-0.2 degrees, 28.5 +/-0.2 degrees, 31.8 +/-0.2 degrees and 35.1 +/-0.2 degrees.
In some embodiments of the invention, crystalline form i of rosmarinic acid has an XRPD pattern as shown in figure 1.
In some embodiments of the invention, the XRPD pattern analysis data of crystalline form i of rosmarinic acid is shown in table 1:
TABLE 1X-ray powder diffraction Pattern analysis data of crystalline form I of Rosesarta according to the invention measured using Cu-Ka
In some embodiments of the invention, the crystalline form I of the Rosesarta preparation has an endothermic peak at 124.1 + -3 deg.C, 151.7 + -3 deg.C, 211.6 + -3 deg.C in its differential scanning calorimetry curve.
In some embodiments of the present invention, crystalline form i of rosmarinic acid has a DSC profile as shown in figure 2.
In some embodiments of the present invention, the crystalline form i of rosmarinic acid has a thermogravimetric analysis curve with a weight loss of about 1.7% at 118 ± 3 ℃ and a weight loss of about 3.1% at 118-180 ± 3 ℃.
In some embodiments of the invention, the crystalline form i of the rosmarinic acid has a TGA profile as shown in figure 3.
The invention provides a method for preparing crystalline form i of roxasistat, comprising the following steps: 1) dissolving the rosxastat in a first organic solvent; 2) filtering with a filter membrane, and adding a second organic solvent; and 3) volatile crystallization.
In one embodiment, the first organic solvent is a mixed solvent of methanol and anisole.
In one embodiment, the first organic solvent is a mixed solvent of methanol and ethyl acetate.
In one embodiment, the first organic solvent is a mixed solvent of methanol and acetone.
In one embodiment, the second organic solvent is anisole.
The invention provides a crystalline form II of roxasistat, which is characterized in that an X-ray powder diffraction pattern of the crystalline form II has characteristic diffraction peaks at the following 2theta angles: 16.3 +/-0.2 degrees, 28.3 +/-0.2 degrees and 33.8 +/-0.2 degrees.
In some embodiments of the invention, the crystalline form ii of rosisasetate has an X-ray powder diffraction pattern, measured using Cu-ka, with characteristic diffraction peaks at 5 or more 2 Θ angles selected from the group consisting of: 16.3 +/-0.2 degrees, 17.2 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.0 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.9 +/-0.2 degrees, 28.3 +/-0.2 degrees, 33.0 +/-0.2 degrees, 33.8 +/-0.2 degrees and 37.9 +/-0.2 degrees.
In some embodiments of the invention, the crystalline form ii of rosmarinic acid has an XRPD pattern as shown in figure 4.
In some embodiments of the invention, the XRPD pattern analysis data of crystalline form ii of rosxastat is shown in table 2:
TABLE 2X-ray powder diffraction Pattern analysis data of crystalline form II of Rosesarta according to the invention measured using Cu-Ka
In some embodiments of the invention, the crystalline form ii of rosisasetamide has an exothermic peak at 191.1 ± 3 ℃ and an endothermic peak at 212.1 ± 3 ℃ in its differential scanning calorimetry curve.
In some embodiments of the present invention, the crystalline form ii of rosmarinic acid has a DSC profile as shown in figure 5.
In some embodiments of the invention, the crystalline form ii of rosmarinic acid has a thermogravimetric analysis curve with a weight loss of about 0.09% at 198 ± 3 ℃.
In some embodiments of the invention, the crystalline form ii of rosmarinic acid has a TGA profile as shown in figure 6.
The invention provides a method for preparing crystalline form II of roxasistat, which comprises the following steps: heating the crystal form I to 175 ℃, and obtaining a crystal form II after losing the solvent.
The invention provides a crystalline form III of roxasistat, which is characterized in that an X-ray powder diffraction pattern of the crystalline form III has characteristic diffraction peaks at the following 2theta angles: 5.0 +/-0.2 degrees, 24.9 +/-0.2 degrees and 27.4 +/-0.2 degrees.
In some embodiments of the invention, the crystalline form iii of rosisasetate has characteristic diffraction peaks at 5 or more 2 θ angles selected from the group consisting of: 5.0 +/-0.2 degrees, 11.3 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.0 +/-0.2 degrees, 21.0 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.2 +/-0.2 degrees, 24.9 +/-0.2 degrees, 27.4 +/-0.2 degrees and 32.1 +/-0.2 degrees.
In some embodiments of the invention, the crystalline form iii of rosmarinic acid has an XRPD pattern as shown in figure 7.
In some embodiments of the invention, the XRPD pattern analysis data of crystalline form iii of rosmarintat is shown in table 3:
TABLE 3X-ray powder diffraction Pattern analysis data of crystalline form III of Rosesarta according to the invention measured with Cu-Ka
In some embodiments of the invention, the crystalline form iii of rosisasetast has an endothermic peak at 210.7 ± 3 ℃ in its differential scanning calorimetry curve.
In some embodiments of the invention, the crystalline form iii of rosmarinic acid has a DSC profile as shown in figure 8.
In some embodiments of the invention, the crystalline form iii of rosmarinic acid has a thermogravimetric analysis curve with a weight loss of about 0.4% at 145 ± 3 ℃.
In some embodiments of the invention, the crystalline form iii of rosmarinic acid has a TGA profile as shown in figure 9.
The invention provides a method for preparing crystalline form III of roxasistat, which comprises the following steps: and heating the crystal form I or the crystal form II to 200 ℃ to obtain an anhydrous crystal form III.
The invention also provides application of the crystalline form of the roxasistat in preparation of a medicine for treating anemia.
Drawings
Figure 1 shows the X-ray powder diffraction pattern of crystalline form i of the rosuvastatin according to the present invention.
Figure 2 shows the differential scanning calorimetry curve of crystalline form i of the present invention.
Figure 3 shows a thermogravimetric analysis curve of crystalline form i of the rosuvastatin according to the present invention.
Figure 4 shows an X-ray powder diffraction pattern of crystalline form ii of rosuvastatin according to the present invention.
Figure 5 shows a differential scanning calorimetry curve for crystalline form ii of the invention.
Figure 6 shows a thermogravimetric analysis curve of crystalline form ii of the rosuvastatin according to the present invention.
Figure 7 shows an X-ray powder diffraction pattern of crystalline form iii of rosuvastatin according to the present invention.
Figure 8 shows a differential scanning calorimetry curve for crystalline form iii of rosuvastatin according to the present invention.
Figure 9 shows a thermogravimetric analysis curve of crystalline form iii of rosxastat of the present invention.
Detailed Description
The invention is further described below with reference to the figures and examples. It should be understood, however, that these examples are for the purpose of illustrating the invention in more detail, and are not to be construed as limiting the invention in any way.
The reagents and methods employed in the examples of the invention are conventional in the art. It will be clear to those skilled in the art that, unless otherwise specified, temperatures are expressed in degrees Celsius (C.) and operating temperatures are carried out at ambient temperature, which is 10 deg.C to 30 deg.C, preferably 20 deg.C to 25 deg.C; the allowable error of the melting point is +/-1%; the yield is mass percent.
Experimental methods
X-ray powder diffraction (XRPD)
XRPD data for the crystalline form was determined by brueck (d8 advance) and diffraction parameters were as follows:
x-ray: the concentration of Cu, k alpha,
1.54060
x-ray light pipe setting: 40kV and 25mA
Divergent slit: automatic
A monochromator: is free of
Scanning mode: continuous
Scan range (° 2 Theta): 4-40 degree
Scanning speed (sec/step): 0.5
2. Differential Scanning Calorimetry (DSC)
The DSC data of the crystalline form are determined by a differential scanning calorimeter of type TA (DSC 25) with the following thermal analysis parameters:
temperature range (. degree. C.): 30-250
Scanning rate (. degree. C./min): 10
Protective gas: nitrogen gas
3. Thermogravimetric analysis (TGA)
TGA data for the crystalline form was determined by a TA (TGA 550) instrument with the following thermal analysis parameters:
temperature range (. degree. C.): 30-350 deg.C
Scanning rate (. degree. C./min): 10
Protective gas: nitrogen gas
Technical effects
The crystal form has the advantages of low water content, high purity, good solubility and high product stability.
Examples
The following examples are intended to illustrate specific embodiments of the present invention, but are not intended to limit the invention in any way.
Example 1 preparation of crystalline form I of Rosesarta
Dissolving 50mg of roxasistat in 2ml of anisole and 0.5ml of methanol, filtering the solution by using a membrane, dropwise adding 20ml of anisole, and slowly volatilizing the solution in an open manner to obtain a crystal form I. The crystalline form was measured for its X-ray powder diffraction pattern, differential scanning calorimetry curve and thermogravimetric analysis curve by the methods described above.
Example 2 preparation of crystalline form I of Rosesarta
Dissolving 80mg of roxasistat in 2ml of ethyl acetate and 0.5ml of methanol, filtering the solution by using a membrane, dropwise adding 20ml of anisole, and slowly volatilizing the mixture in an open manner to obtain a crystal form I.
Example 3 preparation of crystalline form I of Rosesarta
Dissolving 80mg of roxasistat in 2ml of acetone and 1ml of methanol, filtering the solution by using a membrane, dropwise adding 20ml of anisole, and slowly volatilizing the mixture in an open manner to obtain a crystal which is a crystal form I.
Example 4 preparation of crystalline form II of Rosesarta
5mg of the crystal form I is heated to 175 ℃, and the solvent is lost to obtain the crystal form II. The crystalline form was measured for its X-ray powder diffraction pattern, differential scanning calorimetry curve and thermogravimetric analysis curve by the methods described above.
Example 5 preparation of crystalline form III of Rosesarta
5mg of the crystal form I or the crystal form II is heated to 200 ℃ to obtain the anhydrous crystal form III. The crystalline form was measured for its X-ray powder diffraction pattern, differential scanning calorimetry curve and thermogravimetric analysis curve by the methods described above.
Example 6 stability experiment
Taking the crystal form II, the crystal form III and the original crystal form A for stability test, and obtaining the following experimental results:
the stability experiment result shows that the crystal form II and the crystal form III can achieve the same effect on related substances and the original crystal form, and the crystal forms are stable.
Example 7 solubility experiment
According to the solubility test method of pharmacopoeia, weighing the fine powder of the test sample, adding the fine powder into a certain amount of solvent at 25 +/-2 ℃, shaking strongly for 30 seconds every 5 minutes, and observing the dissolution condition within 30 minutes, wherein if no visible particles or liquid drops exist, the fine powder is regarded as complete dissolution.
According to the solubility result, the solubility of the crystal form III in water is improved by 2-3 times, and the solubility of the crystal form II in water is improved by 8-10 times, so that the medicine has the effect of obviously improving the solubility of the medicine, and the in-vivo bioavailability can be improved.
It should be understood that the above examples are for illustrative purposes only and are not intended to limit the scope of the present invention, and that various insubstantial modifications and adaptations of the invention may be made by those skilled in the art in light of the above teachings.
Claims (26)
1. Crystalline form I of rosuvastatin characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 θ angles: 6.3 +/-0.2 degrees, 12.6 +/-0.2 degrees and 18.9 +/-0.2 degrees.
2. Crystalline form I of rosxastat of claim 1 having characteristic diffraction peaks at 5 or more 2 θ angles selected from the group consisting of: 6.3 +/-0.2 degrees, 9.5 +/-0.2 degrees, 12.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.0 +/-0.2 degrees, 22.2 +/-0.2 degrees, 25.3 +/-0.2 degrees, 25.9 +/-0.2 degrees, 28.5 +/-0.2 degrees, 31.8 +/-0.2 degrees and 35.1 +/-0.2 degrees.
3. Crystalline form I of rosxastat of claim 1 having an XRPD pattern as shown in figure 1.
4. Crystalline form I of rosuvastatin according to claim 1, having a differential scanning calorimetry curve with endothermic peaks at 124.1 ± 3 ℃, 151.7 ± 3 ℃, 211.6 ± 3 ℃.
5. Crystalline form I of rosxastat of claim 1 having a DSC profile as shown in figure 2.
6. Crystalline form I of rosalastat of claim 1 having a thermogravimetric analysis curve with a weight loss of about 1.7% at 118 ± 3 ℃ and a weight loss of about 3.1% at 118-180 ± 3 ℃.
7. Crystalline form I of rosalastat of claim 1 having a TGA profile as shown in figure 3.
8. A process for preparing crystalline form I of roxasistat comprising: 1) dissolving the rosxastat in a first organic solvent; 2) filtering with a filter membrane, and adding a second organic solvent; and 3) volatile crystallization.
9. The method of claim 8, wherein the first organic solvent is a mixed solvent of methanol and ethyl acetate or acetone or anisole, and/or the second organic solvent is anisole.
10. Crystalline form II of rosuvastatin characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 θ angles: 16.3 +/-0.2 degrees, 28.3 +/-0.2 degrees and 33.8 +/-0.2 degrees.
11. Crystalline form ii of rosxastat according to claim 10 having characteristic diffraction peaks at 5 or more 2 Θ angles selected from the group consisting of: 16.3 +/-0.2 degrees, 17.2 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.0 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.9 +/-0.2 degrees, 28.3 +/-0.2 degrees, 33.0 +/-0.2 degrees, 33.8 +/-0.2 degrees and 37.9 +/-0.2 degrees.
12. Crystalline form II of rosxastat according to claim 10 having an XRPD pattern as shown in figure 4.
13. Crystalline form II of rosuvastatin according to claim 10 having a differential scanning calorimetry curve with an exothermic peak at 191.1 ± 3 ℃ and an endothermic peak at 212.1 ± 3 ℃.
14. Crystalline form II of rosxastat according to claim 10 having a DSC profile as shown in figure 5.
15. Crystalline form ii of rosxastat according to claim 10 having a thermogravimetric analysis curve with a weight loss of about 0.09% at 198 ± 3 ℃.
16. Crystalline form II of rosalastat of claim 10 having a TGA profile as shown in figure 6.
17. A process for preparing crystalline form ii of roxasistat comprising: heating the crystal form A to 175 ℃, and obtaining a crystal form II after losing the solvent.
18. Crystalline form III of Rosesarta characterised by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 θ angles: 5.0 +/-0.2 degrees, 24.9 +/-0.2 degrees and 27.4 +/-0.2 degrees.
19. Crystalline form iii of rosisasotate of claim 18, having characteristic diffraction peaks at 5 or more 2 Θ angles selected from the group consisting of: 5.0 +/-0.2 degrees, 11.3 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.0 +/-0.2 degrees, 21.0 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.2 +/-0.2 degrees, 24.9 +/-0.2 degrees, 27.4 +/-0.2 degrees and 32.1 +/-0.2 degrees.
20. Crystalline form iii of rosixastat of claim 18 having an XRPD pattern as shown in figure 7.
21. Crystalline form iii of rosixatas as claimed in claim 18 having an endotherm at 210.7 ± 3 ℃ in a differential scanning calorimetry curve.
22. Crystalline form iii of rosxastat of claim 18 having a DSC profile as shown in figure 8.
23. Crystalline form iii of rosisasotat of claim 18, having a thermogravimetric analysis curve with a weight loss of about 0.4% at 145 ± 3 ℃.
24. Crystalline form iii of rosisasotate of claim 18 having a TGA profile as shown in figure 9.
25. A method of preparing crystalline form iii of roxasistat comprising: and heating the crystal form I or the crystal form II to 200 ℃ to obtain an anhydrous crystal form III.
26. Use of the crystalline form of rosxastat of any one of claims 1-7, 10-16, 18-24 or prepared by the process of any one of claims 8, 17 or 25 for the preparation of a medicament for the treatment of anemia.
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