CN101781347B - Polymorphic substances of decitabine and medical compositions - Google Patents
Polymorphic substances of decitabine and medical compositions Download PDFInfo
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- CN101781347B CN101781347B CN2010101276063A CN201010127606A CN101781347B CN 101781347 B CN101781347 B CN 101781347B CN 2010101276063 A CN2010101276063 A CN 2010101276063A CN 201010127606 A CN201010127606 A CN 201010127606A CN 101781347 B CN101781347 B CN 101781347B
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- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 title claims abstract description 159
- 229960003603 decitabine Drugs 0.000 title claims abstract description 92
- 239000000126 substance Substances 0.000 title abstract description 16
- 239000000203 mixture Substances 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 47
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- 239000003960 organic solvent Substances 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 25
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000001035 drying Methods 0.000 claims description 19
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- -1 octane-iso Chemical compound 0.000 claims description 16
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- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 9
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Abstract
The invention discloses polymorphic substances I and II of decitabine, and a preparation method and medical compositions thereof.
Description
Technical field
The present invention relates to the polymorphic form of medical compounds, more particularly, relate to the polymorphic form of NSC 127716, in addition, the invention still further relates to the preparation method and the pharmaceutical composition thereof of this polymorphic form.
Background technology
Supergen Inc. has put down in writing three kinds of polymorphic forms of NSC 127716 and the preparation method of its polycrystalline thing is provided in one Chinese patent application CN200580029911.6 (application number is hereinafter to be referred as No. 116, patented claim), its preparation method is respectively:
Form A: pulp in methylene dichloride or hexane solvent (environment), 12 days, vacuum oven dry (environment); Slowly cooling in methanol solvate, vacuum oven dry (environment); Pulp in 2-propyl alcohol solvent (50 ℃), 12 days, vacuum oven dry (environment);
Form B: at methylene dichloride: pulp (environment) in methyl alcohol (1: the 1) solvent, rapid evaporation; 1,1,1,3,3, rapid evaporation or slowly evaporation in 3-hexafluoro-2-propyl alcohol solvent; Rapid evaporation in methanol solvate;
Form A: at 2,2,2 tfifluoroethyl alcohol: decompression centrifugal evaporation (environment) or vacuum oven dry (environment) in water (9: the 1) solvent.
Because NSC 127716 is insoluble in water or methylene dichloride, trichloromethane, methyl-sulfide, 1; 1; Organic solvents such as 1-trichloroethane, hexane, acetone, acetonitrile, methyl alcohol, ETHYLE ACETATE even under heating state, also need use a large amount of solvents, are unfavorable for the industrially scalable preparation; In addition, No. 116 described methods of patented claim do not have to reduce the related substance in the product significantly, long-time heating or with the solvent contact process in very easily cause degraded to destroy, related substance is significantly increased.
On the other hand, the preparation method taught of polycrystalline thing does not consider that when the finished product are synthetic, should avoid the use of harmful (like halohydrocarbon and methyl-sulfide etc.) organic solvent that toxic action is big more than two types or two types understands the detrimentally affect that residual organic solvent causes human body to reduce as far as possible in the product yet in this patent application document.
For the polymorphic of medicine, different polymorphics can have different chemistry and physical property, comprises fusing point, chemicalstability, apparent solubility, dissolution rate, optics and mechanical properties, vp and density.These character can directly influence the processing or the production of bulk drug and preparation, and can influence stability of formulation, solubleness and bioavailability.Therefore, the polymorphic of medicine has great importance for quality, security and the validity of pharmaceutical prepn.For NSC 127716, this area exists such demand: be suitable for commercial scale prodn, the excellent novel polymorphic of physicochemical property.
Summary of the invention
Contriver of the present invention has been surprisingly found out that new decitabine polymorphs through a large amount of research, has successfully solved the deficiency that prior art exists, and it has physico-chemical property excellence, a good stability, be more suitable for advantage such as industrially scalable preparation.
The purpose of this invention is to provide new decitabine polymorphs.
Another object of the present invention provides the preparation method of above-mentioned novel polymorphic thing.
The 3rd purpose of the present invention provides the medicinal compsns that contains above-mentioned novel polymorphic thing.
Specifically, the invention provides a kind of decitabine polymorphs I that is substantially free of other solvent.
The polymorphic form I of NSC 127716 provided by the present invention; Use the Cu-Ka radiation, its typical X-x ray diffration pattern x, 2 θ that show with kilsyth basalt have diffraction peak 19.2 ± 0.2 and 23.3 ± 0.2; Particularly; In 12.8 ± 0.2,16.3 ± 0.2,27.9 ± 0.2,31.7 ± 0.2 one or more in addition (with arbitrary combination, comprising more than two, perhaps whole) diffraction peak; Especially, diffraction peak is arranged, see Fig. 1 at 12.8 ± 0.2,16.3 ± 0.2,19.2 ± 0.2,23.3 ± 0.2,27.9 ± 0.2,31.7 ± 0.2 places.
The polymorphic form I of NSC 127716
| The peak numbering | 2θ | The Flex width | The d-value | Intensity | L/ |
| 1 | 6.420 | 0.259 | 13.7561 | 2076 | 14 |
| 3 | 12.840 | 0.306 | 6.8888 | 6700 | 44 |
| 5 | 14.660 | 0.282 | 6.0374 | 2903 | 19 |
| 6 | 16.340 | 0.282 | 5.4203 | 5827 | 38 |
| 7 | 18.580 | 0.353 | 4.7716 | 2724 | 18 |
| 8 | 19.240 | 0.306 | 4.6093 | 9924 | 64 |
| 12 | 23.300 | 0.282 | 3.8145 | 15551 | 100 |
| 18 | 27.140 | 0.353 | 3.2829 | 2117 | 14 |
| 19 | 27.880 | 0.282 | 3.1974 | 9366 | 61 |
| 23 | 31.660 | 0.306 | 2.8238 | 3706 | 24 |
| 24 | 33.200 | 0.306 | 2.6962 | 2505 | 17 |
| 25 | 34.140 | 0.329 | 2.6241 | 2088 | 14 |
In addition, decitabine polymorphs I of the present invention is characterized by at about 3303.5cm with the infrared absorption pattern that the KBr compressing tablet records
-1, 3242.1cm
-1, 3108.9cm
-1, 2934.0cm
-1, 1696.4cm
-1, 1654.6cm
-1, 1627.6cm
-1, 1508.8cm
-1, 1303.9cm
-1, 1096.1cm
-1, 792.9cm
-1There is absorption peak at the place; See Fig. 2.
Decitabine polymorphs I provided by the present invention, the maximum endothermic transition of its DSC scanning be about 178 ℃ to 193 ℃, preferably, and about 187 ℃ or about 190 ℃.
(50 ℃ of NSC 127716s provided by the present invention; Drying makes under-0.095MPa the condition) polymorphic form I; The maximum endothermic transition of its DSC scanning is about about 190 ℃, and the typical DSC collection of illustrative plates of decitabine polymorphs I of the present invention is seen Fig. 3, and the TGA collection of illustrative plates is seen Fig. 4.
The polymorphic form I of NSC 127716 provided by the present invention (80 ℃, drying makes under-0.095MPa the condition), its typical X-powder x ray diffration pattern x is seen Fig. 5; The maximum endothermic transition of its DSC scanning is about about 187 ℃, and the typical DSC collection of illustrative plates of decitabine polymorphs I is seen Fig. 6.
In embodiments of the invention, the invention provides decitabine polymorphs I, this method comprises the steps:
(1) NSC 127716 is added in the N (DMF), wherein: the volume of N and NSC 127716 and mass ratio are generally greater than 1: 1; Preferably, be selected from: the volume of N and NSC 127716 and weight ratio are greater than 2: 1; Most preferably, be selected from: the volume of anhydrous dimethyl formamide and NSC 127716 and weight ratio are greater than 3.5: 1 to 4: 1;
Perhaps: NSC 127716 is added in the methyl-sulphoxide (DMSO), wherein: the volume of methyl-sulphoxide and NSC 127716 and mass ratio are generally greater than 1: 1; Preferably, be selected from: the volume of methyl-sulphoxide and NSC 127716 and weight ratio are greater than 2: 1; Most preferably, be selected from: the volume of methyl-sulphoxide and NSC 127716 and weight ratio are greater than 3.5: 1 to 4: 1;
And stirring heating makes NSC 127716 be dissolved in N (DMF) or methyl-sulphoxide (DMSO); Here Heating temperature can be in 60 ℃, and preferably, being selected from Heating temperature can be in 50 ℃, and most preferably, being selected from Heating temperature can be between 35 to 45 ℃.
(2) drip water or insoluble with NSC 127716 or the sl. sol. organic solvent mixed solution of water that is several times as much as the N volume.Here, the volume of water or water and organic solvent mixed solution and N volume ratio usually should be greater than 1: 1; Preferably, be selected from water or water and organic solvent mixeding liquid volume and N volume ratio, most preferably, be selected from water or water and organic solvent mixeding liquid volume and N volume ratio greater than 3: 1 greater than 2: 1.Here; Saidly be selected from acetonitrile, trichloromethane, hexanaphthene, 1 for the insoluble organic solvent of NSC 127716; 2-Ethylene Dichloride, methylene dichloride, 1; 2-glycol dimethyl ether, dioxane, cellosolvo, terepthaloyl moietie, normal hexane, methyl alcohol, 2-methyl cellosolve, methyl butyl ketone, methylcyclohexane, N-Methyl pyrrolidone, pyridine, tetraline, THF, toluene, 1; 1; 2-trieline, YLENE, acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ETHYLE ACETATE, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid-butanols, butanone, MIBK, isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1; 1-di ethyl propyl ether, 1; 1-Methylal(dimethoxymethane), 2, a kind of solvent in 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, MIPK, methyltetrahydrofuran, the sherwood oil or more than one mixed solvent; Most preferably; Be selected from: acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ETHYLE ACETATE, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid-butanols, butanone, MIBK, isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1; 1-di ethyl propyl ether, 1; 1-Methylal(dimethoxymethane), 2, a kind of solvent of 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, MIPK, methyltetrahydrofuran, sherwood oil etc. or two or more mixed solvents;
Perhaps: drip insoluble with NSC 127716 or the sl. sol. organic solvent mixture of water that is several times as much as the methyl-sulphoxide volume.Here, the volume of water and organic solvent mixture and methyl-sulphoxide volume ratio usually should be greater than 1: 1; Preferably, be selected from water and organic solvent volume of mixture and methyl-sulphoxide volume ratio, most preferably, be selected from water and organic solvent volume of mixture and methyl-sulphoxide volume ratio greater than 3: 1 greater than 2: 1.Here; Saidly be selected from acetonitrile, trichloromethane, hexanaphthene, 1 for the insoluble organic solvent of NSC 127716; 2-Ethylene Dichloride, methylene dichloride, 1; 2-glycol dimethyl ether, dioxane, cellosolvo, terepthaloyl moietie, normal hexane, methyl alcohol, 2-methyl cellosolve, methyl butyl ketone, methylcyclohexane, N-Methyl pyrrolidone, pyridine, tetraline, THF, toluene, 1; 1; 2-trieline, YLENE, acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ETHYLE ACETATE, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid-butanols, butanone, MIBK, isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1; 1-di ethyl propyl ether, 1; 1-Methylal(dimethoxymethane), 2, a kind of solvent in 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, MIPK, methyltetrahydrofuran, the sherwood oil or more than one mixed solvent; Most preferably; Be selected from: acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ETHYLE ACETATE, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid-butanols, butanone, MIBK, isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1; 1-di ethyl propyl ether, 1; 1-Methylal(dimethoxymethane), 2, a kind of solvent of 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, MIPK, methyltetrahydrofuran, sherwood oil etc. or two or more mixed solvents;
(3) cooling makes and separates out solid under the stirring, preferably is cooled to 0～5 ℃;
(4) filtered and recycled solid.
(5) it is dry down to collect the solid decompression obtain, preferably, in about 50 ℃, helps at Vanadium Pentoxide in FLAKES and to do down drying under reduced pressure under-0.095MPa; Perhaps, in about 80 ℃, help at Vanadium Pentoxide in FLAKES and to do down drying under reduced pressure under-0.095MPa.
In embodiments of the invention; The invention provides another kind of decitabine polymorphs II; Use the Cu-Ka radiation, its typical X-XRD X collection of illustrative plates, 2 θ that show with kilsyth basalt have diffraction peak 14.1 ± 0.2 and 21.1 ± 0.2; Particularly; Diffraction peak in 6.9 ± 0.2,12.7 ± 0.2,17.1 ± 0.2,18.7 ± 0.2,22.6 ± 0.2,23.6 ± 0.2,24.5 ± 0.2,26.4 ± 0.2,29.3 ± 0.2,30.3 ± 0.2,31.1 ± 0.2 one or more in addition (with arbitrary combination, comprising more than two, perhaps whole); Especially, at 6.9 ± 0.2,12.7 ± 0.2,14.1 ± 0.2,17.1 ± 0.2,18.7 ± 0.2,21.1 ± 0.2,22.6 ± 0.2,23.6 ± 0.2,24.5 ± 0.2,26.4 ± 0.2,29.3 ± 0.2,30.3 ± 0.2,31.1 ± 0.2 places diffraction peak is arranged; See Figure 17.
Decitabine polymorphs II
| The peak numbering | 2θ | The Flex width | The d-value | Intensity | L/ |
| 1 | 6.920 | 0.282 | 12.7632 | 7167 | 54 |
| 2 | 12.680 | 0.259 | 6.9754 | 4773 | 36 |
| 3 | 14.060 | 0.282 | 6.2937 | 11394 | 86 |
| 5 | 17.020 | 0.282 | 5.2052 | 4236 | 32 |
| 6 | 18.680 | 0.282 | 4.7462 | 4511 | 34 |
| 8 | 20.140 | 0.235 | 4.4054 | 1800 | 14 |
| 9 | 21.020 | 0.282 | 4.2229 | 13303 | 100 |
| 10 | 21.520 | 0.212 | 4.1259 | 1780 | 14 |
| 11 | 22.520 | 0.259 | 3.9449 | 4977 | 38 |
| 12 | 23.580 | 0.259 | 3.7699 | 8023 | 61 |
| 13 | 24.480 | 0.424 | 3.6333 | 4657 | 36 |
| 15 | 26.420 | 0.259 | 3.3707 | 3811 | 29 |
| 18 | 29.320 | 0.518 | 3.0436 | 3066 | 24 |
| 19 | 30.220 | 0.259 | 2.9550 | 2013 | 16 |
| 20 | 31.100 | 0.282 | 2.8733 | 2588 | 20 |
NSC 127716 provided by the present invention (the DMSO/ aqueous systems makes) polymorphic form II, its typical X-ray powder diffraction pattern is seen Figure 18.
Decitabine polymorphs II provided by the present invention with the infrared absorption pattern that the KBr compressing tablet records, is characterized by at about 3345.8cm
-1, 3226.4cm
-1, 3077.9cm
-1, 2942.0cm
-1, 2918.3cm
-1, 1704.8cm
-1, 1669.9cm
-1, 1619.2cm
-1, 1518.5cm
-1, 1301.8cm
-1, 1099.6cm
-1, 799.2cm
-1There is absorption peak at the place; See Figure 19.
Decitabine polymorphs II provided by the present invention, its DSC scanning endotherm(ic)peak is that maximum endotherm(ic)peak is about about 194 ℃; The typical DSC collection of illustrative plates of decitabine polymorphs II of the present invention is seen Figure 20, and the TGA collection of illustrative plates is seen Figure 21.
In embodiments of the invention, the invention provides the preparation method of decitabine polymorphs II, this method comprises the steps:
In embodiments of the invention, the invention provides decitabine polymorphs II, this method comprises the steps:
(1) NSC 127716 is added in the N (DMF), wherein: the volume of N and NSC 127716 and mass ratio are usually greater than 1: 1; Preferably, be selected from: the volume of N and NSC 127716 and mass ratio were greater than 2: 1; Most preferably, be selected from: the volume of N and NSC 127716 and mass ratio are 3.5: 1 to 4: 1.
Perhaps, NSC 127716 is added in the DMSO 99.8MIN. (DMSO), wherein: the volume of DMSO 99.8MIN. and NSC 127716 and mass ratio are usually greater than 1: 1; Preferably, be selected from: the volume of DMSO 99.8MIN. and NSC 127716 and mass ratio were greater than 2: 1; Most preferably, be selected from: the volume of DMSO 99.8MIN. and NSC 127716 and mass ratio are 3.5: 1 to 5: 1;
And stirring heating makes NSC 127716 be dissolved in N (DMF) or DMSO 99.8MIN. (DMSO); Here Heating temperature can be in 60 ℃, and preferably, being selected from Heating temperature can be in 50 ℃, and most preferably, being selected from Heating temperature can be between 35 to 45 ℃.
(2) in the solution of the N (DMF) of above-mentioned NSC 127716, drip the insoluble or sl. sol. organic solvent of one or more NSC 127716s; Wherein, the volume ratio of the organic solvent volume of dropping and N usually should be greater than 1: 1; Preferably, be selected from: the volume of the organic solvent of dropping and the volume ratio of N should be greater than 2: 1; Most preferably, be selected from: the volume of the organic solvent of dropping and the volume ratio of N should be greater than 3: 1.Wherein, Insoluble or the sl. sol. organic solvent of said NSC 127716 is selected from acetonitrile, hexanaphthene, 1; 2-Ethylene Dichloride, 1; 2-glycol dimethyl ether, dioxane, cellosolvo, terepthaloyl moietie, normal hexane, methyl alcohol, 2-methyl cellosolve, methyl butyl ketone, methylcyclohexane, N-Methyl pyrrolidone, pyridine, tetraline, THF, 1; 1; 2-trieline, acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ETHYLE ACETATE, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid-butanols, butanone, MIBK, isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1; 1-di ethyl propyl ether, 1,1-Methylal(dimethoxymethane), 2, a kind of solvent in 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, MIPK, methyltetrahydrofuran, the sherwood oil or more than one mixed solvent; Most preferably; Be selected from: acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ETHYLE ACETATE, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid-butanols, butanone, MIBK, isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1; 1-di ethyl propyl ether, 1; 1-Methylal(dimethoxymethane), 2, a kind of solvent in 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, MIPK, methyltetrahydrofuran, the sherwood oil or more than one mixed solvent.
Perhaps, in the solution of the DMSO 99.8MIN. (DMSO) of the NSC 127716 of above-mentioned (1), drip water or drip the insoluble or sl. sol. organic solvent of one or more NSC 127716s; Wherein, the volume ratio of the volume of the water of dropping or organic solvent and DMSO 99.8MIN. usually should be greater than 1: 1; Preferably, be selected from: the volume ratio of the water of dropping or the volume of organic solvent and DMSO 99.8MIN. should be greater than 2: 1; Most preferably, be selected from: the volume ratio of the water of dropping or the volume of organic solvent and DMSO 99.8MIN. should be greater than 3: 1.Wherein, Saidly be selected from acetonitrile, hexanaphthene, 1 for the insoluble or sl. sol. organic solvent of NSC 127716; 2-Ethylene Dichloride, 1; 2-glycol dimethyl ether, dioxane, cellosolvo, terepthaloyl moietie, normal hexane, methyl alcohol, 2-methyl cellosolve, methyl butyl ketone, methylcyclohexane, N-Methyl pyrrolidone, pyridine, tetraline, THF, 1; 1; 2-trieline, acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ETHYLE ACETATE, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid-butanols, butanone, MIBK, isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1; 1-di ethyl propyl ether, 1,1-Methylal(dimethoxymethane), 2, a kind of solvent in 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, MIPK, methyltetrahydrofuran, the sherwood oil or more than one mixed solvent; Most preferably; Be selected from: acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ETHYLE ACETATE, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid-butanols, butanone, MIBK, isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1; 1-di ethyl propyl ether, 1; 1-Methylal(dimethoxymethane), 2, a kind of solvent in 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, MIPK, methyltetrahydrofuran, the sherwood oil or more than one mixed solvent.
(3) under agitation cooling makes and separates out solid, preferably is cooled to 0～5 ℃;
(4) filtered and recycled solid;
(5) the solid drying under reduced pressure of collecting preferably, in about 50 ℃, helps down dried-0.095MPa drying under reduced pressure at Vanadium Pentoxide in FLAKES.
In the present invention, X-powdery diffractometry testing tool and test condition involved in the present invention are: anode changes target x-ray diffractometer D/max-2500/PC type (Japan is of science); It is 3～40 ° of 0.3mm, 5 °/min of sweep velocity, sweep limit that copper target, graphite monochromator, tube voltage 40kv, tube current 100mA, divergent slit and anti-scatter slit are 1 °, reception slit.
DSC testing tool and test condition involved in the present invention are: U.S. Perkin ElmerDiamond DSC; With the heating of 10 ℃/min speed, from 25 ℃ to 300 ℃.
TGA testing tool and test condition involved in the present invention are: U.S. Perkin ElmerThermal Analysis Pyris 1TGA; With the heating of 10 ℃/min speed, from 25 ℃ to 500 ℃.
NSC 127716 content involved in the present invention and related substance testing conditions: measure according to HPLC (two appendix V of Chinese Pharmacopoeia version in 2005 D).
The condition of HPLC: use the octadecylsilane chemically bonded silica of improvement to be weighting agent; Potassium dihydrogen phosphate (using the sodium hydroxide adjusting pH value of 4mol/L is 6.8 ± 0.1) with 0.03mol/L is moving phase; Detect wavelength 220nm; Flow velocity is 2ml/min; Column temperature is 15 ℃ ± 2 ℃.
The characteristic of decitabine polymorphs I
One, solubility experiment in water:
Method: it is an amount of that precision takes by weighing decitabine polymorphs I, slowly adds a certain amount of pure water, and the dissolving situation in 30 minutes is observed in every powerful jolting 30 seconds at a distance from 5 minutes, and the result sees table 1.
The solubility test of table 1 decitabine polymorphs I
| Solvent | Trial-product amount (mg) | Add quantity of solvent (ml) | Solute: solvent | The dissolving | Conclusion |
| Water | |||||
| 120 | 10 | 12∶1 | Clarification | Dissolving |
Solubility experiment shows that the solvability of decitabine polymorphs I in pure water is slightly larger than polymorphic form A or B.
Two, stability
1, exposure experiments to light
Decitabine polymorphs I is evenly shared to uncovered petridish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, detects respectively at sampling in 5,10 days, and contrasts with 0 day result.The result sees table 2.10 days x-ray diffraction pattern of decitabine polymorphs I strong illumination is seen Fig. 7; 10 days DSC of decitabine polymorphs I strong illumination figure sees Fig. 8.
Table 2 exposure experiments to light (4500 ± 500lx)
Annotate: range of temperature is 23～26 ℃; The relative humidity variations scope is 56%～63%
2, high temperature test
Decitabine polymorphs I raw material is positioned in the clean vial of sealing, places 60 ℃ of thermostatic drying chambers, detect, and contrast with 0 day result respectively at sampling in 5,10 days.The result sees table 3.60 ℃ of x-ray diffraction patterns of investigating 10 days are seen Fig. 9; 60 ℃ of DSC figure that investigate 10 days see Figure 10.
Table 3 high temperature test (60 ℃)
Annotate: the relative humidity variations scope is 54%～62%
3, high wet test
Decitabine polymorphs I raw material is evenly shared to uncovered petridish, and thickness≤5mm places room temperature (about 25 ℃), and relative humidity is in 75 ± 5% the fixed temperature and humidity incubator, measures respectively at sampling in 5,10 days, and contrasts with 0 day result.The result sees table 4.Relative humidity is that 10 days x-ray diffraction pattern of 75 ± 5% high humiditys is seen Figure 11; The DSC scintigram is seen Figure 12; TGA figure sees 13.
The high wet test of table 4 (room temperature, relative humidity, 75 ± 5%)
Annotate: range of temperature is 23～26 ℃
4, accelerated test
The raw material of decitabine polymorphs I is packed with the polyvinylidene film plastic bag sealing, placed 40 ± 2 ℃, relative humidity is in 75 ± 5% the fixed temperature and humidity incubator; Placed six months, respectively at 1,2; 3,6 the end of month, sampling detected, and contrasted with 0 month result.The result sees table 5.6 months x-ray diffraction pattern is seen Figure 14; The DSC scintigram is seen Figure 15; TGA figure sees Figure 16.
Table 5 accelerated test (40 ℃, relative humidity 75%)
Can know by The above results, the decitabine polymorphs I that the present invention obtains, in exposure experiments to light and high temperature test (60 ℃), outward appearance, related substance and content all do not have than about-face, explain that its character is relatively stable; These article its outward appearance, related substance and content in high wet test all do not have considerable change, and experimental data shows that its water absorbability is less.These article are not observed crystal formation and are changed in long-term reserved sample observing test.
Experiment shows that this polymorphous crystal habit is relatively stable.
The characteristic of NSC 127716 polycrystalline thing II:
One, solubility experiment in water:
Method: it is an amount of that precision takes by weighing decitabine polymorphs II, slowly adds a certain amount of pure water, and the dissolving situation in 30 minutes is observed in every powerful jolting 30 seconds at a distance from 5 minutes, and the result sees table 6.
The solubility test of table 6 decitabine polymorphs II
| Solvent | Trial-product amount (mg) | Add quantity of solvent (ml) | Solute: solvent | The dissolving | Conclusion |
| Water | |||||
| 120 | 10 | 12∶1 | Clarification | Dissolving |
Solubility experiment shows that the solvability of decitabine polymorphs II in pure water is slightly larger than polymorphic form A or B.
Two, stability
1, exposure experiments to light
NSC 127716 polymorphic II raw material is evenly shared to uncovered petridish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, detects respectively at sampling in 5,10 days, and contrasts with 0 day result.The result sees table 7.10 days x-ray diffraction pattern of illumination is seen Figure 22, and Figure 23 is seen in 10 days DSC of illumination scanning.
Table 7 exposure experiments to light (4500 ± 500lx)
Annotate: range of temperature is 23～26 ℃; The relative humidity variations scope is 56%～63%
2, high temperature test
Decitabine polymorphs II raw material is positioned in the clean vial of sealing, places 60 ℃ of thermostatic drying chambers, detect, and contrast with 0 day result respectively at sampling in 5,10 days.The result sees table 8.10 days x-ray diffraction pattern of high temperature is seen Figure 24; 10 days DSC scintigram of high temperature is seen Figure 25.
Table 8 high temperature test (60 ℃)
Annotate: the relative humidity variations scope is 54%～62%
3, high wet test
Decitabine polymorphs II raw material is evenly shared to uncovered petridish, and thickness≤5mm places room temperature (about 25 ℃); Relative humidity is in 75 ± 5% the fixed temperature and humidity incubator; Measure respectively at sampling in 5,10 days, and contrast with 0 day result.The result sees table 9.10 days x-ray diffraction pattern of high humidity experiment is seen Figure 26, and 10 days DSC scintigram of high humidity experiment is seen Figure 27, and 10 days TGA scintigram of high humidity experiment is seen Figure 28.
The high wet test of table 9 (room temperature, relative humidity, 75 ± 5%)
Annotate: range of temperature is 23～26 ℃
4, accelerated test
Decitabine polymorphs II raw material is packed with the polyvinylidene film plastic bag sealing, placed 40 ± 2 ℃, relative humidity is in 75 ± 5% the fixed temperature and humidity incubator; Placed six months, respectively at 1,2; 3,6 the end of month, sampling detected, and contrasted with 0 month result.The result sees table 10.40 ℃ of x-ray diffraction patterns that quickened 6 months are seen Figure 29, and 40 ℃ of DSC scintigrams that quickened 6 months are seen Figure 30, and 40 ℃ of TGA scintigrams that quickened 6 months are seen Figure 31.
Table 10 accelerated test (40 ℃, relative humidity 75%)
Can be known that by The above results the decitabine polymorphs II that the present invention obtains is in exposure experiments to light and high temperature (60 ℃) test, outward appearance, related substance and content all do not have than about-face, explain that its character is relatively stable; These article its outward appearance, related substance and content in high wet test all do not have considerable change, but performance has less water absorbability; Do not observe the conversion between the polymorphic form in the test that keeps sample for a long time of high humidity.
Experimental data shows that this crystal habit is relatively stable.
In another embodiment of the invention; The invention provides the medicinal compsns of one or both and the pharmaceutical excipient that contain above-mentioned two kinds of decitabine polymorphs I, II; Preferably; This medicinal compsns contains one or both 1-500mg of above-mentioned two kinds of decitabine polymorphs I, II, particularly preferably, contains above-mentioned two kinds of decitabine polymorphs I, II one or both about 25,50,75,100 milligrams.According to the instruction of state of the art, and with reference to the patent that the present invention quoted, medicinal compsns of the present invention can be made into various formulations, and selects suitable pharmaceutical excipient.For example; According to waiting to treat disease and object; Medicinal compsns of the present invention, administered through oral, parenteral (for example intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or perfusion, subcutaneous injection or perfusion), suction spraying, nose, vagina, rectum, hypogloeeis or topical administration, preferably; Be parenteral (for example intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or perfusion, subcutaneous injection or perfusion) preparation, for example formulation such as freeze-dried prepn, injection.
The present invention comprises the medicinal compsns of decitabine polymorphs, optionally also can contain other therapeutic component.
Medicinal compsns of the present invention is once a day or repeatedly per daily dose and administration, and per daily dose is about the 10-1000 mg/day, more preferably about 10-250 mg/day.Perhaps, administration every other day, about 10-150 mg/day, or about 10-250 mg/day.
The example that decitabine polymorphs of the present invention can be used for treating disease and symptom includes but not limited to: diseases such as treatment myeloproliferative disease, osteomyelodysplasia syndromes, vasculogenesis, cancer, pain, degeneration of macula, osteomyelodysplasia syndromes, asbestosis, anemia, nervous system disorders, dyssomnia, tetter, pulmonary hypertension, immune deficiency disorder, management of parasitic diseases, central nervous system injury.
Useful technique effect of the present invention is embodied in: although the report of No. 116, prior art-patented claim three kinds of decitabine polymorphs and preparation method thereof, the method for the polymorphic form of the preparation NSC 127716 of No. 116 instructions of patented claim is not suitable for the needs of mass-producing stably manufactured.
The preparation method that No. 116, patented claim joins in the insoluble,practically organic solvent of NSC 127716 after the heating for dissolving cooling with NSC 127716 to separate out crystal or long-time solid-liquid two-phase pulp and stir and change crystalline substance and make.
The form A of NSC 127716 in No. 116, the patented claim: pulp in methylene dichloride or hexane solvent (environment), 12 days, vacuum oven dry (environment); Slowly cooling in methanol solvate, vacuum oven dry (environment); Pulp in 2-propyl alcohol solvent (50 ℃), 12 days, vacuum oven dry (environment)
The form B of NSC 127716 in No. 116, the patented claim: at methylene dichloride: pulp (environment) in methyl alcohol (1: the 1) solvent, rapid evaporation; 1,1,1,3,3, rapid evaporation or slowly evaporation in 3-hexafluoro-2-propyl alcohol solvent; Rapid evaporation in methanol solvate;
The form A of NSC 127716 in No. 116, the patented claim: at 2,2,2 tfifluoroethyl alcohol: decompression centrifugal evaporation (environment) or vacuum oven dry (environment) in water (9: the 1) solvent.
Because NSC 127716 is insoluble in methylene dichloride, trichloromethane, methyl-sulfide, 1; 1; Organic solvents such as 1-trichloroethane, hexane, acetone, acetonitrile, methyl alcohol, ETHYLE ACETATE even under heating state, also need use a large amount of solvents, are unfavorable for the requirement of the stable preparation of mass-producing;
In addition, the preparation method of the polycrystalline thing of instruction can't accomplish to reduce significantly the related substance in the product in No. 116, the patented claim; On the contrary, the method for instructing in this patent documentation need NSC 127716 under solution state long-time heating or with solvent Long contact time whipping process in very easily cause NSC 127716 to destroy degraded, the related substance of product is significantly increased.
The preparation method taught of polycrystalline thing is not considered yet and when the finished product are synthetic, should be avoided the use of harmful (like halohydrocarbon and methyl-sulfide etc.) organic solvent that toxic action is big more than two types or two types to reduce in the product detrimentally affect that can residual organic solvent human body be caused as far as possible in No. 116, the patented claim.
The preparation method of the polycrystalline thing of instruction changes brilliant technology length consuming time in No. 116, the patented claim, and quality controllability is poor, is not suitable for the scale stabilization and produces.
In a word: the polymorphous method of preparation of existing method instruction is inappropriate for the scale stabilization and produces.
Yet, the invention provides two kinds of decitabine polymorphs that are suitable for suitability for industrialized production, overcome the problem that exists in the prior art.
Two kinds of novel polymorphic things of NSC 127716 of the present invention, its crystallization condition fully take into account that NSC 127716 does not dissolve or indissoluble is separated in the solvent of the overwhelming majority and this product impurity is difficult to the characteristics of purifying, have adopted simple and easy to do preparation method:
1, preparation technology of the present invention is simple, easy handling very, and large-scale production is convenient, and the quality controllable and polymorphic form good stability that makes is suitable for long-term seasoning;
2, the brilliant scheme of commentaries on classics has been removed at an easy rate or has been reduced the strong impurity of polarity and made relative substance significantly to reduce, and the quality of product can significantly improve;
3, the disclosed polymorphic I of the present invention, the stability experiment result of II in water are superior to the aqueous stability of disclosed polymorphic A, B in No. 116, the patented claim, and this makes polymorphic form of the present invention be of value to the requirement of freeze-dried prepn or injection more;
4, the polymorphous method of preparation of the present invention can reduce organic solvent usage quantity when changeing brilliant greatly, shortens preparation time, has fallen at the end preparation cost;
5, method alternative of the present invention makes water or hypotoxic 3 types of organic solvents prepare polymorphic form of the present invention, can avoid using in No. 116, the patented claim to the toxic action of the bigger organic solvent residue such as halohydrocarbon of human toxicity to human body.
Above advantage is of value to the present invention the quality of product is significantly improved and be more suitable for suitability for industrialized production.
Description of drawings
Fig. 1 is the typical X RPD figure of decitabine polymorphs I of the present invention
Fig. 2 is the IR infrared absorpting light spectra of decitabine polymorphs I of the present invention
Fig. 3 is the DSC scintigram of decitabine polymorphs I of the present invention
Fig. 4 is the TGA scintigram of decitabine polymorphs I of the present invention
Fig. 5 is the typical X RPD figure of decitabine polymorphs I of the present invention
Fig. 6 is the DSC scintigram of decitabine polymorphs I of the present invention
Fig. 7 is 10 days XRPD of decitabine polymorphs I strong illumination of the present invention figure
Fig. 8 is 10 days DSC differential scannings of decitabine polymorphs I strong illumination of the present invention figure
Fig. 9 investigates 10 days XRPD figure in 60 ℃ of environment of decitabine polymorphs I of the present invention
Figure 10 is 60 ℃ of 10 days DSC differential scanning figure of decitabine polymorphs I of the present invention
Figure 11 is the XRPD figure that decitabine polymorphs I high humidity of the present invention was investigated 10 days
Figure 12 is that decitabine polymorphs I high humidity of the present invention is investigated 10 days DSC scintigrams
Figure 13 is that decitabine polymorphs I high humidity of the present invention is investigated 10 days TGA scintigrams
Figure 14 is that decitabine polymorphs I of the present invention puts investigation XRPD in June figure in 40 ℃ of environment
Figure 15 is the DSC scintigram that decitabine polymorphs I of the present invention puts 40 ℃ of June
Figure 16 is the TGA scintigram that decitabine polymorphs I of the present invention puts 40 ℃ of June
Figure 17 is the typical X RPD figure of decitabine polymorphs II of the present invention
Figure 18 is the typical X RPD figure of decitabine polymorphs II of the present invention
Figure 19 is the IR infrared absorpting light spectra of decitabine polymorphs II of the present invention
Figure 20 is the DSC scintigram of decitabine polymorphs II of the present invention
Figure 21 is the TGA scintigram of decitabine polymorphs II of the present invention
Figure 22 is 10 days XRPD of decitabine polymorphs II rayed of the present invention figure
Figure 23 is 10 days DSC differential scannings of decitabine polymorphs II rayed of the present invention figure
Figure 24 is 60 ℃ of 10 days XRPD figure of decitabine polymorphs II of the present invention
Figure 25 is 60 ℃ of 10 days DSC differential scanning figure of decitabine polymorphs II of the present invention
Figure 26 is 10 days XRPD of decitabine polymorphs II high humidity of the present invention figure
Figure 27 is 10 days DSC scintigrams of decitabine polymorphs II high humidity of the present invention
Figure 28 is 10 days TGA scintigrams of decitabine polymorphs II high humidity of the present invention
Figure 29 is that decitabine polymorphs II of the present invention puts the XRPD figure that keeps sample 40 ℃ of June
Figure 30 is the DSC scintigram that decitabine polymorphs II of the present invention puts 40 ℃ of June
Figure 31 is the TGA scintigram that decitabine polymorphs II of the present invention puts 40 ℃ of June
Figure 32 is the infrared comparison diagram of decitabine polymorphs I of the present invention, II
Embodiment
The preparation of embodiment 1 polymorphic form I
NSC 127716 50.0g is added in the reaction flask, add DMSO100ml, be warming up to about 35 ℃ under stirring.The dissolving back adds acetone 400ml, water 400ml, is cooled to 0～5 ℃ of growing the grain 30min behind the stir about 10min.Suction filtration, filter cake are used small amount of acetone drip washing.Filter cake in 50 ℃ ,-the 0.095MPa drying under reduced pressure, help dried with Vanadium Pentoxide in FLAKES.Get white solid 31.0g.Yield: 62%.
NSC 127716 50.0g is added in the reaction flask, add DMF750ml, be warming up to about 35 ℃ under stirring.Add entry 3000ml after the dissolving, suction filtration behind the stir about 30min.Filter cake is used small amount of acetone drip washing.Filter cake in 50 ℃ ,-the 0.095MPa drying under reduced pressure, help dried with Vanadium Pentoxide in FLAKES.Get white solid 31.0g.Yield: 62%.
Scheme 3,
NSC 127716 50.0g is added in the reaction flask, add DMF250ml, water 750ml, be warming up to 50 ℃ under stirring.The dissolving back adds acetone 750ml, is cooled to 0～5 ℃ of growing the grain 30min behind the stir about 10min.Suction filtration, filter cake are used small amount of acetone drip washing.Filter cake in 50 ℃ ,-the 0.095MPa drying under reduced pressure, help dried with Vanadium Pentoxide in FLAKES.Get white solid 24.0g.Yield: 48%.
The preparation of embodiment 2 polymorphic form II
NSC 127716 50.0g is added in the reaction flask, add DMF750ml, be warming up to about 35 ℃ under stirring.The dissolving back adds acetone 1500ml, is cooled to 0～5 ℃ of growing the grain 30min behind the stir about 10min.Suction filtration, filter cake are used acetone drip washing.Filter cake in 50 ℃ ,-the 0.095MPa drying under reduced pressure, help dried with Vanadium Pentoxide in FLAKES.Get white solid 40.0g.Yield: 80%.
NSC 127716 50.0g is added in the reaction flask, add DMF750ml, be warming up to about 35 ℃ under stirring.The dissolving back adds ETHYLE ACETATE 1500ml, is cooled to 0～5 ℃ of growing the grain 30min behind the stir about 10min.Suction filtration, filter cake are used ETHYLE ACETATE drip washing.Filter cake in 50 ℃ ,-the 0.095MPa drying under reduced pressure, help dried with Vanadium Pentoxide in FLAKES.Get white solid 33.1g.Yield: 66.2%.
Scheme 3,
NSC 127716 50.0g is added in the reaction flask, add DMSO125ml, be warming up to about 60 ℃ under stirring.Add entry 1250ml after the dissolving.Be cooled to 0～5 ℃ of growing the grain 30min under stirring.Suction filtration, filter cake are used less water drip washing.Filter cake in 50 ℃ ,-the 0.095MPa drying under reduced pressure, help dried with Vanadium Pentoxide in FLAKES.Get white solid 29.0g.Yield: 58%.
| Outward appearance | The off-white color crystalline powder | White crystalline powder |
| Related substance | 0.57％ | 0.15％ |
| TGA weightless (20-190 ℃) | 0.64％ | 0.16％ |
| The DSC fusing point | 187.5℃ | 193.1℃ |
NSC 127716 50.0g is added in the reaction flask, add DMSO250ml, be warming up to about 35 ℃ under stirring.The dissolving back adds acetone 1750ml, is cooled to 0～5 ℃ of growing the grain 30min behind the stir about 10min.Suction filtration, filter cake are used acetone drip washing.Filter cake in 50～60 ℃ ,-the 0.095MPa drying under reduced pressure, help dried with Vanadium Pentoxide in FLAKES.Get white solid 41.0g.Yield: 82%.
The preparation technology of embodiment 3 NSC 127716 aseptic powder preparations:
NSC 127716 raw material 50 grams are dissolved in the solution of N or DMSO 99.8MIN. 250ml; Be heated to 40 ℃ under stirring and make its dissolving; Adding gac stirred ten minutes; With the filtering with microporous membrane of 0.45um, filtrating is used the filtering with microporous membrane of 0.22um again, and the filtrating of filtering gained changes aseptic clean area over to;
With the about 2000ml of mixed solution of water or acetone or water and acetone, add activated carbon and stirred ten minutes, with the filtering with microporous membrane of 0.45um, use the filtering with microporous membrane of 0.22um again, the filtrating of filtering gained changes aseptic clean area over to;
In the sterile solution of above-mentioned NSC 127716 N or DMSO 99.8MIN., about 15 minutes, drip the aseptic mixed solution of water or organic solvent or water and organic solvent.Dropwise the back and stir after ten minutes, be cooled to 0～5 ℃ of growing the grain 30min.Suction filtration, filter cake is washed with the acetone top.Filter cake in 60 ℃ ,-the 0.095MPa drying under reduced pressure is to constant weight.Make the aseptic powder of corresponding polymorphic form I of NSC 127716 or II.
The aseptic powder of the mixture of above-mentioned decitabine polymorphs I or II or I and II is sub-packed in cillin bottle, and every bottle contains NSC 127716 aseptic powder 50mg.
The prescription and the preparation technology of embodiment 4 decitabine freeze-dried sterile preparations:
With several kinds of vehicle the arbitrary proportion mixture of above-mentioned decitabine polymorphs I or II or I, II is mixed with every injection that contains 50mg as follows.
The method of manufacture of freeze-drying sterile preparation of mixture that contains the arbitrary proportion of decitabine polymorphs I, II or above-mentioned two kinds of polymorphic forms is that the mixture with the arbitrary proportion of above-mentioned vehicle and decitabine polymorphs I, II or above-mentioned two kinds of polymorphic forms mixes; It is an amount of to add the injection water, stirs and makes dissolving.About regulator solution pH value to 7.0.Add needle-use activated carbon (about 0.1%), stir, filtering decarbonization, filtrating is through the smart filter of 0.22 μ m millipore filtration.The filtrating sterile filling is in the 20ml cillin bottle, and freeze-drying gets decitabine freeze-dried sterile preparation.
The prescription and the preparation technology of embodiment 5 NSC 127716s injection sterile preparation:
With several kinds of vehicle the arbitrary proportion mixture of above-mentioned decitabine polymorphs I or II or I, II is mixed with every injection that contains 50mg as follows.
The method of manufacture of freeze-drying sterile preparation of mixture that contains the arbitrary proportion of decitabine polymorphs I, II or above-mentioned two kinds of polymorphic forms is that the mixture with the arbitrary proportion of above-mentioned vehicle and decitabine polymorphs I, II or above-mentioned two kinds of polymorphic forms mixes; Other takes by weighing the N.F,USP MANNITOL of recipe quantity; It is an amount of to add the injection water, stirs and makes dissolving.About regulator solution pH value to 7.0.Add needle-use activated carbon (about 0.1%), stir, filtering decarbonization, filtrating is through the smart filter of 0.22 μ m millipore filtration.The filtrating sterile filling is in the 20ml cillin bottle, and freeze-drying gets decitabine freeze-dried sterile preparation.
Simultaneous test:
1, preparing decitabine polymorphs A, B, C (being designated hereinafter simply as " polymorphic form A, B, C ") with disclosed method among the CN200580029911.6 is representative, and polymorphic form I of the present invention, II (being designated hereinafter simply as " polymorphic form I, II ") dissolubility data contrast and the stability of solution data comparing result in 20 ℃ of pure water in pure water:
Experimental technique: solubleness and the study on the stability result in 20 ℃ of aqueous solution in the water of table 16 polymorphic form A, B, C and polymorphic form I, II:
2, with the preparation technology of disclosed decitabine polymorphs A among the CN200580029911.6, B (being designated hereinafter simply as " polymorphic form A, B, "), the result who same batch of NSC 127716 sample of above-mentioned two kinds of rotating crystal methods is changeed brilliant back outward appearance, related substance and content with the preparation technology of polymorphic form I of the present invention, II (being designated hereinafter simply as " polymorphic form I, II ") relatively.(disclosed decitabine polymorphs C among the CN200580029911.6, explaining it according to its patent documentation is that a unsettled semihydrate is not so do reference)
Experimental technique: the preparation technology of polymorphic form A, B is with the preparation method of disclosed decitabine polymorphs among the CN200580029911.6; The preparation technology of polymorphic form I of the present invention, II is with the preparation method of the decitabine polymorphs of specification sheets and embodiment.
Experimental result shows: decitabine polymorphs I of the present invention or II are more suitable for processing the medicine of freeze-dried prepn.
Claims (10)
1. the polymorphic form I of a NSC 127716 uses the Cu-Ka radiation, its x-ray diffraction pattern, and 2 θ that show with kilsyth basalt have diffraction peak at 12.8 ± 0.2,16.3 ± 0.2,19.2 ± 0.2,23.3 ± 0.2,27.9 ± 0.2,31.7 ± 0.2 places.
2. polymorphic form I according to claim 1, its x-ray diffraction pattern such as Fig. 1.
3. polymorphic form I according to claim 1 and 2, its DSC scanning has maximum endothermic transition at 178 ℃ to 193 ℃.
4. polymorphic form I according to claim 1 and 2 with the infrared absorption pattern that the KBr compressing tablet records, is characterized by at about 3303.5cm
-1, 3242.1cm
-1, 3108.9cm
-1, 2934.0cm
-1, 1696.4cm
-1, 1654.6cm
-1, 1627.6cm
-1, 1508.8cm
-1, 1303.9cm
-1, 1096.1cm
-1, 792.9cm
-1There is absorption peak at the place.
5. the preparation method of the said polymorphic form I of arbitrary claim in the claim 1 to 4 comprises the steps:
(1) NSC 127716 is added in N or the DMSO 99.8MIN., stirring heating makes its dissolving, and here, described Heating temperature is in 60 ℃;
(2) in the solution of the DMSO 99.8MIN. of NSC 127716, drip the mixed solution of water and organic solvent, here, described organic solvent is insoluble or sl. sol. one or more mixed solvents of NSC 127716; Perhaps, in the solution of the N of NSC 127716, drip the mixing solutions of water or water and organic solvent, here, described organic solvent is insoluble or sl. sol. one or more mixed solvents of NSC 127716,
(3) under agitation cooling makes and separates out solid;
(4) reclaim solid, decompression is dry down.
6. preparation method according to claim 5; Wherein, Organic solvent described in the step (2) is selected from: acetone, anisole, propyl carbinol, sec-butyl alcohol, butylacetate, t-butyl methyl ether, isopropyl benzene, ethanol, ETHYLE ACETATE, ether, ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl isophthalic acid-butanols, butanone, MIBK, isopropylcarbinol, Skellysolve A, Pentyl alcohol, n-propyl alcohol, Virahol, propyl acetate, 1; 1-di ethyl propyl ether, 1; 1-Methylal(dimethoxymethane), 2, a kind of solvent in 2-Propanal dimethyl acetal, octane-iso, isopropyl ether, MIPK, methyltetrahydrofuran, the sherwood oil or two or more mixed solvents.
7. preparation method according to claim 6, wherein, the organic solvent described in the step (2) is an acetone.
8. preparation method according to claim 5 wherein, is cooled to 0～5 ℃ in the step (3).
9. preparation method according to claim 5, wherein, decompression described in the step (4) down drying is: in about 50 ℃, help at Vanadium Pentoxide in FLAKES and to do down drying under reduced pressure under-0.095MPa; Perhaps, in about 80 ℃, help at Vanadium Pentoxide in FLAKES and to do down drying under reduced pressure under-0.095MPa.
10. pharmaceutical composition that comprises the said decitabine polymorphs I of arbitrary claim in the claim 1 to 4.
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