CN103130814A - Two types of 9-nitro comptothecin novel crystal forms and preparation method thereof - Google Patents
Two types of 9-nitro comptothecin novel crystal forms and preparation method thereof Download PDFInfo
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- CN103130814A CN103130814A CN2011103852457A CN201110385245A CN103130814A CN 103130814 A CN103130814 A CN 103130814A CN 2011103852457 A CN2011103852457 A CN 2011103852457A CN 201110385245 A CN201110385245 A CN 201110385245A CN 103130814 A CN103130814 A CN 103130814A
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Abstract
The invention provides a 9-nitro comptothecin novel crystal form I and a preparation method of the 9-nitro comptothecin novel crystal form I.The stability against heat and wet of the crystal form I is superior to the stability against heat and wet of the existing 9-nitro comptothecin crystal form. The invention further provides a 9-nitro comptothecin novel crystal form II and a preparation method of the 9-nitro comptothecin novel crystal form II. The solubility of the crystal form II is larger than the solubility of the existing 9-nitro comptothecin crystal form. The preparation method of the 9-nitro comptothecin crystal form I and the preparation method of the 9-nitro comptothecin crystal form II are simple, easy to operate and suitable for technologized production.
Description
Technical field
The present invention relates to two kinds of new crystal of 9-nitrocamptothecin (claiming again rubitecan): crystal formation I and crystal form II, and preparation method thereof.
Background technology
9-nitrocamptothecin, chemical name: 4 (S)-ethyl-4 hydroxyls-10-nitro-1H-pyrans also [3 ', 4 ': 6,7] benzazole also [1,2-b] quinoline-3,14 (4H, 12H)-diketone, be a kind of novel semi-synthetic camptothecin derivative, belong to the topoisomerase enzyme inhibitor of new research and development in recent years.9-nitrocamptothecin is oral preparations, is used for the treatment of carcinoma of the pancreas and other solid tumor by the new drug of SuperGen company research and development, and great advantage is to take in the non-while in hospital, so patient can treat at home.
Clinical pharmacology experimental study proof 9-nitrocamptothecin is less than other camptothecine toxic side effect that has now dropped into clinical use, and its unique advantage is oral effective.9-nitrocamptothecin has very strong tumor-suppression activity to multiple cancer cells, and more in site distribution such as pancreas, ovary, prostate glands, may become the certain drug of carcinoma of the pancreas, ovarian cancer and prostate cancer, especially the treatment of carcinoma of the pancreas there is special-effect, american cancer research organization thinks that 9-nitrocamptothecin very likely becomes a line medication for the treatment of advanced pancreatic cancer, has very large clinical value.
At present there has been the crystal formation of the 9-nitrocamptothecin of patent report that seven kinds of crystal formations announcing in WO03/072027 are arranged.Solvent when this patent also discloses this seven kinds of crystal formations of recrystallization can be: acetone, methylene dichloride, tetrahydrofuran (THF) and acetonitrile etc., and the muffin crystal formation that obtains with acetone, methylene dichloride, tetrahydrofuran (THF), acetonitrile recrystallization obtains in dry DMF and moisture DMF.A kind of crystal formation that cooling down obtains in methyl alcohol is disclosed in CN1611505.
Summary of the invention
Technical problem to be solved by this invention has been to provide two kinds of novel 9-nitrocamptothecin crystal formations, crystal formation I and crystal form II.Crystal formation I of the present invention is better than existing 9-nitrocamptothecin crystal formation to heat and wet stability, and the solubleness of crystal form II is greater than existing 9-nitrocamptothecin crystal formation.The present invention also provides respectively the preparation method of 9-nitrocamptothecin crystal formation I and crystal form II.
the invention provides a kind of crystal formation I of 9-nitrocamptothecin, this crystal formation I is in the powder x-ray diffraction spectrum that uses source of radiation as Cu-K α, in diffraction angle 2 θ=6.100, 8.392, 10.932, 12.197, 12.591, 13.381, 13.932, 15.055, 16.535, 16.873, 18.332, 18.885, 19.674, 21.292, 21.607, 21.964, 22.753, 23.958, 24.433, 25.041, 25.360, 25.674, 26.957, 27.962, 28.771, 29.719, 30.352, 31.596, 32.603, 35.937, 37.001, 38.463 and there is characteristic peak at 39.960 degree places, 2 θ limit of error are ± 0.2.
Wherein, the fusing point of the crystal formation I of described 9-nitrocamptothecin is generally 263 ± 1 ℃.
The present invention also provides the preparation method of the crystal formation I of described 9-nitrocamptothecin, and it comprises the steps: that (1) is dissolved in 9-nitrocamptothecin in organic solvent; (2) adopt method of evaporation to remove solvent, namely get the crystal formation I of 9-nitrocamptothecin; Wherein said organic solvent is to be selected from the single solvent of following solvents or the mixed solvent that is comprised of following solvents: methyl alcohol, ethyl formate, ethyl acetate, isobutyl acetate, dithiocarbonic anhydride, tetrahydrofuran (THF), 2-butanone and n-propyl alcohol.
In step (1), described 9-nitrocamptothecin can be various forms of 9-nitrocamptothecin crystal formations or unformed 9-nitrocamptothecin in this area.
In step (1), the consumption of described organic solvent does not have particular requirement, as long as can dissolve 9-nitrocamptothecin fully.
In step (1), when described organic solvent was mixed solvent, this mixed solvent was preferably by 2 kinds of solvent compositions, and the volume ratio of two kinds of solvents is preferably 5: 1-7: 1.
In step (1), described single solvent is preferably tetrahydrofuran (THF), n-propyl alcohol or 2-butanone.Described mixed solvent is preferably ethyl acetate and methyl alcohol, isobutyl acetate and methyl alcohol, ethyl formate and methyl alcohol, or dithiocarbonic anhydride and methyl alcohol, wherein the volume ratio of ethyl acetate, isobutyl acetate, ethyl formate or dithiocarbonic anhydride and methyl alcohol is preferably 5: 1-7: 1.
In step (2), the vaporization temperature of described method of evaporation is preferably 25～60 ℃, is more preferably 25～40 ℃.
In step (2), the evaporating pressure of described method of evaporation is preferably 0.05～0.1MP.
In step (2), preferably carry out vacuum-drying after removing solvent with method of evaporation, described vacuum drying pressure is preferably 65～165mBar.
The present invention also provides a kind of crystal form II of 9-nitrocamptothecin, this crystal form II is in the powder x-ray diffraction spectrum that uses source of radiation as Cu-K α, there is characteristic peak at the place at diffraction angle 2 θ=7.834,8.863,12.058,14.248,14.623,16.025,18.035,19.755,21.156,22.004,23.524,25.773,26.565,27.054,28.911 and 32.700 degree, and 2 θ limit of error are ± 0.2.
Wherein, the fusing point of the crystal form II of described 9-nitrocamptothecin is 156 ± 1 ℃.
The present invention also provides the preparation method of the crystal form II of described 9-nitrocamptothecin, and it comprises the steps: that (1) mix 9-nitrocamptothecin with organic solvent, heats up to stir 9-nitrocamptothecin is dissolved fully; (2) cooling down namely gets the crystal form II of 9-nitrocamptothecin; Wherein said organic solvent is selected from acetone or 2-butanone etc.
In step (1), described 9-nitrocamptothecin can be various forms of 9-nitrocamptothecin crystal formations or unformed 9-nitrocamptothecin in this area.
In step (1), the consumption of described organic solvent does not have particular requirement, as long as can dissolve 9-nitrocamptothecin fully, gets final product.
In step (1), the terminal temperature of described intensification is preferably 45～55 ℃.
In step (1), described temperature-rise period preferably carries out under agitation condition.
In step (2), described cooling temperature is preferably below 28 ℃.
In step (2), preferably adopt the method for this area routine to carry out solid-liquid separation after described cooling down, then carry out drying.Described solid-liquid separation adopts conventional solid-liquid separating method, for example evaporating solvent or filtration at normal temperatures and pressures.Described filtration can be adopted the filter method of the various routines in this area, as vacuum filtration.
In the present invention, but above-mentioned optimum condition arbitrary combination on the basis that meets this area general knowledge namely gets each preferred embodiment of the present invention.
Raw material of the present invention and reagent is commercially available getting all.
Positive progressive effect of the present invention is:
1, the invention provides a kind of crystal formation I of 9-nitrocamptothecin, this crystal formation I is better than existing 9-nitrocamptothecin crystal formation to heat and wet stability.
2, the present invention also provides a kind of crystal form II of 9-nitrocamptothecin, and the solubleness of this crystal form II is greater than existing 9-nitrocamptothecin crystal formation.
3, the preparation method of the crystal formation I of 9-nitrocamptothecin of the present invention and crystal form II is simple to operation, and suitable technique changes into product.
Description of drawings
Fig. 1 is the DSC-TGA analysis chart of the crystal formation I of 9-nitrocamptothecin.
Fig. 2 is the powder X-ray RD collection of illustrative plates of the crystal formation I of 9-nitrocamptothecin.
Fig. 3 is the DSC-TGA analysis chart of the crystal form II of 9-nitrocamptothecin.
Fig. 4 is the powder X-ray RD collection of illustrative plates of the crystal form II of 9-nitrocamptothecin.
Fig. 5 is the humidity stability figure of crystal formation I, crystal form II and the bulk drug of 9-nitrocamptothecin.
Above-mentioned explanation and the following examples are only exemplary and illustrative, and its protection should be not limited to this.
Embodiment
The present invention is described in further detail below in conjunction with embodiment, but the present invention is not limited to this.
The preparation of embodiment 1-16 9-nitrocamptothecin crystal formation I
Embodiment 1
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add THF200ml, stir and make its dissolving, under normal temperature and pressure, evaporating solvent obtains crystal formation I, preserves after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add ethyl acetate 700ml and 100ml methyl alcohol, stir and make its dissolving, under normal temperature and pressure, the evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add isobutyl acetate 700ml and 100ml methyl alcohol, stir and make its dissolving, under normal temperature and pressure, the evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add ethyl formate 700ml and 100ml methyl alcohol, stir and make its dissolving, under normal temperature and pressure, the evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying that obtains.
Embodiment 5
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add dithiocarbonic anhydride 700ml and 100ml methyl alcohol, stir and make its dissolving, under normal temperature and pressure, evaporating solvent obtains crystal formation I, preserves after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add n-propyl alcohol 700ml, after stirring 8h, under normal temperature and pressure, evaporating solvent obtains crystal formation I, preserves after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add 2-butanone 500ml, stir and make its dissolving, under normal temperature and pressure, the evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add THF200ml, stir and make its dissolving, 40 ℃ of lower evaporating solvent crystallizations of normal pressure obtain crystal formation I, preserve after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add ethyl acetate 700ml and 100ml methyl alcohol, stir and make its dissolving, 40 ℃ of lower evaporating solvent crystallizations of normal pressure obtain crystal formation I, preserve after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add isobutyl acetate 700ml and 100ml methyl alcohol, stir and make its dissolving, 40 ℃ of lower evaporating solvent crystallizations of normal pressure obtain crystal formation I, preserve after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add ethyl formate 700ml and 100ml methyl alcohol, stir and make its dissolving, 40 ℃ of lower evaporating solvent crystallizations of normal pressure obtain crystal formation I, preserve after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add dithiocarbonic anhydride 700ml and 100ml methyl alcohol, stir and make its dissolving, 40 ℃ of lower evaporating solvent crystallizations of normal pressure obtain crystal formation I, preserve after the crystal vacuum-drying that obtains.
Dropping into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add n-propyl alcohol 700ml, are 60 ℃ of lower evaporating solvent crystallizations of normal pressure (carried out recrystallization with which kind of solvent after stirring 8h?) obtain crystal formation I, preserve after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add 2-butanone 500ml, stir and make its dissolving, 40 ℃ of lower evaporating solvent crystallizations of normal pressure obtain crystal formation I, preserve after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add to stir under 60 ℃ of 700ml methyl alcohol and make its dissolving, after keeping 60 ℃ of stirring 3h, cool to 40 ℃ of lower evaporating solvent crystallizations and obtain crystal formation I, preserve after the crystal vacuum-drying that obtains.
Drop into 9-nitrocamptothecin 1g in 1 liter of reaction flask, add the stirring of 800ml ethyl acetate and make its dissolving, under normal temperature condition, the evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying that obtains.
The preparation of the crystal form II of embodiment 17-19 9-nitrocamptothecin
Claim 9-nitrocamptothecin 0.5g to put in the 1000ml crystallizer, add 250ml acetone, heat up 55 ℃ and stir 3h, be slow cooling under room temperature condition, obtain crystal form II under normal temperature and pressure after evaporating solvent, preserve after the crystal vacuum-drying that obtains.
Embodiment 18
The title 9-nitrocamptothecin claims 0.5mg to put in the 1000ml crystallization, adds the 350ml butanone, heats up 45 ℃ and stirs 3h, is slow cooling to stop stirring the long crystalline substance of static 0.5h under 5 ℃ of conditions, filters, drains, and normal-temperature vacuum oven for drying 48h obtains crystal form II.
Embodiment 19
Claim 9-nitrocamptothecin 0.5g to put in the 1000ml crystallization, add 300ml acetone, heat up 55 ℃ and stir 3h, be slow cooling under 5 ℃ of conditions, obtain crystal form II under normal temperature and pressure after evaporating solvent.
The crystal formation I of effect embodiment 1 9-nitrocamptothecin
The crystal formation I of the 9-nitrocamptothecin that embodiment 1-16 is obtained carries out powder x-ray diffraction, and source of radiation is Cu-K α, and spectrogram is seen Fig. 2, and the specific features peak value of crystal formation I sees Table 1.
The PXRD characteristic peak of the crystal formation I of table 1 9-nitrocamptothecin
The crystal form II of effect embodiment 2 9-nitrocamptothecins
The crystal form II of the 9-nitrocamptothecin that embodiment 17-19 is obtained carries out powder x-ray diffraction, and source of radiation is Cu-K α, and spectrogram is seen Fig. 4, and the specific features peak value of crystal form II sees Table 2.
The PXRD characteristic peak of the crystal form II of table 2 9-nitrocamptothecin
Crystal formation I to the 9-nitrocamptothecin of embodiment 1 detects with differential scanning calorimetric (DSC) method, from 20 ℃, is warming up to 350 ℃ with the speed of 10 ℃/min, and it has located endotherm(ic)peak at 263 ± 1 ℃, specifically sees Fig. 1.The TGA figure of this crystal formation I sees Fig. 1 equally.The DSC of other embodiment and TGA figure are with this embodiment.
Detect with the crystal form II of differential scanning calorimetric (DSC) method to the 9-nitrocamptothecin in embodiment 17, from 20 ℃, be warming up to 350 ℃ with the speed of 10 ℃/min, it has located endotherm(ic)peak at 156 ± 1 ℃, specifically sees Fig. 3.The TGA figure of this crystal form II sees Fig. 3 equally.The DSC of other crystal form IIs embodiment and TGA figure are with this embodiment.
1, solubleness
What the test of solubleness was adopted is to use the HPLC method, measures with external standard method, and the condition of HPLC is as follows:
Pillar model: Synergi 4 μ hydro-RP 80A 250mm*4.60mm
Moving phase: methyl alcohol: water=0.6: 0.4
Column temperature: 30 ℃
Wavelength: 287nm
Detected result is as follows:
| The sample title | Crystal formation I | Crystal form II | Bulk drug |
| Solubleness μ g/ml | 0.946 | 2.329 | 1.234 |
2, humidity stability
Crystal formation I of the present invention is the most stable crystal formation through detecting, and finds that bulk drug and newfound crystal form II have the tendency that is converted into crystal formation I, and crystal formation I does not transform under experiment condition.Experiment condition: get appropriate crystal formation I, crystal form II and bulk drug under 97% humidity condition, timing sampling detects respectively.
Claims (10)
1. the crystal formation I of a 9-nitrocamptothecin, this crystal formation I is in the powder x-ray diffraction spectrum that uses source of radiation as Cu-K α, in diffraction angle 2 θ=6.100, 8.392, 10.932, 12.197, 12.591, 13.381, 13.932, 15.055, 16.535, 16.873, 18.332, 18.885, 19.674, 21.292, 21.607, 21.964, 22.753, 23.958, 24.433, 25.041, 25.360, 25.674, 26.957, 27.962, 28.771, 29.719, 30.352, 31.596, 32.603, 35.937, 37.001, 38.463 and there is characteristic peak at 39.960 degree places, 2 θ limit of error are ± 0.2.
2. crystal formation I as claimed in claim 1, it is characterized in that: its fusing point is 263 ± 1 ℃.
3. the preparation method of crystal formation I as claimed in claim 1 or 2, it comprises the steps: that (1) is dissolved in 9-nitrocamptothecin in organic solvent; (2) adopt method of evaporation to remove solvent, namely get the crystal formation I of 9-nitrocamptothecin; Wherein said organic solvent is to be selected from the single solvent of following solvents or the mixed solvent that is comprised of following solvents: methyl alcohol, ethyl formate, ethyl acetate, isobutyl acetate, dithiocarbonic anhydride, tetrahydrofuran (THF), 2-butanone and n-propyl alcohol; In step (1), when described organic solvent was mixed solvent, this mixed solvent was preferably by 2 kinds of solvent compositions, and the volume ratio of two kinds of solvents is preferably 5: 1-7: 1.
4. preparation method as claimed in claim 3, it is characterized in that: in step (1), described single solvent is tetrahydrofuran (THF), n-propyl alcohol or 2-butanone; Described mixed solvent is ethyl acetate and methyl alcohol, isobutyl acetate and methyl alcohol, ethyl formate and methyl alcohol, or dithiocarbonic anhydride and methyl alcohol, and wherein the volume ratio of ethyl acetate, isobutyl acetate, ethyl formate or dithiocarbonic anhydride and methyl alcohol is preferably 5: 1-7: 1.
5. preparation method as described in claim 3 or 4, it is characterized in that: in step (2), the vaporization temperature of described method of evaporation is 25～60 ℃, is preferably 25～40 ℃; The evaporating pressure of described method of evaporation is 0.05～0.1MP; And/or preferably carrying out vacuum-drying after removing solvent with method of evaporation, described vacuum drying pressure is preferably 65～165mBar.
6. the crystal form II of a 9-nitrocamptothecin, this crystal form II is in the powder x-ray diffraction spectrum that uses source of radiation as Cu-K α, there is characteristic peak at the place at diffraction angle 2 θ=7.834,8.863,12.058,14.248,14.623,16.025,18.035,19.755,21.156,22.004,23.524,25.773,26.565,27.054,28.911 and 32.700 degree, and 2 θ limit of error are ± 0.2.
7. crystal form II as claimed in claim 6, it is characterized in that: its fusing point is 156 ± 1 ℃.
8. as the preparation method of claim 6 or 7 described crystal form IIs, it comprises the steps: that (1) mix 9-nitrocamptothecin with organic solvent, and heating up to stir dissolves 9-nitrocamptothecin fully; (2) cooling down namely gets the crystal form II of 9-nitrocamptothecin; Wherein said organic solvent is acetone or 2-butanone.
9. preparation method as claimed in claim 8, it is characterized in that: in step (1), the terminal temperature of described intensification is 45～55 ℃; In step (2), described cooling temperature is below 28 ℃.
10. preparation method as claimed in claim 9, it is characterized in that: in step (1), described temperature-rise period carries out under agitation condition; In step (2), carry out solid-liquid separation after described cooling down, then carry out drying; Described solid-liquid separation preferably is evaporating solvent or filtration at normal temperatures and pressures.
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Citations (6)
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|---|---|---|---|---|
| WO2003072027A2 (en) * | 2002-02-21 | 2003-09-04 | Supergen, Inc | Compositions and formulations of 9- nitrocamptothecin polymorphs and methods of use thereof |
| CN1611505A (en) * | 2004-01-07 | 2005-05-04 | 重庆医药工业研究院有限责任公司 | Novel 9-nitro campotothecin crystal form and medicinal composition |
| CN1724535A (en) * | 2004-07-21 | 2006-01-25 | 王洋 | Production method of 9-nitro camptothecin |
| CN1760195A (en) * | 2005-01-21 | 2006-04-19 | 华东理工大学 | Method for separating and purifying 9-nitro camptothecin |
| CN1781923A (en) * | 2004-11-29 | 2006-06-07 | 中国科学院成都有机化学有限公司 | Method for preparing 9-nitro-20(s)-camptothecine |
| CN102229615A (en) * | 2011-07-27 | 2011-11-02 | 河南东泰制药有限公司 | Method for synthesizing 9-nitrocamptothecin |
-
2011
- 2011-11-25 CN CN201110385245.7A patent/CN103130814B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003072027A2 (en) * | 2002-02-21 | 2003-09-04 | Supergen, Inc | Compositions and formulations of 9- nitrocamptothecin polymorphs and methods of use thereof |
| CN1611505A (en) * | 2004-01-07 | 2005-05-04 | 重庆医药工业研究院有限责任公司 | Novel 9-nitro campotothecin crystal form and medicinal composition |
| CN1724535A (en) * | 2004-07-21 | 2006-01-25 | 王洋 | Production method of 9-nitro camptothecin |
| CN1781923A (en) * | 2004-11-29 | 2006-06-07 | 中国科学院成都有机化学有限公司 | Method for preparing 9-nitro-20(s)-camptothecine |
| CN1760195A (en) * | 2005-01-21 | 2006-04-19 | 华东理工大学 | Method for separating and purifying 9-nitro camptothecin |
| CN102229615A (en) * | 2011-07-27 | 2011-11-02 | 河南东泰制药有限公司 | Method for synthesizing 9-nitrocamptothecin |
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