CN107540711A - A kind of method for crystallising of endoxan - Google Patents
A kind of method for crystallising of endoxan Download PDFInfo
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- CN107540711A CN107540711A CN201710882263.3A CN201710882263A CN107540711A CN 107540711 A CN107540711 A CN 107540711A CN 201710882263 A CN201710882263 A CN 201710882263A CN 107540711 A CN107540711 A CN 107540711A
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- endoxan
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Abstract
The invention provides a kind of method for crystallising of endoxan, belong to pharmaceutical formulating art.The method for crystallising includes：By endoxan or its hydrate with water according to mass ratio 1：5~15 mixing, and obtain the endoxan aqueous solution after being dissolved at 30~50 DEG C；The endoxan aqueous solution is cooled at 10~5 DEG C again, standing or stirring and crystallizing.This method is using water as recrystallisation solvent, there are certain solubility and its solubility with temperature in water to reduce and have the characteristic of large change in water using endoxan, crystalline rate is controlled by controlling temperature, any organic solvent need not be used in whole process, it is green；Crystal formation rule, the purity of obtained endoxan crystal are high, and impurity-eliminating effect is obvious.
Description
Technical field
The present invention relates to pharmaceutical formulating art, in particular to a kind of method for crystallising of endoxan.
Background technology
Endoxan, molecular formula C7H17Cl2N2O3P, shown in formula I, it is white crystals to the structural formula of its monohydrate
Or crystalline powder, stablize at room temperature；Water is dissolved in, but solubility is little, and the aqueous solution is unstable.Endoxan nonreactive in vitro
Tumor promotion, first aldophosphamide is changed into through particulate body function oxidizing ferment in liver into rear in vivo.And aldehyde acid amides is unstable,
Acid amides mustargen and methacrylaldehyde are resolved into tumour cell, acid amides mustargen has CDCC to tumour cell.Commercially available ring phosphinylidyne
The sterile dry mixture of endoxan monohydrate during amine product.
At present, the method for crystallising of existing endoxan, be endoxan or endoxan hydrate are dissolved in it is organic molten
In agent, the e.g. organic solvent such as acetone, ethanol is then mixed and cooled with water and stirring and is evaporated off in vacuum distillation again
Gradual crystallization during organic solvent.However, in this kind of method for crystallising, because endoxan is soluble in organic solvent, lead to
Cross vacuum distillation and be evaporated off crystallizing during organic solvent and cooling crystallization very fast, whard to control, the crystal that is formed is irregular,
Crystal grain is larger, the problems such as heap density is poor also be present, and the organic solvent of residual is also mixed with resulting product, is unfavorable for using
Medicine security.
The content of the invention
It is an object of the invention to provide a kind of method for crystallising of endoxan, this method passes through using water as recrystallisation solvent
Control temperature crystallizes endoxan, and the crystal form purity formed is high and is free of organic solvent.
In order to realize the above-mentioned purpose of the present invention, spy uses following technical scheme：
A kind of method for crystallising of endoxan, it includes：
By endoxan or its hydrate with water according to mass ratio 1：5~15 mixing, and obtained after being dissolved at 30~50 DEG C
To the endoxan aqueous solution；The endoxan aqueous solution is cooled at -10~5 DEG C again, standing or stirring and crystallizing.
Compared with prior art, beneficial effects of the present invention for example including：
Present disclosure provide this endoxan method for crystallising, first by the crude product of endoxan or its hydrate with
Water mixes, and because solubility of the endoxan in water is smaller, solution is heated to make endoxan therein at 30~50 DEG C
Or its hydrate is completely dissolved, saturated solution or supersaturated solution are formed, then again drops the resulting endoxan aqueous solution
At extremely -10~5 DEG C of temperature, during temperature reduces, the solubility of endoxan or its hydrate in water presents larger
Change, easily separate out crystallization.
This method has certain solubility and its dissolving in water using endoxan using water as recrystallisation solvent in water
Degree reduces with temperature and has the characteristic of large change, controls crystallization well by controlling temperature, need not make in whole process
It is green with any organic solvent；Crystal formation rule, the purity of obtained endoxan crystal are high, and impurity-eliminating effect is obvious.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the present invention.It is unreceipted specific in embodiment
Condition person, the condition suggested according to normal condition or manufacturer are carried out.Agents useful for same or the unreceipted production firm person of instrument, it is
The conventional products that can be obtained by commercially available purchase.
Present embodiment provides a kind of method for crystallising of endoxan, and it comprises the following steps：
Step S1：By endoxan or its hydrate with water according to mass ratio 1：5~15 mixing, and it is molten at 30~50 DEG C
The endoxan aqueous solution is obtained after solution.
Endoxan or the mass ratio of its hydrate and water are controlled, can effectively control the concentration of solution cyclophosphamide,
And then control its crystallization speed.Further, in the endoxan aqueous solution, endoxan or the mass ratio of its hydrate and water are
1：8~10, the endoxan aqueous solution obtained in the range of this mass ratio is in hypersaturated state, easily further cooling analysis
It is brilliant.
Temperature when dissolving endoxan is 30~50 DEG C, be either 35~45 DEG C or is 38~42 DEG C, or is 40
℃.In this temperature range, the solubility of endoxan improves, and dissolving is complete.Inventor, which studies, to be found, in the process,
Temperature should not excessively 50 DEG C, and when temperature is too high, endoxan can resolve into other materials.
Further, before decrease temperature crystalline is carried out to the endoxan aqueous solution, in addition to：Filter the endoxan aqueous solution
The step of.It is preferential to remove the insoluble composition being mixed with the endoxan aqueous solution by filtering, be advantageous to improve endoxan knot
Brilliant purity.
Further, before decrease temperature crystalline is carried out to the endoxan aqueous solution, in addition to：By the endoxan aqueous solution with
Activated carbon mixes, and stirs 10~60min.The endoxan aqueous solution is mixed with activated carbon, using the suction-operated of activated carbon, removed
The impurity such as the endotoxin gone in solution.
Step S2：The endoxan aqueous solution is cooled at -10~5 DEG C, standing or stirring and crystallizing.
During the endoxan aqueous solution is cooled into -10~5 DEG C at 30~50 DEG C, in the process that temperature reduces
In, larger change is presented in the solubility of endoxan or its hydrate in water, easily separates out crystallization.
The final temperature of cooling is -10~5 DEG C, be either -8~0 DEG C or is -6~-4 DEG C, or is -5 DEG C.Enter one
Step ground, the time for standing crystallization is 0.5~2h, is either 0.8~1.5h or is 1~1.2h.During standing so that
The temperature of endoxan aqueous solution core reaches -10~5 DEG C, so as to improve the crystallization effect of endoxan.Stand analysis
The brilliant time is too short, and part endoxan separates out incomplete due to not being cooled to a certain degree；Crystallization overlong time is stood, is held
Easily influence the purity of crystallization.
Further, the endoxan aqueous solution is cooled at -10~0 DEG C, after standing crystallization, after being warming up to 0~10 DEG C
Filtering.After the endoxan aqueous solution is cooled at -10~0 DEG C, while crystallization, the water in solution also can gradually form
Ice, therefore, it is necessary to first by ice-out Cheng Shui during later separation crystallizes, then filtered.Due to the crystalline substance of endoxan
Body can gradually dissolve at slightly higher temperature, therefore in the process, it is necessary to control temperature to make condensation at not higher than 10 DEG C
Ice melts as water, and the yield of endoxan is improved with this.
Further, the endoxan aqueous solution is cooled at -10~5 DEG C, after standing crystallization, in addition to：At 0~10 DEG C
Under melt the ice into water after, filter and dry step.The endoxan crystal separation of solid and liquid, then by drying in the air after filtering of precipitation
The modes such as dry, vacuum drying, freeze-drying are dried, the endoxan after being crystallized.
Further, it will be dissolved at 30~50 DEG C and obtain the endoxan aqueous solution, after naturally cooling to 15~25 DEG C, then
- 10~0 DEG C is cooled in 30~120min, and 0.5~2h is stood at -10~0 DEG C.By effectively controlling rate of temperature fall,
To control the crystalline rate of endoxan, crystallization purity is improved.
Further, the endoxan aqueous solution is made to be cooled to -10~0 DEG C at 15~25 DEG C using cold-trap, using cold-trap,
Can relatively accurate control rate of temperature fall, detection endoxan aqueous solution institute temperature in the environment, effectively control crystallization fast
Rate, and then improve the purity of endoxan crystal.
The method for crystallising that present embodiment provides has certain dissolving using endoxan using water as recrystallisation solvent in water
Degree and its solubility with temperature in water are reduced and have the characteristic of large change, and knot is controlled well by controlling temperature
Crystalline substance, any organic solvent need not be used in whole process, it is green；The crystal formation of obtained endoxan crystal is regular, pure
Degree is high, and impurity-eliminating effect is obvious.
The feature and performance of the present invention are described in further detail with reference to embodiments：
Embodiment 1
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan and water according to mass ratio 1：10 mixing, and it is water-soluble to obtain endoxan after being dissolved at 40 DEG C
Liquid；
B. the endoxan aqueous solution is cooled at 0 DEG C, crystallization 1.5h is stirred with 60 revs/min of rotating speed.
Embodiment 2
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：5 mixing, and obtain ring phosphinylidyne after being dissolved at 50 DEG C
Amine aqueous solution；
B. the endoxan aqueous solution is cooled at -10 DEG C, stands crystallization 0.5h.
Embodiment 3
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：15 mixing, and obtain ring phosphinylidyne after being dissolved at 30 DEG C
Amine aqueous solution；
B. the endoxan aqueous solution is cooled at 5 DEG C, stands crystallization 2h.
Embodiment 4
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：8 mixing, and obtain ring phosphinylidyne after being dissolved at 45 DEG C
Amine aqueous solution, filtering；
B. the endoxan aqueous solution is cooled at -5 DEG C, after being stirred crystallization 1h with 90 revs/min of rotating speed, risen
Temperature is to 5 DEG C, filtering, dry endoxan crystal after the ice dissolving in solution.
Embodiment 5
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：10 mixing, and obtain ring phosphinylidyne after being dissolved at 35 DEG C
Amine aqueous solution, filtering；
B. the endoxan aqueous solution is cooled at 0 DEG C, after standing crystallization 2h, is warming up to 10 DEG C, treats in solution
Filtering, dry endoxan crystal after ice dissolving.
Embodiment 6
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：9 mixing, and obtain ring phosphinylidyne after being dissolved at 40 DEG C
Amine aqueous solution, filtering；
B. the endoxan aqueous solution is cooled at -5 DEG C, after being stirred crystallization 1h with 150 revs/min of rotating speed,
5 DEG C are warming up to, filtering, dry endoxan crystal after the ice dissolving in solution.
Embodiment 7
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：8 mixing, and obtain ring phosphinylidyne after being dissolved at 50 DEG C
Amine aqueous solution；
B. it will be dissolved at 50 DEG C and obtain the endoxan aqueous solution, after naturally cooling to 25 DEG C, then dropped in 90min
Temperature is warming up to 10 DEG C to -3 DEG C, and after standing 2h at -3 DEG C, filtering, dry endoxan after the ice dissolving in solution
Crystal.
Embodiment 8
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：9 mixing, and obtain ring phosphinylidyne after being dissolved at 40 DEG C
Amine aqueous solution；
B. it will be dissolved at 40 DEG C and obtain the endoxan aqueous solution, after naturally cooling to 20 DEG C, then in 120min
It is cooled to -5 DEG C, and after standing 1h at -5 DEG C, is warming up to 5 DEG C, filtering, dry endoxan after the ice dissolving in solution
Crystal.
Embodiment 9
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：9 mixing, and obtain ring phosphinylidyne after being dissolved at 30 DEG C
Amine aqueous solution；
B. it will be dissolved at 30 DEG C and obtain the endoxan aqueous solution, after naturally cooling to 15 DEG C, then dropped in 60min
Temperature is warming up to 10 DEG C to -8 DEG C, and after standing 0.5h at -8 DEG C, filtering, dry ring phosphinylidyne after the ice dissolving in solution
Amine crystal.
Embodiment 10
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：9 mixing, and obtain ring phosphinylidyne after being dissolved at 40 DEG C
Amine aqueous solution；
B. activated carbon is added in the endoxan aqueous solution, stirs 30min.
C. by the endoxan aqueous solution, under conditions of stirring, after naturally cooling to 20 DEG C, then be cooled in 30min-
5 DEG C, and after standing 1h at -5 DEG C, 5 DEG C are warming up to, filtering, dry endoxan crystal after the ice dissolving in solution.
Embodiment 11
Present embodiment provides a kind of method for crystallising of endoxan, and it includes：
A. by endoxan monohydrate and water according to mass ratio 1：5 mixing, and obtain ring phosphinylidyne after being dissolved at 40 DEG C
Amine aqueous solution；
B. activated carbon is added in the endoxan aqueous solution, stirs 30min.
C. by the endoxan aqueous solution, under conditions of stirring, after naturally cooling to 20 DEG C, then be cooled in 30min-
5 DEG C, and after stirring 1h at -5 DEG C, 5 DEG C are warming up to, filtering, dry endoxan crystal after the ice dissolving in solution.
Although illustrate and describing the present invention with specific embodiment, but will be appreciated that without departing substantially from the present invention's
Many other change and modification can be made in the case of spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of method for crystallising of endoxan, it is characterised in that it includes：
By endoxan or its hydrate with water according to mass ratio 1：5~15 mixing, and obtain ring after being dissolved at 30~50 DEG C
Phosphinylidyne amine aqueous solution；The endoxan aqueous solution is cooled at -10~5 DEG C again, standing or stirring and crystallizing.
2. the method for crystallising of endoxan according to claim 1, it is characterised in that the endoxan aqueous solution is stood
The time of crystallization is 0.5~2h.
3. the method for crystallising of endoxan according to claim 1, it is characterised in that also include：By the endoxan
The aqueous solution is cooled at -10~0 DEG C, after standing crystallization, is filtered after being warming up to 0~10 DEG C.
4. the method for crystallising of endoxan according to claim 1, it is characterised in that drop the endoxan aqueous solution
At extremely -10~5 DEG C of temperature, after standing crystallization, in addition to：After water being melted the ice at 0~10 DEG C, filtering and the step dried.
5. the method for crystallising of endoxan according to claim 1, it is characterised in that also include：Will be at 30~50 DEG C
Dissolving obtains the endoxan aqueous solution, after naturally cooling to 15~25 DEG C, then -10~0 is cooled in 30~120min
DEG C, and 0.5~2h is stood at -10~0 DEG C.
6. the method for crystallising of endoxan according to claim 5, it is characterised in that make the endoxan using cold-trap
The aqueous solution is cooled to -10~0 DEG C at 15~25 DEG C.
7. the method for crystallising of endoxan according to claim 1, it is characterised in that by the endoxan aqueous solution
During being cooled at -10~5 DEG C, in addition to the step of stirring endoxan aqueous solution.
8. the method for crystallising of endoxan according to claim 1, it is characterised in that to the endoxan aqueous solution
Before carrying out decrease temperature crystalline, in addition to：The step of filtering the endoxan aqueous solution.
9. the method for crystallising of endoxan according to claim 1, it is characterised in that to the endoxan aqueous solution
Before carrying out decrease temperature crystalline, in addition to：The endoxan aqueous solution is mixed with activated carbon, stirs 10~60min.
10. the method for crystallising of endoxan according to claim 1, it is characterised in that in the endoxan aqueous solution,
The endoxan or the mass ratio of its hydrate and water are 1：8~10.
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| CN201710882263.3A CN107540711A (en) | 2017-09-26 | 2017-09-26 | A kind of method for crystallising of endoxan |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114437130A (en) * | 2022-02-18 | 2022-05-06 | 安徽普利药业有限公司 | Method for refining cyclophosphamide |
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2017
- 2017-09-26 CN CN201710882263.3A patent/CN107540711A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114437130A (en) * | 2022-02-18 | 2022-05-06 | 安徽普利药业有限公司 | Method for refining cyclophosphamide |
| CN114437130B (en) * | 2022-02-18 | 2024-05-17 | 安徽普利药业有限公司 | Process for purifying cyclophosphamide |
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