CN109748934A - A kind of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form and preparation method thereof - Google Patents
A kind of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form and preparation method thereof Download PDFInfo
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- CN109748934A CN109748934A CN201910115156.7A CN201910115156A CN109748934A CN 109748934 A CN109748934 A CN 109748934A CN 201910115156 A CN201910115156 A CN 201910115156A CN 109748934 A CN109748934 A CN 109748934A
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Abstract
The invention belongs to chemicals crystallization technique fields, more particularly to a kind of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form and preparation method thereof, phosphoric acid l-ornidazole ester disodium heptahydrate X-ray powder diffraction figure of the invention is 6.6, 12.0, 13.1, 14.1, 14.8, 16.5, 17.9, 19.2, 19.7, 20.5, 21.2, 22.1, 23.1, 24.2, 24.6, 25.1, 25.5, 26.3, 27.5, 28.2, 28.6, 30.4, 31.3, 31.7, 32.0, 32.7, 33.1, 33.6, 34.5, 35.2, 36.0, 36.4, 37.8, 41.5, 53.9, there is characteristic peak at 55.0, crystal form For rhombic system, P212121 space group, cell parameter and calculating unit-cell volume are as follows:A=90o, β=90o, γ=90o,Phosphoric acid l-ornidazole ester disodium heptahydrate crystal form provided by the invention, purity is high, stability of crystal form is good, and preparation method is easy, is suitable for industrialized production.
Description
Technical field
The invention belongs to chemicals crystallization technique fields, and in particular to a kind of phosphoric acid l-ornidazole ester disodium heptahydrate
Crystal form and preparation method thereof.
Background technique
Ornidazole is nitro imidazole derivatives, is the drug of a kind of strength anaerobe resistant and antigen insect infection, and after
Curative effect is higher, curative effect is shorter, tolerance is more preferable, is distributed wider array of third generation nitroimidazole in vivo made of newly developing after metronidazole
Analog derivative.
In the further research to Ornidazole, it has been found that, after Ornidazole use, a degree of maincenter poison can be generated
Property, and its single levo-enantiomer maincenter toxicity will be well below its raceme, this has guided one for the research of Ornidazole
New direction.
Phosphoric acid l-ornidazole ester disodium is the pro-drug of laevo-ornidazole, can be dropped under phosphatide enzyme effect in vivo after administration
Solution is that laevo-ornidazole plays drug effect.A kind of l-ornidazole phosphate ester and preparation method thereof is referred in patent CN100451023C
And purposes.A kind of l-ornidazole disodium hydrogen phosphate hydrate and its preparation method and application is referred in patent CN101177433.Specially
It refers to obtain different two sodium crystals of phosphoric acid l-ornidazole ester by changing solvent and leaching condition in sharp CN106467558A
And provide four kinds of crystal form X-ray powder diffraction figure characteristics.I is at two sodium crystal of phosphoric acid l-ornidazole ester of company's development
Heptahydrate, at present there is no pertinent literature reports.Research finds discovery 7 hydrate crystal forms of phosphoric acid l-ornidazole ester disodium, and there are two
Kind form, i.e. 6 crystallizations water add 1 free water (form 1) and 7 crystallizations water (form 1), both X-ray powder spread out
It is identical to penetrate the presentation of figure Partial Feature peak, but its physics and chemical property still have notable difference, form 1 is held in storage process
Easily loses free water and switch to 6 hydrate of phosphoric acid l-ornidazole ester disodium；Form 2 is stable rhombic system because of it
(P212121) structure, storage process will not dehydration turn crystalline substances.For drug, there may be different physics and chemistry for different crystal forms
Property, such as fusing point, solubility, stability, these information directly will affect the stability, dissolubility or even shadow of pharmaceutical preparation
Ring clinical efficacy.
It therefore, is significantly, still to the crystal form preparation and research of phosphoric acid l-ornidazole ester disodium heptahydrate
The crystal form of phosphoric acid l-ornidazole ester disodium heptahydrate is studied, while distinguishing 6 crystallizations water and adding the phosphorus of 1 crystallization water
Sour l-ornidazole ester disodium meta-stable structure crystal form.
Summary of the invention
For blank of the existing technology, the present invention provide a kind of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form and
Preparation method, it is therefore an objective to the phosphoric acid l-ornidazole ester disodium meta-stable structure crystal form that 6 crystallizations water add 1 crystallization water is distinguished,
Research and development for Ornidazole drug provides support.
Phosphoric acid l-ornidazole ester disodium heptahydrate Chinese chemical name of the invention is the chloro- 3- of phosphoric acid -1- (2- methyl -5-
Nitro -1H- imidazoles -1- base) propyl alcohol ester disodium heptahydrate, molecular formula C7H9ClN3Na2O6P.7H2O, molecular weight are
469.68 structural formula is as follows:
The present invention also provides amount phosphoric acid l-ornidazole ester disodium heptahydrate crystal form X-ray powder diffraction figure characteristic peak,
It is as follows:
The XRPD map of the crystal form can also be further above-mentioned 2θAngle Position has characteristic peak: 6.6,12.0,13.1,
14.1、14.8、16.5、17.9、19.2、19.7、20.5、21.2、22.1、23.1、24.2、24.6、25.1、25.5、26.3、
27.5、28.2、28.6、30.4、31.3、31.7、32.0、32.7、33.1、33.6、34.5、35.2、36.0、36.4、37.8、
41.5、53.9、55.0。
The angle of crystal form characteristic peak of the present invention uses the expression method of this field routine, and allowable error is when being accurate to 0.1 °
+0.2.The principle usually to round up, as other 2θThe demonstration of accuracy.
The third aspect of the invention provides the crystallographic structure number of phosphoric acid l-ornidazole ester disodium heptahydrate monocrystalline
According to and structure refinement parameter, it is as follows:
The test data is only one kind when describing this product test.Its data can have a little according to the difference of determination condition
Variation should still be interpreted as the model great waves of this patent protection.
Phosphoric acid l-ornidazole ester disodium heptahydrate crystal form of the present invention has stable space structure, with the chemical combination
Other crystal forms of object compare, and stability is more preferable, can guarantee mass conservation for a long time, effectively extend guaranteeing the quality for product
Phase.
Another aspect of the present invention provides the preparation method of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form, it includes
Following preparation method:
Phosphoric acid l-ornidazole ester disodium is taken, solvent dissolved clarification is added, is filtered into monocrystalline bottle, crystal seed is added, in assigned temperature
Lower stirring or standing are precipitated to solid, filtering, and it is brilliant to obtain phosphoric acid l-ornidazole ester disodium heptahydrate for solid to 20~30 DEG C of dryings
Type.
The solvent is mixed solvent, and one of solvent should be water；Organic solvent is methanol, acetone, acetonitrile, second
The one or more of alcohol, normal propyl alcohol, isopropanol, n-butanol.
Preferably 15~35 DEG C of the assigned temperature, further preferably 20~30 DEG C.
Times amount that the solvent uses is 10~200 times of amounts (W/V) of phosphoric acid l-ornidazole ester disodium.
Compared with prior art, the features of the present invention and beneficial effect are:
The preparation method of phosphoric acid l-ornidazole ester disodium heptahydrate provided by the invention is easy, is suitable for industrialized production.
The phosphoric acid l-ornidazole ester disodium heptahydrate crystal form that the present invention obtains, purity is high, stability of crystal form are good.
Detailed description of the invention
Fig. 1 is the compounds of this invention phosphoric acid l-ornidazole ester disodium heptahydrate crystal PLM photo；
Fig. 2 is the compounds of this invention phosphoric acid l-ornidazole ester disodium heptahydrate mono-crystalline structures cell schematics；
Fig. 3 is that the packed structures of molecule in the compounds of this invention phosphoric acid l-ornidazole ester disodium heptahydrate mono-crystalline structures are shown
It is intended to (in terms of a axis direction)；
Fig. 4 is that the packed structures of molecule in the compounds of this invention phosphoric acid l-ornidazole ester disodium heptahydrate mono-crystalline structures are shown
It is intended to (in terms of b axis direction)；
Fig. 5 is that the packed structures of molecule in the compounds of this invention phosphoric acid l-ornidazole ester disodium heptahydrate mono-crystalline structures are shown
It is intended in (in terms of c-axis direction)；
Fig. 6 is the compounds of this invention phosphoric acid l-ornidazole ester disodium heptahydrate XRPD map.
Specific embodiment
Embodiment 1
Phosphoric acid l-ornidazole ester disodium 10g is taken, 100ml mixed solvent (water/ethyl alcohol=1:20, v/v) dissolved clarification, filtering is added
Into new single-crystal bottle, a small amount of sample is added as crystal seed, is precipitated at 5~25 DEG C to solid, filtering, solid to 20~30 DEG C it is dry
It is dry, obtain phosphoric acid l-ornidazole ester disodium heptahydrate crystal form.
The present embodiment product yield is 85%, and purity 99.8%, compound crystal is shown in Fig. 1.
Embodiment 2
Phosphoric acid l-ornidazole ester disodium 10g is taken, 200ml mixed solvent (water/methanol=1:10, v/v) dissolved clarification, filtering is added
Into new single-crystal bottle, a small amount of sample is added as crystal seed, is precipitated at 10~30 DEG C to solid, filtering, solid is to 20~30 DEG C
It is dry, obtain phosphoric acid l-ornidazole ester disodium heptahydrate crystal form.
The present embodiment product yield is 80%, purity 99.9%.
Embodiment 3
Phosphoric acid l-ornidazole ester disodium 10g is taken, 300ml mixed solvent (water/acetone=1:15, v/v) dissolved clarification, filtering is added
Into new single-crystal bottle, a small amount of sample is added as crystal seed, is precipitated at 10~20 DEG C to solid, filtering, solid is to 20~30 DEG C
It is dry, obtain phosphoric acid l-ornidazole ester disodium heptahydrate crystal form.
The present embodiment product yield is 75%, purity 99.6%.
Embodiment 4
Phosphoric acid l-ornidazole ester disodium 15g is taken, it is molten that 300ml mixed solvent (water/normal propyl alcohol=1:15, v/v) stirring is added
Solution is filtered into new single-crystal bottle, and a small amount of sample is added as crystal seed, is precipitated at 10~20 DEG C to solid, filtering, solid to 20
~30 DEG C of dryings obtain two sodium crystal of phosphoric acid l-ornidazole ester, yield 78%.
Embodiment 5
Phosphoric acid l-ornidazole ester disodium 50g is taken, 1000ml mixed solvent (water/ethanol/acetone=1:15:15, v/v/ is added
V) stirring and dissolving is filtered into new single-crystal bottle, and a small amount of sample is added as crystal seed, is precipitated at 10~20 DEG C to solid, filtering,
Solid obtains phosphoric acid l-ornidazole ester disodium heptahydrate crystal form to 20~30 DEG C of dryings.
The present embodiment product yield is 86%, purity 99.9%.
Embodiment 6
Phosphoric acid l-ornidazole ester disodium 20g is taken, 500ml mixed solvent (water/ethyl alcohol=1:15, v/v) stirring and dissolving is added,
Filtering is added a small amount of sample as crystal seed, is precipitated at 5~20 DEG C to solid into new single-crystal bottle, filtering, solid to 20~30
DEG C forced air drying, obtains phosphoric acid l-ornidazole ester disodium heptahydrate crystal form, yield 90%.
Embodiment 7
Phosphoric acid l-ornidazole ester disodium 50g is taken, it is molten that 1000ml mixed solvent (water/acetonitrile=1:10, v/v) stirring is added
Solution is filtered into new single-crystal bottle, and a small amount of sample is added as crystal seed, is precipitated at 5~20 DEG C to solid, filtering, solid to 20
~30 DEG C of forced air dryings obtain phosphoric acid l-ornidazole ester disodium heptahydrate crystal form, yield 83%.
Embodiment 8
Phosphoric acid l-ornidazole ester disodium 100g is taken, 5000ml mixed solvent (water/isopropanol=1:20, v/v) stirring is added
Dissolution is filtered into new single-crystal bottle, and a small amount of sample is added as crystal seed, is precipitated at 10~25 DEG C to solid, filtering, solid is extremely
20~30 DEG C of forced air dryings obtain phosphoric acid l-ornidazole ester disodium heptahydrate crystal form.
The present embodiment product yield is 81%, purity 99.4%.
Embodiment 9
Phosphoric acid l-ornidazole ester disodium 10g is taken, 500ml mixed solvent (water/ethyl alcohol=1:15, v/v) dissolved clarification, filtering is added
Into new single-crystal bottle, a small amount of sample is added as crystal seed, is precipitated at 10~25 DEG C to solid, filtering, solid is to 20~30 DEG C
Forced air drying obtains phosphoric acid l-ornidazole ester disodium heptahydrate crystal form.
The present embodiment product yield is 82%, purity 99.9%.
Embodiment 10
Phosphoric acid l-ornidazole ester disodium heptahydrate crystal form is compared with other stability of crystal form of this compound:
Phosphoric acid l-ornidazole ester disodium heptahydrate crystal form and other crystal forms of this compound prepared by above-described embodiment 9 is put
It is as follows to set 60 DEG C of 10 days stability comparison results:
Chromatographic column: octadecylsilane chemically bonded silica be filler (C18,250 × 4.6mm, 5 μm of Waters XBridge or
Efficiency is comparable)
Mobile phase: mobile phase A, 0.05mol/L potassium dihydrogen phosphate (contain 0.5% triethylamine, extremely with phosphorus acid for adjusting pH value
3.0), using methanol as Mobile phase B
Column temperature: 35 DEG C；Flow velocity: 1ml/min；Detection wavelength: 312nm
The above results show the stability of phosphoric acid l-ornidazole ester disodium heptahydrate of the invention compared with this compound its
His stability of crystal form is good.
The embodiments described above only express several embodiments of the present invention, and but it cannot be understood as to invention
The limitation of the scope of the patents.It should be pointed out that for those of ordinary skill in the art, not departing from present inventive concept
Under the premise of, various modifications and improvements can be made, and these are all within the scope of protection of the present invention.The protection model of the invention patent
Enclosing should be determined by the appended claims.
Claims (9)
1. a kind of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form, which is characterized in that phosphoric acid l-ornidazole ester disodium seven is hydrated
Object structural formula is as follows:
2. a kind of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form according to claim 1, it is characterised in that: phosphoric acid is left
The X-ray powder diffraction figure of Ornidazole ester disodium heptahydrate 6.6,12.0,13.1,14.1,14.8,16.5,17.9,
19.2、19.7、20.5、21.2、22.1、23.1、24.2、24.6、25.1、25.5、26.3、27.5、28.2、28.6、30.4、
31.3, there is feature at 31.7,32.0,32.7,33.1,33.6,34.5,35.2,36.0,36.4,37.8,41.5,53.9,55.0
Peak.
3. phosphoric acid l-ornidazole ester disodium heptahydrate crystal form according to claim 2, it is characterised in that: the X-ray
Powder diagram is as shown in Figure of description 6.
4. phosphoric acid l-ornidazole ester disodium heptahydrate crystal form according to claim 1, it is characterised in that: the crystal form is positive
Hand over crystallographic system, P212121 space group, cell parameter and calculating unit-cell volume are as follows: A=90o, β=90o, γ=90o,
5. a kind of preparation method of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form described in claim 1, it is characterised in that
It follows the steps below:
Phosphoric acid l-ornidazole ester disodium is taken, solvent dissolved clarification is added, is filtered into monocrystalline bottle, crystal seed is added, stirs under assigned temperature
It mixes or stands and be precipitated to solid, filtering, solid to 20~30 DEG C of dryings obtains phosphoric acid l-ornidazole ester disodium heptahydrate.
6. the preparation method of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form according to claim 5, it is characterised in that
The solvent is the mixed solvent of water and organic solvent, and the organic solvent is methanol, acetone, acetonitrile, ethyl alcohol, positive third
The one or more of alcohol, isopropanol, n-butanol.
7. the preparation method of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form according to claim 5, it is characterised in that
The assigned temperature is 15~35 DEG C.
8. the preparation method of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form according to claim 7, it is characterised in that
The assigned temperature is 20~30 DEG C.
9. the preparation method of phosphoric acid l-ornidazole ester disodium heptahydrate crystal form according to claim 5, it is characterised in that
Times amount that the solvent uses is 10~200 times of disodium amounts (W/V) of phosphoric acid nitre azoles ester.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107151257A (en) * | 2016-03-04 | 2017-09-12 | 陕西合成药业股份有限公司 | A kind of phosphoric acid l-ornidazole ester disodium hexahydrate crystal formation and preparation method thereof |
| CN107857779A (en) * | 2016-09-22 | 2018-03-30 | 天地人和生物科技有限公司 | A kind of method for preparing high-purity phosphoric acid l-ornidazole ester disodium |
| CN108409786A (en) * | 2018-02-10 | 2018-08-17 | 扬子江药业集团南京海陵药业有限公司 | A kind of industrialized preparing process of phosphoric acid l-ornidazole ester disodium hydrate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107151257A (en) * | 2016-03-04 | 2017-09-12 | 陕西合成药业股份有限公司 | A kind of phosphoric acid l-ornidazole ester disodium hexahydrate crystal formation and preparation method thereof |
| CN107857779A (en) * | 2016-09-22 | 2018-03-30 | 天地人和生物科技有限公司 | A kind of method for preparing high-purity phosphoric acid l-ornidazole ester disodium |
| CN108409786A (en) * | 2018-02-10 | 2018-08-17 | 扬子江药业集团南京海陵药业有限公司 | A kind of industrialized preparing process of phosphoric acid l-ornidazole ester disodium hydrate |
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