CN104610356A - Stable phosphate crystal and preparation method thereof - Google Patents
Stable phosphate crystal and preparation method thereof Download PDFInfo
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- CN104610356A CN104610356A CN201410611786.0A CN201410611786A CN104610356A CN 104610356 A CN104610356 A CN 104610356A CN 201410611786 A CN201410611786 A CN 201410611786A CN 104610356 A CN104610356 A CN 104610356A
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- ornidazole
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Abstract
The invention relates to an s-ornidazole phosphate crystal with good stability and a preparation method thereof. The method comprises the following steps: reacting s-ornidazole with phosphorus oxychloride; carrying out hydrolyzing; and then carrying out recrystallizing by using an acetone/water mixed solvent so as to obtain s-ornidazole phosphate. According to the Cu-Ka radiation results of the obtained s-ornidazole phosphate, 2theta expressed in degrees has no diffraction peaks within 0 to 20 degrees and has diffraction peaks at 23.219 degrees and 32.938 degrees. Research results show that the crystal provided by the invention has good stability.
Description
Technical field
The present invention relates to crystallisate of a kind of levo-ornidazole phosphate and preparation method thereof.
Background technology
Phosphation is a kind of common Prodrug formed designs method, can improve parent drug water-soluble, improve pharmacokinetic property, improve targeting, reduce poisonous side effect of medicine, increase medicine stability etc., obtain in modern medicines research and development and pay attention to widely and application.
The compound of a kind of novel structure that levo-ornidazole phosphate disodium (I) obtains according to the exploitation of this principle just, this product is as the prodrug of Levo-ornidazole, comparatively ornidazole has significant clinical advantage, be in clinical investigation phase in recent years, the potential Antibiotics usage as a new generation is in clinical.
Chinese patent CN200610166893.2 discloses Levo-ornidazole ester and the application in anaerobe resistant and indigenous microorganisms infection thereof, and schematically illustrate with methyl alcohol/sherwood oil, and methanol/ethanol is that mixed solvent carries out crystallization, prepare levo-ornidazole phosphate disodium, the specific optical rotation disclosing products obtained therefrom in literary composition is-19.8 ° of crystal formation data not disclosing gained sample further, research shows that the specific optical rotation of levo-ornidazole phosphate disodium pentahydrate is about-19.5 °, therefore can think that the method prepares for containing the levo-ornidazole phosphate disodium being about 5 crystal water.
Chinese patent CN200710188487.0 discloses levo-ornidazole phosphate disodium pentahydrate, and preparation method thereof and purposes, the document provides the method preparing crystallinity levo-ornidazole phosphate disodium pentahydrate, namely with 95-70% ethanol for medium carries out recrystallization.Then the document does not provide the relevant physicochemical constant of the crystal material of gained, such as X-ray, IR, the data such as fusing point, and only the situation in conjunction with crystal water is investigated in employing thermogravimetric analysis and moisture determination, namely containing 5 crystal water.
Chinese patent application 201210032972.X discloses levo-ornidazole phosphate disodium hexahydrate, and preparation method thereof and purposes, the document provides preparation crystallinity levo-ornidazole phosphate disodium hexahydrated method, namely with 90% ethanol for medium carries out recrystallization.The document discloses the single crystal diffraction data of products obtained therefrom, illustrate that this product has the trend losing crystal water simultaneously.
In further studying, we find that Levo-ornidazole phosphodiester sodium adopts Chinese patent CN200610166893.2, the crystal formation that what CN200710188487.0 and patent application 201210032972.X all obtained is containing 5-7 Bound moisture, and this crystal formation has certain unstable, than being easier to lose Bound moisture, thus affect the stability of product.For this reason, we further study the crystal formation of levo-ornidazole phosphate disodium, obtain a kind of new levo-ornidazole phosphate crystallization unexpectedly, this crystal material is not containing sodium salt, and not containing crystal water, research shows that this product has satisfactory stability, and suitable suitability for industrialized production.
Summary of the invention
The invention provides a kind of levo-ornidazole phosphate crystallisate and preparation method thereof, this stable crystal form, suitable suitability for industrialized production.
Specifically, the invention provides a kind of levo-ornidazole phosphate crystallisate, its X-ray powder diffraction pattern is as shown in table 1.
The X-ray diffraction data of table 1 levo-ornidazole phosphate crystallisate
| Peak is numbered | 2θ | D value | Intensity | I/I 0 |
| 1 | 23.219 | 3.828 | 183 | 15.9 |
| 2 | 32.938 | 2.717 | 1153 | 100 |
Levo-ornidazole phosphate new crystal provided by the invention, its DSC scanning has endotherm(ic)peak between 180-210 DEG C, and Fig. 2 is shown in by its DSC collection of illustrative plates, and Fig. 3 is shown in by TG collection of illustrative plates.
In embodiment of the present invention, provide the preparation method of levo-ornidazole phosphate new crystal, comprise the steps:
(1) Levo-ornidazole is dissolved in organic solvent, slow dropping phosphorus oxychloride, temperature control 30-50 DEG C to reacting completely, wherein organic solvent is selected from ethyl acetate, acetonitrile, tetrahydrofuran (THF) etc., organic solvent is 5:1 ~ 20:1 with the volume mass ratio of Levo-ornidazole, and phosphorus oxychloride is 0.8:1 ~ 5:1 with the volume mass ratio of Levo-ornidazole;
(2) react complete, add suitable quantity of water, continue to stir in room temperature, then concentrating under reduced pressure is levo-ornidazole phosphate except desolventizing obtains oily matter;
(2) in oily matter, add acetone/water, stirring and crystallizing, the volume ratio of acetone and water is 10 ~ 50:1, about 1 to 10 hour crystallization time;
(4) filter, dry levo-ornidazole phosphate.
Related substance testing conditions involved in the present invention and method are: measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D):
Chromatographic condition and system suitability: be weighting agent with octadecane silane group silica gel: with the potassium dihydrogen phosphate-methyl alcohol (80:20) of 0.05mol/l for moving phase, determined wavelength is 320nm, and theoretical plate number calculates should be not less than 2000 by levo-ornidazole phosphate disodium peak.The resolution at levo-ornidazole phosphate disodium peak and other impurities peak should meet the requirements.
Assay method sample thief, add moving phase and dissolve and make the solution of every 1ml containing 0.5mg, measure 20 μ l, inject liquid chromatography respectively, record color atlas is to 3 times of principal constituent peak retention time.
The characteristic of levo-ornidazole phosphate crystallization:
1, solvability: test with reference to Chinese Pharmacopoeia version in 2010 two notes on the use
Method: it is appropriate that precision takes levo-ornidazole phosphate, and slowly add a certain amount of solvent, the powerful jolting 30 seconds every 5 minutes, observes the dissolving situation in 30 minutes, the results are shown in Table 2.
Table 2 levo-ornidazole phosphate crystals solubility is tested
| Solvent | Trial-product amount (g) | Quantity of solvent (ml) | Dissolving situation | Conclusion |
| Methyl alcohol | 0.1 | 12 | Dissolve clarification | Dissolve |
| Ethanol | 0.1 | 18 | Dissolve clarification | Slightly molten |
| Water | 0.1 | 3.2 | Dissolve clarification | Soluble |
2, water content
Three batch sample measured results are as follows:
| Lot number | Moisture (%) |
| 201305001 | 1.2％ |
| 201305002 | 0.8％ |
| 201305003 | 1.1％ |
From above-mentioned water content detection data, this product is not containing crystal water.
3, compare with the hexahydrated stability of levo-ornidazole phosphate disodium
3.1 exposure experiments to light
Levo-ornidazole phosphate (A) and levo-ornidazole phosphate disodium hexahydrate (B) opening being placed on is equipped with in the illumination apparatus of fluorescent lamp, thickness≤5mm, intensity of illumination is place 10 days under the condition of 4500lx ± 500lx, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, and contrast with the result of 0 day.The results are shown in Table 3.
Table 3 illumination experiment result
In summary, compd A and compd B under light illumination quality product are all stable, related substance, content, and outward appearance and moisture all do not demonstrate otherness.
3.2 high wet tests
Levo-ornidazole phosphate (A) and levo-ornidazole phosphate disodium hexahydrate (B) opening are put in climatic chamber, place 10 days at 25 ± 5 DEG C of temperature, relative humidity is 92.5%, thickness≤5mm, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, and contrast with the result of 0 day.The results are shown in Table 4
Table 4 high humidity test-results
Correlation data can find, the related substance of compd A, content (deduction moisture), and appearance change is less, has certain water-absorbent, and compd B content reduces, and moisture increases obviously, and content reduces simultaneously.In summary, compd A comparatively compd B stablize at high humidity.
3.4 high temperature test
Levo-ornidazole phosphate (A) and levo-ornidazole phosphate disodium hexahydrate (B) opening are put in suitable clean container, place 10 days at 60 DEG C of temperature, thickness≤5mm, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, and contrast with the result of 0 day.The results are shown in Table 5
Table 5 high temperature test result
Correlation data can find, the related substance of compd A, content, and outward appearance and moisture are all without noticeable change, and the index of correlation of compd B then all has change to a certain degree.In summary, compd A is compared with compd B, more stable under high-temperature.
3.5 Acceleration study
Levo-ornidazole phosphate disodium crystalline hydrate (A) and levo-ornidazole phosphate disodium hexahydrate (B) polyethylene film plastic bag sealing are packed, be placed in 40 ± 2 DEG C, relative humidity is in the climatic chamber of 75 ± 5%, sample respectively once 1st month, 2 months, 3 months, 6 the end of month at duration of test, detect by stability high spot reviews project, and contrast with 0 month result.The results are shown in Table 6
Table 6 Acceleration study
In summary, all there is not obvious change in the outward appearance, content, related substance etc. of sample A, and sample B as a comparison, related substance increases by 7.5 times, there is obvious phenomenon of losing water simultaneously.Result of study show sample A under the condition of accelerated test comparatively sample B there is satisfactory stability more.
Accompanying drawing explanation
Accompanying drawing 1: the X-ray collection of illustrative plates of levo-ornidazole phosphate
Accompanying drawing 2: the DSC collection of illustrative plates of levo-ornidazole phosphate
Accompanying drawing 3: the TG collection of illustrative plates of levo-ornidazole phosphate
Embodiment
The preparation of embodiment 1 levo-ornidazole phosphate crystallisate
Left-handed nitre 100g difficult to understand, adds ethyl acetate 800ml, slowly drips phosphorus oxychloride 150ml, 45 DEG C of stirring reactions, react complete, in reaction solution, add water 50ml, stir 30min, concentrating under reduced pressure obtains oily matter, in oily matter, add acetone 200ml, water 40ml, stir crystallization, obtain levo-ornidazole phosphate in 30 DEG C of vacuum-dryings, moisture determination value is 1.2%.
The preparation of embodiment 2 levo-ornidazole phosphate crystallisate
Left-handed nitre 100g difficult to understand, adds ethyl acetate 600ml, slowly drips phosphorus oxychloride 120ml, 30 DEG C of stirring reactions, react complete, in reaction solution, add water 30ml, stir 30min, concentrating under reduced pressure obtains oily matter, in oily matter, add acetone 300ml, water 10ml, stir crystallization, obtain levo-ornidazole phosphate in 30 DEG C of vacuum-dryings, moisture determination value is 0.8%.
The hexahydrated preparation of embodiment 3 levo-ornidazole phosphate disodium
Levo-ornidazole phosphate disodium 20g, adds 420ml 90% ethanol, slow crystallization, and suction filtration, filter cake, through drying, obtain levo-ornidazole phosphate disodium hexahydrate, and moisture determination value is 24.21%.
Claims (3)
1. the crystal material of compound (I):
It is characterized in that, use Cu-Ka radiation, to spend the 2 θ salt free ligands peak in 0 ~ 20 represented, 23.219,32.938 have diffraction peak.
2. crystal material according to claim 1 and 2, its DSC scanning has an endotherm(ic)peak between 180 ~ 210 DEG C.
3. the preparation method of crystal material described in arbitrary claim in claims 1 to 3, comprises the steps:
(1) Levo-ornidazole is dissolved in organic solvent, slow dropping phosphorus oxychloride, temperature control 30-50 DEG C to reacting completely, wherein organic solvent is selected from ethyl acetate, acetonitrile, tetrahydrofuran (THF) etc., organic solvent is 5:1 ~ 20:1 with the volume mass ratio of Levo-ornidazole, and phosphorus oxychloride is 0.8:1 ~ 5:1 with the volume mass ratio of Levo-ornidazole;
(2) react complete, add suitable quantity of water, continue to stir in room temperature, then concentrating under reduced pressure is levo-ornidazole phosphate except desolventizing obtains oily matter;
(3) in oily matter, add acetone/water, stirring and crystallizing, the volume ratio of acetone and water is 10 ~ 50:1, about 1 to 10 hour crystallization time;
(4) filter, dry levo-ornidazole phosphate.
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Cited By (2)
| 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 |
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| CN1803811A (en) * | 2006-01-06 | 2006-07-19 | 西安新安医药科技有限公司 | Nitro imidazole derivative, its preparation method and uses |
| CN101007823A (en) * | 2006-01-06 | 2007-08-01 | 西安新安医药科技有限公司 | Levo-ornidazole phosphate, preparing process and use thereof |
| CN101177433A (en) * | 2007-12-05 | 2008-05-14 | 陕西新安医药科技有限公司 | (s)-ornidazole disodium phosphate pentahydrate as well as preparation method and uses thereof |
| CN102516298A (en) * | 2011-12-09 | 2012-06-27 | 陕西合成药业有限公司 | Stable pharmaceutical salt of L-aonitrate phosphate ester, its preparation method and application |
| CN102731571A (en) * | 2012-02-14 | 2012-10-17 | 陕西合成药业有限公司 | Novel crystalline s-(-)-ornidazole phosphate disodium hydrate and application thereof |
| US20130202698A1 (en) * | 2005-07-08 | 2013-08-08 | Nanjing Sanhome Pharmaceutical Co., Ltd. | L-ornidazole formulations and their applications in treatment of parasitic infections |
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2014
- 2014-11-04 CN CN201410611786.0A patent/CN104610356A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130202698A1 (en) * | 2005-07-08 | 2013-08-08 | Nanjing Sanhome Pharmaceutical Co., Ltd. | L-ornidazole formulations and their applications in treatment of parasitic infections |
| CN1803811A (en) * | 2006-01-06 | 2006-07-19 | 西安新安医药科技有限公司 | Nitro imidazole derivative, its preparation method and uses |
| CN101007823A (en) * | 2006-01-06 | 2007-08-01 | 西安新安医药科技有限公司 | Levo-ornidazole phosphate, preparing process and use thereof |
| CN101177433A (en) * | 2007-12-05 | 2008-05-14 | 陕西新安医药科技有限公司 | (s)-ornidazole disodium phosphate pentahydrate as well as preparation method and uses thereof |
| CN102516298A (en) * | 2011-12-09 | 2012-06-27 | 陕西合成药业有限公司 | Stable pharmaceutical salt of L-aonitrate phosphate ester, its preparation method and application |
| CN102731571A (en) * | 2012-02-14 | 2012-10-17 | 陕西合成药业有限公司 | Novel crystalline s-(-)-ornidazole phosphate disodium hydrate and application thereof |
Cited By (2)
| 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 |
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Application publication date: 20150513 |