CN109748934B - Levoornidazole disodium phosphate heptahydrate crystal form and preparation method thereof - Google Patents
Levoornidazole disodium phosphate heptahydrate crystal form and preparation method thereof Download PDFInfo
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- CN109748934B CN109748934B CN201910115156.7A CN201910115156A CN109748934B CN 109748934 B CN109748934 B CN 109748934B CN 201910115156 A CN201910115156 A CN 201910115156A CN 109748934 B CN109748934 B CN 109748934B
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Abstract
The invention belongs toThe invention relates to a crystal form of disodium l-ornidazole phosphate heptahydrate and a preparation method thereof, and belongs to the technical field of chemical drug crystallization, wherein an X-ray powder diffraction pattern of the disodium l-ornidazole phosphate heptahydrate has characteristic peaks at 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 and 55.0, the crystal form is an orthorhombic crystal form, a P212121 space group, and the unit cell parameters and the calculated volume are as follows:
a＝90o，β＝90o，γ＝90o，
the crystal form of the disodium levoornidazole phosphate heptahydrate provided by the invention has the advantages of high purity, good crystal form stability and simple and convenient preparation method, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical drug crystallization, and particularly relates to a crystal form of disodium levoornidazole phosphate heptahydrate and a preparation method thereof.
Background
The ornidazole is a nitroimidazole derivative, is a drug for strongly resisting anaerobic bacteria and protozoan infection, and is a third-generation nitroimidazole derivative which is newly developed after metronidazole and has higher curative effect, shorter curative effect, better tolerance and wider in vivo distribution.
In the further research on ornidazole, people find that after ornidazole is used, a certain degree of central toxicity is generated, and the central toxicity of a single levorotatory enantiomer is far lower than that of a racemate thereof, so that a new direction is guided for the research on ornidazole.
The disodium levoornidazole phosphate is a pro-drug of the levoornidazole, and can be degraded into the levoornidazole to play a drug effect under the action of phospholipase in vivo after administration. Patent CN100451023C mentions a levoornidazole phosphate ester, its preparation method and application. Patent CN101177433 mentions a levoornidazole disodium phosphate hydrate, its preparation method and application. Patent CN106467558A mentions that different crystal forms of disodium levoornidazole phosphate are obtained by changing the solvent and dissolution conditions and provides characteristic data of X-ray powder diffraction patterns of four crystal forms. The crystal form of the disodium levoornidazole phosphate developed by the company is heptahydrate, and no relevant literature report exists at present. Research finds that the crystal form of the disodium l-ornidazole phosphate 7 hydrate has two forms, namely 6 crystal waters plus 1 free water (form 1) and 7 crystal waters (form 1), partial characteristic peaks of X-ray powder diffraction patterns of the two crystals are the same, but the physical and chemical properties of the two crystals are obviously different, and the form 1 is easy to lose the free water and is converted into the disodium l-ornidazole phosphate 6 hydrate in the storage process; form 2 does not lose water and transform crystals during storage because it is a stable orthorhombic (P212121) structure. For a drug, different crystal forms may have different physicochemical properties, such as melting point, solubility, stability, etc., and such information directly affects the stability, solubility, and even clinical efficacy of a pharmaceutical preparation.
Therefore, the preparation and research of the crystal form of the disodium levoornidazole phosphate heptahydrate are very meaningful, so that the research on the crystal form of the disodium levoornidazole phosphate heptahydrate is carried out, and the metastable structural crystal form of the disodium levoornidazole phosphate with 6 crystal waters and 1 crystal water is distinguished.
Disclosure of Invention
Aiming at the blank existing in the prior art, the invention provides a crystal form of disodium levoornidazole phosphate heptahydrate and a preparation method thereof, aiming at distinguishing a metastable structural crystal form of disodium levoornidazole phosphate with 6 crystal waters and 1 crystal water, and providing support for research and development of ornidazole medicaments.
The chemical name of the disodium levoornidazole phosphate heptahydrate is disodium levoornidazole phosphate heptahydrate, the molecular formula of the disodium levoornidazole phosphate heptahydrate is C7H9ClN3Na2O6P.7H2O, molecular weight of 469.68, and structural formula as follows:
the invention also provides characteristic peaks of an X-ray powder diffraction pattern of the crystal form of the disodium levoornidazole phosphate heptahydrate, which are as follows:
the XRPD pattern of the crystal form can be further in the 2θThe angular position has a 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 the characteristic peak of the crystal form adopts the conventional expression method in the field, and the allowable error is +0.2 when the angle is accurate to 0.1 degrees. General rounding principle, as further 2θDemonstration of accuracy.
The third aspect of the invention provides crystallographic structure data and structure refinement parameters of the single crystal of the disodium levoornidazole phosphate heptahydrate, which are as follows:
this test data is only one of the tests that describe this product. The data may vary slightly depending on the measurement conditions and should still be understood as the scope of the protection of this patent.
The crystal form of the disodium levoornidazole phosphate heptahydrate has a stable spatial structure, has better stability compared with other crystal forms of the compound, can ensure the quality to be unchanged for a long time, and effectively prolongs the quality guarantee period of the product.
On the other hand, the invention provides a preparation method of the crystal form of the disodium levoornidazole phosphate heptahydrate, which comprises the following preparation methods:
adding a solvent into the disodium levoornidazole phosphate to dissolve, filtering the mixture to a single crystal bottle, adding seed crystals, stirring or standing the mixture at a specified temperature until solid is separated out, filtering the mixture, and drying the solid at 20-30 ℃ to obtain the crystal form of the disodium levoornidazole phosphate heptahydrate.
The solvent is a mixed solvent, wherein one solvent is water; the organic solvent is one or more of methanol, acetone, acetonitrile, ethanol, n-propanol, isopropanol, and n-butanol.
The specified temperature is preferably 15-35 ℃, and is further preferably 20-30 ℃.
The amount of the solvent used is 10-200 times (W/V) of the amount of the levoornidazole disodium phosphate.
Compared with the prior art, the invention has the characteristics and beneficial effects that:
the preparation method of the disodium levoornidazole phosphate heptahydrate is simple and convenient, and is suitable for industrial production.
The crystal form of the sodium levoornidazole phosphate heptahydrate obtained by the invention has high purity and good crystal form stability.
Drawings
FIG. 1 is a picture of a crystalline PLM of the disodium levoornidazole phosphate heptahydrate of the compound of the present invention;
FIG. 2 is a schematic diagram of a single crystal structural unit of the compound of disodium levoornidazole phosphate heptahydrate of the present invention;
fig. 3 is a schematic diagram (viewed from the a-axis direction) of the stacking structure of molecules in the single crystal structure of the compound of disodium levoornidazole phosphate heptahydrate;
fig. 4 is a schematic diagram (viewed from the b-axis direction) of the stacking structure of molecules in the single crystal structure of the compound of disodium levoornidazole phosphate heptahydrate;
fig. 5 is a schematic diagram (seen from the c-axis direction) of the stacking structure of molecules in the single crystal structure of the compound of the invention, i.e., the disodium levoornidazole phosphate heptahydrate;
fig. 6 is an XRPD pattern of disodium levoornidazole phosphate heptahydrate of the compound of the present invention.
Detailed Description
Example 1
Taking 10g of disodium levoornidazole phosphate, adding 100ml of mixed solvent (water/ethanol is 1:20, v/v) for dissolving, filtering to a new single crystal bottle, adding a small amount of sample as seed crystal, separating out solid at 5-25 ℃, filtering, and drying the solid at 20-30 ℃ to obtain the crystal form of disodium levoornidazole phosphate heptahydrate.
The yield of the product in this example is 85% and the purity is 99.8%, and the crystal of the compound is shown in FIG. 1.
Example 2
Taking 10g of disodium levoornidazole phosphate, adding 200ml of mixed solvent (water/methanol is 1: 10, v/v) for dissolving, filtering to a new single crystal bottle, adding a small amount of sample as seed crystal, separating out solid at 10-30 ℃, filtering, and drying the solid at 20-30 ℃ to obtain the crystal form of disodium levoornidazole phosphate heptahydrate.
The product of this example had a yield of 80% and a purity of 99.9%.
Example 3
Taking 10g of disodium levoornidazole phosphate, adding 300ml of mixed solvent (water/acetone is 1: 15, v/v) for dissolving, filtering to a new single crystal bottle, adding a small amount of sample as seed crystal, separating out solid at 10-20 ℃, filtering, and drying the solid at 20-30 ℃ to obtain the crystal form of disodium levoornidazole phosphate heptahydrate.
The product of this example was obtained in 75% yield and 99.6% purity.
Example 4
Taking 15g of disodium levoornidazole phosphate, adding 300ml of mixed solvent (water/n-propanol is 1: 15, v/v), stirring and dissolving, filtering to a new single crystal bottle, adding a small amount of sample as seed crystal, separating out solid at 10-20 ℃, filtering, and drying the solid at 20-30 ℃ to obtain the crystal form of the disodium levoornidazole phosphate, wherein the yield is 78%.
Example 5
Taking 50g of the disodium levoornidazole phosphate, adding 1000ml of a mixed solvent (water/ethanol/acetone is 1: 15: 15, v/v/v), stirring and dissolving, filtering to obtain a new single crystal bottle, adding a small amount of sample as a seed crystal, separating out a solid at 10-20 ℃, filtering, and drying the solid at 20-30 ℃ to obtain the crystal form of the disodium levoornidazole phosphate heptahydrate.
The product of this example had a yield of 86% and a purity of 99.9%.
Example 6
Taking 20g of disodium levoornidazole phosphate, adding 500ml of mixed solvent (water/ethanol is 1: 15, v/v), stirring and dissolving, filtering to a new single crystal bottle, adding a small amount of sample as seed crystal, separating out solid at 5-20 ℃, filtering, and drying the solid by blowing at 20-30 ℃ to obtain the crystal form of the disodium levoornidazole phosphate heptahydrate, wherein the yield is 90%.
Example 7
Taking 50g of disodium levoornidazole phosphate, adding 1000ml of mixed solvent (water/acetonitrile is 1: 10, v/v), stirring and dissolving, filtering to a new single crystal bottle, adding a small amount of sample as seed crystal, separating out solid at 5-20 ℃, filtering, and drying the solid by blowing at 20-30 ℃ to obtain the crystal form of disodium levoornidazole phosphate heptahydrate, wherein the yield is 83%.
Example 8
Taking 100g of disodium levoornidazole phosphate, adding 5000ml of mixed solvent (water/isopropanol is 1:20, v/v), stirring and dissolving, filtering to a new single crystal bottle, adding a small amount of sample as seed crystal, separating out solid at 10-25 ℃, filtering, and drying the solid by blowing at 20-30 ℃ to obtain the crystal form of the disodium levoornidazole phosphate heptahydrate.
The product of this example had a yield of 81% and a purity of 99.4%.
Example 9
Taking 10g of disodium levoornidazole phosphate, adding 500ml of mixed solvent (water/ethanol is 1: 15, v/v) for dissolving, filtering to a new single crystal bottle, adding a small amount of sample as seed crystal, separating out solid at 10-25 ℃, filtering, and drying the solid by blowing at 20-30 ℃ to obtain the crystal form of the disodium levoornidazole phosphate heptahydrate.
The product of this example had a yield of 82% and a purity of 99.9%.
Example 10
The stability of the crystal form of the disodium levoornidazole phosphate heptahydrate is compared with that of other crystal forms of the compound:
the comparison results of the stability of the crystal form of the disodium levoornidazole phosphate heptahydrate prepared in the above example 9 and other crystal forms of the present compound after standing at 60 ℃ for 10 days are as follows:
a chromatographic column: octadecylsilane chemically bonded silica is a filler (Waters Xbridge C18, 250X 4.6mm, 5 μm or equivalent in potency)
Mobile phase: mobile phase A, 0.05mol/L potassium dihydrogen phosphate solution (containing 0.5% triethylamine, pH value adjusted to 3.0 with phosphoric acid), and methanol as mobile phase B
Column temperature: 35 ℃; flow rate: 1 ml/min; detection wavelength: 312nm
The results show that the stability of the disodium levoornidazole phosphate heptahydrate is better than that of other crystal forms of the compound.
The above examples are only illustrative of several embodiments of the present invention, but should not be construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. The protection scope of the present invention should be subject to the appended claims.
Claims (2)
1. The crystal form of the disodium l-ornidazole phosphate heptahydrate is characterized in that the structural formula of the disodium l-ornidazole phosphate heptahydrate is as follows:
2. a method for preparing the crystal form of disodium levoornidazole phosphate heptahydrate according to claim 1, characterised in that it is carried out according to the following steps:
adding a solvent into the levoornidazole disodium phosphate for dissolving, wherein the solvent is a mixed solvent of water and ethanol, the volume ratio of the water to the ethanol is 1:20, and the volume time of the solvent is 10 times of the mass of the metronidazole disodium phosphate; filtering into a single crystal bottle, adding seed crystals, stirring or standing at 5-25 ℃ until solid is separated out, filtering, and drying the solid at 20-30 ℃ to obtain the levoornidazole disodium heptahydrate.
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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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| 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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