Method for removing light-sensitive impurities in metronidazole disodium phosphate

Abstract

The invention discloses a method for removing light-sensitive impurities in metronidazole disodium phosphate. The method comprises the following steps: dissolving; decoloring treatment; crystallizing and purifying; and drying. According to the method for removing the light-sensitive impurities in the metronidazole disodium phosphate, through activated carbon adsorption and organic solvent devitrification, the impurities which cause deepened product color in the metronidazole disodium phosphate are effectively removed, and the purity of the metronidazole disodium phosphate is improved.

Description

Technical Field

[0001] The invention relates to the technical field of organic compound purification, in particular to a method for removing light-sensitive impurities in metronidazole disodium phosphate. Background Art

[0002] Metronidazole disodium phosphate has a strong antibacterial effect on most anaerobic bacteria, but has no effect on aerobic bacteria and facultative anaerobes. Its antibacterial spectrum includes Bacteroides fragilis and other Bacteroides, Fusobacterium, Clostridium perfringens, Eubacterium, Veillonella, Peptococcus and Peptostreptococcus, etc. The bactericidal concentration of metronidazole disodium phosphate is slightly higher than the inhibitory concentration. The nitro group of metronidazole disodium phosphate is reduced to a cytotoxin, which acts on the DNA metabolism process of bacteria, promotes cell death, and achieves bactericidal effect.

[0003] Metronidazole disodium phosphate is an off-white or slightly yellow powder that gradually turns yellow when exposed to light. Long-term storage may cause the color of metronidazole disodium phosphate to darken and its impurities to increase, resulting in a decrease in product quality. Summary of the invention

[0004] The present invention provides a method for removing photosensitivity impurities in metronidazole disodium phosphate, thereby solving the problem that the color of metronidazole disodium phosphate deepens and the impurity content increases due to photochromism during storage.

[0005] In order to solve the above technical problems, the present invention provides a method for removing photosensitivity impurities in metronidazole disodium phosphate, comprising the following steps:

[0006] (1) Dissolving: dissolving the darkened metronidazole disodium phosphate in purified water to prepare a metronidazole disodium phosphate solution;

[0007] (2) Decolorization treatment: adding activated carbon to the obtained metronidazole disodium phosphate solution, stirring to decolorize, and filtering to remove the activated carbon;

[0008] (3) Crystallization and purification: add an organic solvent dropwise to the filtrate after filtering and removing the activated carbon, keep warm for crystallization, filter, and obtain a filter cake;

[0009] (4) Drying: The obtained filter cake is dried under vacuum to obtain metronidazole disodium phosphate after removing the light-sensitive impurities.

[0010] In a preferred embodiment of the present invention, in step (1), the mass concentration of the metronidazole disodium phosphate solution is 0.5-1.0 g / ml.

[0011] In a preferred embodiment of the present invention, in step (2), the amount of activated carbon added is 0.025-0.05 times the mass of metronidazole disodium phosphate; and the stirring decolorization time is 30-60 min.

[0012] In a preferred embodiment of the present invention, in step (3), the dropping speed of the organic solvent is 1.0-3.0 ml / min.

[0013] In a preferred embodiment of the present invention, the amount of the organic solvent added is 1.5-2.0 ml per gram of metronidazole disodium phosphate.

[0014] In a preferred embodiment of the present invention, the organic solvent includes at least one of anhydrous ethanol or propanol.

[0015] In a preferred embodiment of the present invention, in step (3), the temperature of the heat preservation crystallization is 5-10°C and the time is 1-4h.

[0016] In a preferred embodiment of the present invention, in step (4), the process conditions of vacuum drying are: temperature 50-60°C, time 10-12h.

[0017] The beneficial effects of the present invention are as follows: the method for removing light-sensitive impurities in metronidazole disodium phosphate of the present invention effectively removes impurities in metronidazole disodium phosphate that cause the product color to deepen through activated carbon adsorption and organic solvent crystallization, thereby improving the purity of metronidazole disodium phosphate. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the liquid chromatogram of metronidazole disodium phosphate that has not been treated for impurities;

[0019] Figure 2 Liquid chromatogram of metronidazole disodium phosphate after treatment in Example 1 of the present invention;

[0020] Figure 3 Liquid chromatogram of metronidazole disodium phosphate after treatment in Example 2 of the present invention;

[0021] Figure 4 Liquid chromatogram of metronidazole disodium phosphate after treatment in Example 3 of the present invention. DETAILED DESCRIPTION

[0022] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0023] Embodiments of the present invention include:

[0024] The invention discloses a method for removing light-sensitive impurities in metronidazole disodium phosphate, comprising the following steps:

[0025] (1) Dissolving: Dissolving the darkened metronidazole disodium phosphate in a certain amount of purified water at room temperature to prepare a metronidazole disodium phosphate solution with a mass concentration of 0.5-1.0 g / ml;

[0026] (2) Decolorization treatment: add a certain amount of activated carbon to the obtained metronidazole disodium phosphate solution, stir and decolorize for 30-60 minutes, and filter to remove the activated carbon;

[0027] Wherein, the amount of activated carbon added is 0.025-0.05 times the mass of metronidazole disodium phosphate;

[0028] (3) Crystallization purification: adding an organic solvent to the filtrate after filtering and removing the activated carbon at a rate of 1.0-3.0 ml / min, controlling the amount of the organic solvent to be added to 1.5-2.0 ml per gram of metronidazole disodium phosphate, and controlling the temperature during the addition process to be 10-15° C. After the addition is completed, cooling to 5-10° C., standing and keeping the temperature for crystallization for 1-4 hours, and then filtering, and washing the obtained filter cake with an organic solvent; the organic solvent comprises at least one of anhydrous ethanol or propanol;

[0029] (4) Drying: The obtained filter cake is vacuum dried at 50-60° C. and 0.1-0.5 MPa for 10-12 h to obtain metronidazole disodium phosphate after removing light-sensitive impurities.

[0030] The specific scheme of the present invention is described in detail below through specific embodiments.

[0031] Example 1

[0032] Add 32 g of purified water to the reaction bottle, cool to below 25°C, add 20 g of metronidazole disodium phosphonate (the color is more than yellow No. 5) with stirring, rinse the bottle wall with 8 g of water, continue stirring, heat to 25°C, keep warm for 30 minutes, stir to make the sample completely dissolved, and obtain an aqueous solution of metronidazole disodium phosphonate.

[0033] Add 0.5 g of activated carbon to the above reaction bottle, stir and decolorize at 25°C for 30 minutes, and remove the activated carbon by suction.

[0034] The filtrate obtained by filtration was cooled to about 15°C, and then 50 ml of anhydrous ethanol was added dropwise within 20 minutes. After the addition was completed, stirring was turned off, the temperature was cooled to 5-10°C, the temperature was kept for crystallization for 2 hours, filtered, and the filter cake was washed with 10 ml of anhydrous ethanol.

[0035] The obtained filter cake was vacuum dried at 60°C and 0.3 MPa for 10 hours to obtain 18.6 g of a dry product with a yield of 93% and a color of yellow No. 2.

[0036] Example 2

[0037] Add 32 g of purified water to the reaction bottle, cool to below 25°C, add 20 g of metronidazole disodium phosphonate (the color is more than yellow No. 5) with stirring, rinse the bottle wall with 8 g of water, continue stirring, heat to 25°C, keep warm for 30 minutes, stir to make the sample completely dissolved, and obtain an aqueous solution of metronidazole disodium phosphonate.

[0038] Add 0.5 g of activated carbon to the above reaction bottle, stir and decolorize at 25°C for 30 minutes, and remove the activated carbon by suction.

[0039] The filtrate obtained by filtration was cooled to about 15°C, and then 50 ml of anhydrous ethanol was added dropwise within 60 minutes. After the addition was completed, stirring was turned off, the temperature was lowered to 5-10°C, the temperature was kept for crystallization for 2 hours, filtered, and the filter cake was washed with 10 ml of anhydrous ethanol.

[0040] The obtained filter cake was vacuum dried at 60°C and 0.3 MPa for 10 hours to obtain 19.2 g of a dry product with a yield of 96% and a color of yellow No. 2.

[0041] Example 3

[0042] Add 32 g of purified water to the reaction bottle, cool to below 25°C, add 20 g of metronidazole disodium phosphonate (the color is more than yellow No. 5) with stirring, rinse the bottle wall with 8 g of water, continue stirring, heat to 25°C, keep warm for 30 minutes, stir to make the sample completely dissolved, and obtain an aqueous solution of metronidazole disodium phosphonate.

[0043] Add 0.5 g of activated carbon to the above reaction bottle, stir and decolorize at 25°C for 30 minutes, and remove the activated carbon by suction.

[0044] The filtrate obtained by filtration was cooled to about 15°C, and then 50 ml of propanol was added dropwise within 60 minutes. After the addition was completed, stirring was turned off, the temperature was lowered to 5-10°C, the temperature was kept for crystallization for 2 hours, filtered, and the filter cake was washed with 10 ml of propanol.

[0045] The obtained filter cake was vacuum dried at 60°C and 0.3 MPa for 10 hours to obtain 17.8 g of a dry product with a yield of 89% and a color of yellow No. 2.

[0046] The untreated metronidazole disodium phosphonate (color exceeding yellow No. 5) and the metronidazole disodium phosphonate treated in Example 1-3 were respectively detected and analyzed by high performance liquid chromatography, and the detection conditions were as follows:

[0047] Octadecylsilane bonded silica gel was used as filler; 0.68% potassium dihydrogen phosphate solution (pH adjusted to 6.0 with sodium hydroxide solution)-methanol (80:20) was used as mobile phase; and the detection wavelength was 321 nm.

[0048] The detection method is: take an appropriate amount of sample, add a small amount of methanol to dissolve it, add mobile phase to make a solution containing 2.5 mg per 1 ml as the test solution; accurately measure 10 μl of the test solution and inject it into the liquid chromatograph, and record the chromatogram.

[0049] The obtained chromatograms are shown in the attached Figure 1-4 shown.

[0050] The peak results obtained are shown in Tables 1-4 below.

[0051] Table 1 Untreated samples

[0052] Retention time (minutes) Area (μV*sec) Height (microvolt) area(%) 1 4.380 4710873 659843 98.23 2 8.069 15766 1323 0.33 3 11.725 69143 4450 1.44

[0053] Table 2 Samples after treatment in Example 1

[0054] Retention time (minutes) Area (μV*sec) Height (microvolt) area(%) 1 4.404 17718202 2032365 99.98 2 8.256 3167 259 0.02

[0055] Table 3 Samples after treatment in Example 2

[0056] Retention time (minutes) Area (μV*sec) Height (microvolt) area(%) 1 4.369 15902171 1941712 99.98 2 8.191 3205 186 0.02

[0057] Table 4 Samples after treatment in Example 3

[0058] Retention time (minutes) Area (μV*sec) Height (microvolt) area(%) 1 4.450 15324480 1883112 99.96 2 8.394 6079 518 0.04

[0059] From the above test results, it can be seen that activated carbon adsorption and organic solvent crystallization can effectively remove impurities that affect the color of the sample in metronidazole disodium phosphate, reducing its color from a color number greater than 5 to 2, and the impurity content is also reduced from 1.44% and 0.33% to less than 0.05%, respectively, with excellent impurity removal effect.

[0060] In addition, extending the organic solvent addition time can effectively improve the yield of the product. This is because: if the organic solvent is added at a too fast rate, the supersaturation of the solution will increase rapidly, thereby promoting the rapid formation of crystals, but it may also lead to uneven crystal size and even impurities. On the contrary, reducing the drop rate can better control the crystal growth and obtain crystals of better quality.

[0061] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for removing light-sensitive impurities in metronidazole disodium phosphate, characterized in that: The steps include: (1) Dissolving: dissolving the darkened metronidazole disodium phosphate in purified water to prepare a metronidazole disodium phosphate solution; (2) Decolorization treatment: adding activated carbon to the obtained metronidazole disodium phosphate solution, stirring to decolorize, and filtering to remove the activated carbon; (3) Crystallization and purification: add an organic solvent dropwise to the filtrate after filtering and removing the activated carbon, keep warm for crystallization, filter, and obtain a filter cake; (4) Drying: The obtained filter cake is dried under vacuum to obtain metronidazole disodium phosphate after removing the light-sensitive impurities.

2. A method for removing light-sensitive impurities in metronidazole disodium phosphate according to claim 1, characterized in that: In step (1), the mass concentration of the metronidazole disodium phosphate solution is 0.5-1.0 g / ml.

3. A method for removing light-sensitive impurities in metronidazole disodium phosphate according to claim 1, characterized in that: In step (2), the amount of activated carbon added is 0.025-0.05 times the mass of metronidazole disodium phosphate; and the stirring decolorization time is 30-60 min.

4. A method for removing light-sensitive impurities in metronidazole disodium phosphate according to claim 1, characterized in that: In step (3), the dropping speed of the organic solvent is 1.0-3.0 ml / min.

5. A method for removing light-sensitive impurities in metronidazole disodium phosphate according to claim 4, characterized in that: The amount of the organic solvent added is 1.5-2.0 ml per gram of metronidazole disodium phosphate.

6. The method for removing light-sensitive impurities in metronidazole disodium phosphate according to claim 5, characterized in that: The organic solvent includes at least one of anhydrous ethanol or propanol.

7. The method for removing light-sensitive impurities in metronidazole disodium phosphate according to claim 1, characterized in that: In step (3), the temperature of the heat preservation crystallization is 5-10°C and the time is 1-4h.

8. The method for removing light-sensitive impurities in metronidazole disodium phosphate according to claim 1, characterized in that: In step (4), the process conditions of vacuum drying are: temperature 50-60° C., time 10-12 h.

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