A refining method for ceftiofur sodium

Abstract

The present application provides a method for refining cefotaxime sodium, belonging to the technical field of pharmaceutical preparations. The crude cefotaxime hydrochloride is dissolved in a mixed solvent, the pH is adjusted to 2-4, a desalting agent is added for salting out, followed by decolorization, filtration, and the filtrate is retained. The mixed solvent is acetone + alcohol, acetone + alkane, or acetone + alcohol + alkane. The salifying agent is dissolved in the mixed solvent, and the resulting solution is dropped into the filtrate for salting, crystallization, filtration, washing, draining, and vacuum drying to obtain the finished product cefotaxime sodium. Applying the present application to the preparation of cefotaxime sodium not only reduces the impurity content of the product but also helps to reduce the acetone residue, with good product color and high yield.

Description

Technical Field

[0001] The present application relates to a method for refining ceftiofur sodium, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Ceftiofur sodium, with the English name Ceftiofur Sodium, is a veterinary clinical-specific antibiotic of cephalosporins and is a broad-spectrum antibacterial agent. It has strong antibacterial effects against both Gram-positive bacteria and Gram-negative bacteria. It is one of the most widely used cephalosporin antibiotics at present. The structural formula of ceftiofur sodium is: 。

[0003] The current mainstream crystallization method of ceftiofur sodium is as follows: Dissolve ceftiofur hydrochloride in acetone and methanol, prepare ceftiofuric acid by adjusting the pH, then add sodium isooctanoate as a salifying agent for reaction crystallization, and finally wash with pure acetone to prepare ceftiofur sodium. Researchers often only consider the crystallization process in detail and ignore the washing process. However, in fact, the washing process has a great impact on the properties of the final product. Therefore, even if the crystallization process is well controlled, if the washing method is not properly selected, the quality of the final product will also be affected to a certain extent. Most production processes in the market use pure acetone for washing, which has problems such as increased residual solvents such as acetone in the product and difficulty in removing them, seriously affecting the product content and even increasing the risk of drug consumption. In addition, the difference in solubility of different solvents will also lead to differences in the impurity content in the product. Summary of the Invention

[0004] In view of this, the present application provides a method for refining ceftiofur sodium, which not only reduces the impurity content of the product, but also greatly reduces the difficult-to-remove acetone, the product content is increased by 4-5%, and the product has good color and high yield.

[0005] Specifically, the present application is achieved through the following scheme:

[0006] A method for refining ceftiofur sodium, the steps are as follows:

[0007] Step 1, dissolve the crude ceftiofur hydrochloride in a mixed solvent, adjust the pH to 2-4, add a desalting agent to precipitate salts, then decolorize, filter, and retain the filtrate.

[0008] The mixed solvent adopts any one of three forms: a mixture of acetone and alcohol, a mixture of acetone and alkane, a mixture of acetone, alcohol and alkane, that is, any one of the three ways: acetone + alcohol, acetone + alkane, acetone + alcohol + alkane.

[0009] The alcohol is one or more mixtures of methanol, ethanol, and isopropanol.

[0010] The alkane is one or a mixture of both of n-hexane and cyclohexane;

[0011] Step 2: Dissolve the salifying agent in the mixed solvent, and drop the resulting solution into the filtrate of Step 1. Control the temperature at 20-25°C for salification, crystal cultivation, filtration, washing, draining, and vacuum drying to obtain the finished product cefotaxime sodium.

[0012] The mixed solvent is a mixture of methanol and acetone.

[0013] The washing includes two washes. The first wash is with a mixture of methanol and acetone, and the second wash is with acetone, a mixture of acetone and ethanol, or a mixture of acetone and isopropanol, i.e., any one of the three methods: acetone, acetone + ethanol, acetone + isopropanol.

[0014] Further, as a preference:

[0015] In Step 1,

[0016] The added volume ratio of the alcohol to acetone is 3-4:1.

[0017] The added volume ratio of the alkane to acetone is 0.5-1:1.

[0018] The desalting agent is any one of acetone, a mixture of methanol and acetone, a mixture of isopropanol and acetone, or a mixture of n-hexane and acetone, i.e., any one of the four methods: acetone, methanol + acetone, isopropanol + acetone, n-hexane + acetone.

[0019] The pH adjustment is carried out by adding any one of sodium bicarbonate and sodium carbonate.

[0020] In Step 2,

[0021] The salifying agent is any one of sodium isooctanoate and sodium lactate.

[0022] In the first wash, the mixed volume ratio of methanol to acetone is 1:3-4, and the washing temperature is 20-25°C.

[0023] In the second wash, the washing temperature is 30-35°C, the mixed volume ratio of ethanol to acetone is 1:7-9; the mixed volume ratio of isopropanol to acetone is 1:15-50.

[0024] The washing further includes a third wash, which is carried out with ethanol, isopropanol, etc., and the washing temperature is 30-35°C.

[0025] The vacuum drying temperature is 50-60°C.

[0026] In this application, the crude cefotaxime hydrochloride is dissolved in a mixed solvent to form a solution. Then, an alkali agent such as sodium bicarbonate is added to the solution to adjust the pH to a specific range. After adding a desalting agent such as acetone to precipitate salts, decolorization and filtration are carried out. Then, it is dissolved in a mixed solvent with a salifying agent. The obtained salifying agent solution is added to the filtrate. After crystallization, washing is completed by the specific washing method in this case, and a high-quality cefotaxime sodium product with good color, high content, few impurities, and low residual solvents can be obtained. Brief Description of the Drawings

[0027] In order to more clearly illustrate the technical solutions in the embodiments of this application, the following will briefly introduce the drawings required for use in the embodiments or the description of the prior art. Obviously, the following drawings are only some embodiments of this application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0028] Figure 1 It is a comparison diagram of the product obtained by the process of this application and the market product. Detailed Description of the Embodiments

[0029] In order to make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the following will further elaborate on the technical solutions in the embodiments of this application in combination with the drawings in the embodiments of this application. It should be understood that the specific embodiments described here are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope protected by this application.

[0030] Example 1

[0031] This example provides a method for refining cefotaxime sodium, and the process is as follows:

[0032] Add 60 mL of methanol, 20 mL of acetone, and 10 mL of isopropanol to a four-necked flask. Control the temperature at 10°C, and add 20 g of crude cefotaxime hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) and dissolve it while stirring. Slowly add 2.7 g of sodium bicarbonate over 8 minutes to adjust the pH to 3.0. After stirring for 1 hour, add 200 mL of acetone to precipitate salts. Add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate. Dissolve 7.1 g of sodium 2-ethylhexanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone. Control the temperature at 20°C and add the sodium 2-ethylhexanoate solution dropwise to the filtrate from the first step. Finish dropping in 1 hour and age for 1 hour. Filter, wash the first time with a mixed solvent of 20 mL of methanol + 80 mL of acetone, and then wash the second time at 30°C with 10 mL of isopropanol + 90 mL of acetone, and drain. Dry in vacuo at 55°C to obtain a white dry product.

[0033] Example 2

[0034] This embodiment provides a method for refining cefotaxime sodium, and the process is as follows:

[0035] Add 60 mL of methanol, 20 mL of acetone, and 5 mL of isopropanol to a four-necked flask. Control the temperature at 10 °C. While stirring, add 20 g of crude cefotaxime hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) to dissolve. Slowly add 2.7 g of sodium bicarbonate over 8 minutes, adjust the pH to 3.0. After stirring for 1 h, add 200 mL of acetone to precipitate salts. Add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate. Dissolve 7.1 g of sodium isooctanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone. Control the temperature at 20 °C and add the sodium isooctanoate solution dropwise to the filtrate from the first step over 1 h. After dropping, age the crystals for 1 h, filter, wash the first time with a mixed solvent of 20 mL of methanol + 80 mL of acetone, and then wash the second time at 30 °C with 5 mL of isopropanol + 95 mL of acetone, and then drain. Dry the off-white dry product under vacuum at 55 °C.

[0036] Example 3

[0037] This embodiment provides a method for refining cefotaxime sodium, and the process is as follows:

[0038] Add 60 mL of methanol, 20 mL of acetone, and 2 mL of isopropanol to a four-necked flask. Control the temperature at 10 °C. While stirring, add 20 g of crude cefotaxime hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) to dissolve. Slowly add 2.7 g of sodium bicarbonate over 8 minutes, adjust the pH to 3.0. After stirring for 1 h, add 200 mL of acetone to precipitate salts. Add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate. Dissolve 7.1 g of sodium isooctanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone. Control the temperature at 20 °C and add the sodium isooctanoate solution dropwise to the filtrate from the first step over 1 h. After dropping, age the crystals for 1 h, filter, wash the first time with a mixed solvent of 20 mL of methanol + 80 mL of acetone, and then wash the second time at 30 °C with 2 mL of isopropanol + 98 mL of acetone, and then drain. Dry under vacuum at 55 °C to obtain an off-white dry product.

[0039] Comparative Example 1

[0040] This comparative example is the same as the setting of Example 3, except that the washing is carried out in a conventional manner, that is, after aging the crystals for 1 h and filtering, enter the washing step: wash the first time with a mixed solvent of 20 mL of methanol + 80 mL of acetone, and then wash the second time with 100 mL of acetone.

[0041] Example 4

[0042] This embodiment provides a method for refining cefotaxime sodium, and the process is as follows:

[0043] Add 60 mL of methanol, 20 mL of acetone, and 10 mL of ethanol to a four-necked flask. Control the temperature at 10 °C. While stirring, add 20 g of crude cefotaxime hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) and dissolve it. Slowly add 2.7 g of sodium bicarbonate over 8 min, adjust the pH to 3.0. After stirring for 1 h, add 200 mL of acetone to precipitate salts. Add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate. Dissolve 7.1 g of sodium isooctanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone. Control the temperature at 20 °C and add the sodium isooctanoate solution dropwise to the filtrate from the first step over 1 h. After dropping, age for 1 h, filter, wash with a mixed solvent of 20 mL of methanol + 80 mL of acetone for the first time, and then wash with 10 mL of ethanol + 90 mL of acetone at 30 °C for the second time. Filter dry. Dry under vacuum at 55 °C to obtain a white dry product.

[0044] Example 5

[0045] This example provides a method for refining cefotaxime sodium, and the process is as follows:

[0046] Add 60 mL of methanol and 20 mL of acetone to a four-necked flask. Control the temperature at 10 °C. While stirring, add 20 g of crude cefotaxime hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) and dissolve it. Slowly add 2.7 g of sodium bicarbonate over 8 min, adjust the pH to 3.0. After stirring for 1 h, add 200 mL of acetone to precipitate salts. Add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate. Dissolve 7.1 g of sodium isooctanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone. Control the temperature at 20 °C and add the sodium isooctanoate solution dropwise to the filtrate from the first step over 1 h. After dropping, age for 1 h, filter, wash with a mixed solvent of 20 mL of methanol + 80 mL of acetone for the first time, and then wash with 100 mL of acetone for the second time. Cold filter for 1 h, wash with 100 mL of ethanol at 35 °C for the third time, and filter dry. Dry under vacuum at 55 °C to obtain an off-white dry product.

[0047] Example 6

[0048] This example provides a method for refining cefotaxime sodium, and the process is as follows:

[0049] Add 60 mL of methanol and 20 mL of acetone to a four-necked flask. Control the temperature at 10 °C. While stirring, add 20 g of crude cefotaxime hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) and dissolve it. Slowly add 2.7 g of sodium bicarbonate over 8 min, adjust the pH to 3.0. After stirring for 1 h, add 200 mL of acetone to precipitate salts. Add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate. Dissolve 7.1 g of sodium isooctanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone. Control the temperature at 20 °C and add the sodium isooctanoate solution dropwise to the filtrate from the first step over 1 h. After dropping, age the crystals for 1 h, filter, wash with a mixed solvent of 20 mL of methanol + 80 mL of acetone for the first time, then wash with 100 mL of acetone for the second time, perform cold suction for 1 h, wash with 100 mL of isopropanol at 35 °C for the third time, and drain. Dry in vacuo at 55 °C to obtain a pure white dry product.

[0050] Comparative Example 2

[0051] This comparative example is set the same as Example 6, the difference is that the washing is carried out in a conventional manner, that is, age the crystals for 1 h, and enter the washing step after filtration: wash with a mixed solvent of 20 mL of methanol + 80 mL of acetone for the first time, then wash with 100 mL of acetone for the second time. Wash with 100 mL of isopropanol at 35 °C for the third time.

[0052] Example 7

[0053] This example provides a method for refining cefotaxime sodium, and the process is as follows:

[0054] Add 60 mL of methanol, 20 mL of acetone, and 10 mL of n-hexane to a four-necked flask. Control the temperature at 10 °C. While stirring, add 20 g of crude cefotaxime hydrochloride and dissolve it. Slowly add 2.7 g of sodium bicarbonate over 8 min, adjust the pH to 3.0. After stirring for 1 h, add 200 mL of acetone to precipitate salts. Add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate. Dissolve 7.1 g of sodium isooctanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone. Control the temperature at 20 °C and add the sodium isooctanoate solution dropwise to the filtrate from the first step over 1 h. After dropping, age the crystals for 1 h, filter, wash with a mixed solvent of 20 mL of methanol + 80 mL of acetone for the first time, then wash with 100 mL of n-hexane for the second time, perform cold suction for 1 h, wash with 100 mL of acetone at 20 °C for the third time, and drain. Dry in vacuo at 55 °C to obtain a pure white dry product.

[0055] Example 8

[0056] This example provides a method for refining cefotaxime sodium, and the process is as follows:

[0057] Add 60 mL of methanol, 20 mL of acetone, and 10 mL of cyclohexane to a four-necked flask. Control the temperature at 10 °C. While stirring, add 20 g of crude cefotaxime hydrochloride and dissolve it. Slowly add 2.7 g of sodium bicarbonate over 8 min, adjust the pH to 3.0, stir for 1 h, then add 200 mL of acetone to precipitate the salt. Add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate. Dissolve 7.1 g of sodium isooctanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone. Control the temperature at 20 °C and add the sodium isooctanoate solution dropwise to the filtrate from the first step over 1 h. After dropping, age the crystals for 1 h, filter, wash the first time with a mixed solvent of 20 mL of methanol + 80 mL of acetone, then wash the second time with 100 mL of cyclohexane, perform cold suction for 1 h, wash the third time with 100 mL of acetone at 20 °C, and drain. Dry in vacuo at 55 °C to obtain a pure white dry product.

[0058] Comparative Example 3

[0059] This comparative example is the same as that of Example 8, except that the washing is carried out in a conventional manner, that is, age the crystals for 1 h, and enter the washing step after filtration: wash the first time with a mixed solvent of 20 mL of methanol + 80 mL of acetone, then wash the second time with 100 mL of acetone, perform cold suction for 1 h, and wash the third time with 100 mL of acetone at 20 °C.

[0060] The preparation effects of the above examples are shown in Table 1.

[0061] Table 1: Effect comparison table of each scheme

[0062] Yield Content Purity Bulk density Example 1 87.7 % 93.5 % 99.1% <![CDATA[0.39 g / cm 3 <!-- 4 -->]]> Example 2 88.1 % 93.1 % 99.0% <![CDATA[0.41 g / cm 3 > Example 3 88.5 % 91.9 % 98.5% <![CDATA[0.45 g / cm 3 > Example 4 87.5 % 93.4 % 99.1% <![CDATA[0.39 g / cm 3 > Example 5 88.9 % 93.5 % 99.3% <![CDATA[0.52 g / cm 3 > Example 6 88.8 % 93.5 % 99.2% <![CDATA[0.52 g / cm 3 > Example 7 88.2 % 93.2 % 99.1% <![CDATA[0.39 g / cm 3 > Example 8 88.4 % 93.1 % 99.0% <![CDATA[0.41 g / cm 3 > Comparative Example 1 86.1% 87.2% 96.8% <![CDATA[0.45g / cm 3 > Comparative Example 2 88.5% 93.5% 99.4% <![CDATA[0.31g / cm 3 > 86.4% 88.7% 97.1% <![CDATA[0.52g / cm 3 >

[0063] Examples 1 to 8 respectively give different refining conditions. By comparing with the refining, it is proved that the washing method has a great influence on the product quality. The differences between the refining effect parameters are mainly reflected in the product content and bulk density. The main reason for this difference is mainly due to the different solvent ratios and washing methods.

[0064] The influence of different mixed solvents is mainly manifested in reducing the solubility of impurities and reducing the acetone residue, and is specifically reflected in the product content. In particular, the influence of the mixed solvent in which the crude cefotaxime hydrochloride is dissolved is more significant.

[0065] By comparing with Comparative Examples 1, 2, and 3, it can be seen that: compared with the conventional washing method, the washing method in this case can significantly improve the product content and improve the product color.

[0066] In the washing scheme of this case, the difference is mainly reflected in the composition of the second washing. This is because: Examples 1 to 4 use a mixed solvent for washing, and the key lies in controlling the proportion of alcohol, and specifically manifested as: when the proportion of alcohol is high, the product content is high; when the proportion of acetone is high, the product bulk density is high.

[0067] A cold draw is applied once after the second washing, which creates conditions for the third washing. Among them, in Examples 5-6, the cold draw process improves the bulk density of the product. In the third washing, alcohol washing can remove acetone residues and increase the product content; while in Examples 7-8, the cold draw process prevents the acetone washing residues in the third washing from being too high and affecting the product content. Examples 5-8 that adopt the third washing all achieve an increase in the bulk density of the product.

[0068] Combined with the above examples and Table 1, Comparative Example 3 It can be seen that: compared with the market product (manufacturer: Zhejiang Dongying Pharmaceutical Co., Ltd., model: 2408001), the control product is yellow, and the color grade < Y6; while the product obtained in this application is pure white, and the color grade < Y4. The product in this case has good color, and the yield is stable above 87%.

[0069] Taking Example 6 as the representative of this case, a quality comparison is made with the control market product (manufacturer: Zhejiang Dongying Pharmaceutical Co., Ltd., model: 2408001), and the results are shown in Table 2.

[0070] Table 2: Comparison table of test data between the product of this application and the market product

[0071] Figure 1 Content Acetone residue Methanol residue Isopropanol residue 2-Ethylhexanoic acid residue Purity Bulk density Dissolution rate pH Yield 93.50% 0.6% 0.02% 0.09% 0.42% 99.2% <![CDATA[0.52 g / cm 3 > 35 s 6.93 88.80% This case Control 87.10% 2.38% 0.35% / 1.68% 97.06% <![CDATA[0.51 g / cm 3 > 34 s 6.61 86.10%

[0072] It can be seen from Table 2 that: the content of the control market product is only 87.1%, the acetone residue is as high as 2.38%, the methanol residue is as high as 0.35%, the isooctanoic acid residue reaches 1.68%, the purity is only 97.06%, and the yield is 86.1%.

[0073] While in this application, the content can be increased to 93.5%, and the product content is increased by 4-5%; the acetone residue, methanol residue, and isooctanoic acid residue are reduced to 0.6%, 0.02%, and 0.42% respectively, greatly reducing the difficult-to-remove acetone. Although 0.09% of isopropanol residue is introduced, since isopropanol belongs to Class III solvents and the content is extremely small, it does not affect the product quality; while the product purity is increased to 99.2%, and the yield is 88.8%, reducing the impurity content of the product. The above improvements in the product performance of this case mainly show an increase in the effective content of the drug and a reduction in the potential physiological toxicity risk in the use of cefotaxime sodium.

[0074] The above-described embodiments only represent several feasible implementation modes of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. The embodiments are not intended to limit the protection scope in the claims of the present invention. For those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made. Any equivalent implementation or change made without departing from the present invention should be included in the technology of the present invention.

Claims

1. A refining method of cefotaxime sodium, characterized in that: Add 60 mL of methanol and 20 mL of acetone into a four-necked flask, control the temperature at 10 °C, add 20 g of crude cefotaxime hydrochloride and dissolve it under stirring, slowly add 2.7 g of sodium bicarbonate in 8 min, adjust the pH to 3.0, after stirring for 1 h, add 200 mL of acetone to precipitate salts, add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate; dissolve 7.1 g of sodium isooctanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone, control the temperature at 20 °C, dropwise add the sodium isooctanoate solution to the filtrate, finish dropping in 1 h, age for 1 h, filter, wash the first time with a mixed solvent of 20 mL of methanol + 80 mL of acetone, then wash the second time with 100 mL of acetone, perform cold suction for 1 h, wash the third time with 100 mL of isopropanol at 35 °C, and suction dry; dry in vacuum at 55 °C to obtain a pure white dry product.

2. A refining method of cefotaxime sodium, characterized in that: Add 60 mL of methanol and 20 mL of acetone into a four-necked flask, control the temperature at 10 °C, add 20 g of crude cefotaxime hydrochloride and dissolve it under stirring, slowly add 2.7 g of sodium bicarbonate in 8 min, adjust the pH to 3.0, after stirring for 1 h, add 200 mL of acetone to precipitate salts, add 2 g of activated carbon for decolorization twice, filter, and retain the filtrate; dissolve 7.1 g of sodium isooctanoate in a mixed solvent of 10 mL of methanol + 30 mL of acetone, control the temperature at 20 °C, dropwise add the sodium isooctanoate solution to the filtrate, finish dropping in 1 h, age for 1 h, filter, wash the first time with a mixed solvent of 20 mL of methanol + 80 mL of acetone, then wash the second time with 100 mL of acetone, perform cold suction for 1 h, wash the third time with 100 mL of ethanol at 35 °C, and suction dry; dry in vacuum at 55 °C to obtain an off-white dry product.

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