Refining method of ceftiofur sodium

Abstract

The invention provides a refining method of ceftiofur sodium, and belongs to the technical field of pharmaceutical preparations. The method comprises the following steps: dissolving a ceftiofur hydrochloride crude product in a mixed solvent, adjusting the pH value to 2-4, adding a desalting agent to separate out salt, decolorizing, filtering, reserving filtrate, dissolving a salt forming agent in the mixed solvent, dripping the obtained solution into the filtrate, salifying, growing crystal, filtering, washing, pumping and drying in vacuum to obtain the finished product ceftiofur sodium, when the method is used for preparing the ceftiofur sodium, not only is the impurity content of the product reduced, but also acetone residues can be reduced, and the product is good in color and high in 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, also known as Ceftiofur Sodium in English, is a cephalosporin antibiotic used in veterinary clinics and a broad-spectrum antibacterial drug. It has strong antibacterial effects on both Gram-positive and Gram-negative bacteria. It is one of the most widely used cephalosporin antibiotics. The structural formula of Ceftiofur Sodium is: .

[0003] The current mainstream crystallization method of ceftiofur sodium is: dissolve ceftiofur sodium hydrochloride with acetone and methanol, prepare ceftiofuric acid by adjusting the pH, add sodium isooctanoate as a salt-forming agent for reaction and crystallization, and then wash with pure acetone to prepare ceftiofur sodium. Researchers often only consider the crystallization process in detail and ignore the washing process, but in fact the washing process has a great influence on the properties of the final product. Therefore, even if the crystallization process is well controlled, if the washing method is not well selected, the quality of the final product will be affected to a certain extent. Most production processes on the market use pure acetone for washing, which has the problem of increased acetone and other residual solvents in the product and is difficult to remove, which seriously affects the product content and even increases the risk of drug consumption. In addition, the solubility differences of different solvents will also lead to differences in the impurity content of 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 color is good and the yield is high.

[0005] Specifically, the present application is implemented through the following scheme: A method for refining ceftiofur sodium, comprising the following steps: Step 1, dissolving the crude product of ceftiofur hydrochloride in a mixed solvent, adjusting the pH to 2-4, adding a desalting agent to precipitate salt, decolorizing, filtering, and retaining the filtrate, The mixed solvent is in any one of three forms: a mixture of acetone and alcohol, a mixture of acetone and alkane, and a mixture of acetone, alcohol and alkane, that is, any one of the three forms of acetone+alcohol, acetone+alkane, and acetone+alcohol+alkane.

[0006] The alcohol is one or a mixture of methanol, ethanol, isopropanol, The alkane is one of n-hexane and cyclohexane or a mixture of the two; Step 2, dissolving the salt-forming agent in a mixed solvent, dripping the obtained solution into the filtrate of step 1, controlling the temperature to 20-25°C to form salt, growing crystals, filtering, washing, draining, and vacuum drying to obtain the finished product of ceftiofur sodium, The mixed solvent is a mixture of methanol and acetone, The washing comprises two steps, the first step is washing with a mixture of methanol and acetone, and the second step is washing with acetone, a mixture of acetone and ethanol, or a mixture of acetone and isopropanol, i.e., any one of the three methods of acetone, acetone+ethanol, and acetone+isopropanol.

[0007] Further, as a preference: In step one, The added volume ratio of the alcohol to acetone is 3-4:1.

[0008] The volume ratio of the alkane to acetone is 0.5 to 1:1.

[0009] 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, that is, any one of the four types of acetone, methanol+acetone, isopropanol+acetone, and n-hexane+acetone.

[0010] The pH is adjusted by adding either sodium bicarbonate or sodium carbonate.

[0011] In step 2, The salt-forming agent is any one of sodium 2-ethylhexanoate and sodium lactate.

[0012] In the first washing, the mixing volume ratio of methanol to acetone is 1:3-4, and the washing temperature is 20-25°C.

[0013] In the second washing, the washing temperature is 30-35° C., the mixing volume ratio of ethanol to acetone is 1:7-9; and the mixing volume ratio of isopropanol to acetone is 1:15-50.

[0014] The washing also includes a third washing step, in which ethanol, isopropanol or the like is used for washing, and the washing temperature is 30-35°C.

[0015] The vacuum drying temperature is 50-60°C.

[0016] In the present application, a crude product of ceftiofur hydrochloride is dissolved in a mixed solvent to form a solution, an alkali agent such as sodium bicarbonate is added to the solution to adjust the pH to a specific range, a desalting agent such as acetone is added to precipitate salt, the solution is decolorized and filtered, a salt-forming agent is dissolved in a mixed solvent, the obtained salt-forming agent solution is added to the filtrate, and after crystallization, washing is completed in a specific washing method of the present case, so that a high-quality ceftiofur sodium finished product with good color, high content, few impurities and low residual solvent can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0018] Figure 1 This is a comparison chart between the product obtained by the process of this application and the product on the market. DETAILED DESCRIPTION

[0019] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below in conjunction with the drawings in the embodiments of this application. It should be understood that the specific embodiments described herein 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 ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0020] Example 1

[0021] This embodiment provides a method for refining ceftiofur sodium, and the process is as follows: Add 60mL methanol, 20mL acetone, and 10mL isopropanol to a four-necked flask, control the temperature at 10℃, add 20g crude ceftriaxone hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) under stirring to dissolve, slowly add 2.7g sodium bicarbonate over 8 min, adjust pH to 3.0, stir for 1h, add 200mL acetone to precipitate salt, add 2g activated carbon to decolorize twice, filter, and retain the filtrate. 7.1g sodium isooctanoate is dissolved in a mixed solvent of 10mL methanol + 30mL acetone, control the temperature at 20℃, add sodium isooctanoate solution to the first step filtrate, drip it for 1h, grow the crystal for 1h, filter, wash it for the first time with a mixed solvent of 20mL methanol + 80mL acetone, then wash it for the second time with 10mL isopropanol + 90mL acetone at 30℃, and drain it. Vacuum dry at 55℃ to obtain a white dry product.

[0022] Example 2

[0023] This embodiment provides a method for refining ceftiofur sodium, and the process is as follows: Add 60mL methanol, 20mL acetone, and 5mL isopropanol to a four-necked bottle, control the temperature at 10℃, add 20g crude ceftriaxone hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) under stirring to dissolve, slowly add 2.7g sodium bicarbonate over 8 minutes, adjust pH to 3.0, stir for 1h, add 200mL acetone to precipitate salt, add 2g activated carbon to decolorize twice, filter, and retain the filtrate. 7.1g sodium isooctanoate is dissolved in a mixed solvent of 10mL methanol + 30mL acetone, control the temperature at 20℃, add sodium isooctanoate solution to the first step filtrate, drip it for 1h, grow the crystal for 1h, filter, wash it for the first time with a mixed solvent of 20mL methanol + 80mL acetone, then wash it for the second time with 5mL isopropanol + 95mL acetone at 30℃, and drain it. Dry the off-white dry product in a vacuum at 55℃.

[0024] Example 3

[0025] This embodiment provides a method for refining ceftiofur sodium, and the process is as follows: Add 60mL methanol, 20mL acetone, and 2mL isopropanol to a four-necked flask, control the temperature at 10℃, add 20g crude ceftriaxone hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) under stirring to dissolve, slowly add 2.7g sodium bicarbonate over 8 min, adjust pH to 3.0, stir for 1h, add 200mL acetone to precipitate salt, add 2g activated carbon to decolorize twice, filter, and retain the filtrate. 7.1g sodium isooctanoate is dissolved in a mixed solvent of 10mL methanol + 30mL acetone, control the temperature at 20℃, add sodium isooctanoate solution to the first step filtrate, drip it for 1h, grow the crystal for 1h, filter, wash it with a mixed solvent of 20mL methanol + 80mL acetone for the first time, then wash it with 2mL isopropanol + 98mL acetone at 30℃ for the second time, and drain it. Dry it in a vacuum at 55℃ to obtain an off-white dry product.

[0026] Comparative Example 1

[0027] The configuration of this comparative example is the same as that of Example 3, except that the washing is carried out in a conventional manner, i.e., the crystals are grown for 1 hour, filtered, and then enter the washing stage: the first washing is carried out with a mixed solvent of 20 mL of methanol + 80 mL of acetone, and then the second washing is carried out with 100 mL of acetone.

[0028] Example 4 This embodiment provides a method for refining ceftiofur sodium, and the process is as follows: Add 60mL methanol, 20mL acetone, and 10mL ethanol to a four-necked flask, control the temperature at 10℃, add 20g crude ceftriaxone hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) under stirring to dissolve, slowly add 2.7g sodium bicarbonate over 8 minutes, adjust pH to 3.0, stir for 1h, add 200mL acetone to precipitate salt, add 2g activated carbon to decolorize twice, filter, and retain the filtrate. 7.1g sodium isooctanoate is dissolved in a mixed solvent of 10mL methanol + 30mL acetone, control the temperature at 20℃, add sodium isooctanoate solution to the first step filtrate, drip it for 1h, grow the crystal for 1h, filter, wash it with a mixed solvent of 20mL methanol + 80mL acetone for the first time, then wash it with 10mL ethanol + 90mL acetone at 30℃ for the second time, and drain it. Vacuum dry at 55℃ to obtain a white dry product.

[0029] Example 5

[0030] This embodiment provides a method for refining ceftiofur sodium, and the process is as follows: Add 60mL methanol and 20mL acetone to a four-necked bottle, control the temperature at 10℃, add 20g crude ceftriaxone hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) under stirring to dissolve, slowly add 2.7g sodium bicarbonate over 8 min, adjust pH to 3.0, stir for 1h, add 200mL acetone to precipitate salt, add 2g activated carbon to decolorize twice, filter, and retain the filtrate. 7.1g sodium isooctanoate is dissolved in a mixed solvent of 10mL methanol + 30mL acetone, control the temperature at 20℃, add sodium isooctanoate solution to the first step filtrate, drip it for 1h, grow the crystal for 1h, filter, wash it for the first time with a mixed solvent of 20mL methanol + 80mL acetone, then wash it for the second time with 100mL acetone, cold pump for 1h, wash it for the third time with 100mL ethanol at 35℃, and drain it. Dry it in a vacuum at 55℃ to obtain an off-white dry product.

[0031] Example 6

[0032] This embodiment provides a method for refining ceftiofur sodium, and the process is as follows: Add 60mL methanol and 20mL acetone to a four-necked bottle, control the temperature at 10℃, add 20g crude ceftriaxone hydrochloride (manufactured by Zhejiang Dongying Pharmaceutical Co., Ltd.) under stirring to dissolve, slowly add 2.7g sodium bicarbonate over 8 min, adjust pH to 3.0, stir for 1h, add 200mL acetone to precipitate salt, add 2g activated carbon to decolorize twice, filter, and retain the filtrate. 7.1g sodium isooctanoate is dissolved in a mixed solvent of 10mL methanol + 30mL acetone, control the temperature at 20℃, add sodium isooctanoate solution to the first step filtrate, drip it for 1h, grow the crystal for 1h, filter, wash it for the first time with a mixed solvent of 20mL methanol + 80mL acetone, then wash it for the second time with 100mL acetone, cold pump for 1h, wash it for the third time with 100mL isopropanol at 35℃, and drain it. Vacuum dry it at 55℃ to obtain a pure white dry product.

[0033] Comparative Example 2

[0034] The configuration of this comparative example is the same as that of Example 6, except that the washing is carried out in a conventional manner, that is, the crystals are grown for 1 hour, filtered, and then washed for the first time with a mixed solvent of 20 mL methanol + 80 mL acetone, followed by a second washing with 100 mL acetone, and a third washing with 100 mL isopropanol at 35°C.

[0035] Example 7

[0036] This embodiment provides a method for refining ceftiofur sodium, and the process is as follows: Add 60mL methanol, 20mL acetone, and 10mL n-hexane to a four-necked flask, control the temperature at 10℃, add 20g crude ceftriaxone hydrochloride to dissolve under stirring, slowly add 2.7g sodium bicarbonate over 8 min, adjust pH to 3.0, stir for 1h, add 200mL acetone to precipitate salt, add 2g activated carbon to decolorize twice, filter, and retain the filtrate. 7.1g sodium isooctanoate is dissolved in a mixed solvent of 10mL methanol + 30mL acetone, control the temperature at 20℃, add sodium isooctanoate solution to the first step filtrate, drip it for 1h, grow the crystal for 1h, filter, wash it for the first time with a mixed solvent of 20mL methanol + 80mL acetone, then wash it for the second time with 100mL n-hexane, cold pump for 1h, wash it for the third time with 100mL acetone at 20℃, and drain it. Vacuum dry at 55℃ to obtain a pure white dry product.

[0037] Example 8

[0038] This embodiment provides a method for refining ceftiofur sodium, and the process is as follows: Add 60mL methanol, 20mL acetone, and 10mL cyclohexane to a four-necked flask, control the temperature at 10℃, add 20g crude ceftriaxone hydrochloride to dissolve under stirring, slowly add 2.7g sodium bicarbonate over 8 minutes, adjust pH to 3.0, stir for 1h, add 200mL acetone to precipitate salt, add 2g activated carbon to decolorize twice, filter, and retain the filtrate. 7.1g sodium isooctanoate is dissolved in a mixed solvent of 10mL methanol + 30mL acetone, control the temperature at 20℃, add sodium isooctanoate solution to the first step filtrate, drip it for 1h, grow the crystal for 1h, filter, wash it for the first time with a mixed solvent of 20mL methanol + 80mL acetone, then wash it for the second time with 100mL cyclohexane, cold pump for 1h, wash it for the third time with 100mL acetone at 20℃, and drain it. Vacuum dry at 55℃ to obtain a pure white dry product.

[0039] Comparative Example 3

[0040] The configuration of this comparative example is the same as that of Example 8, except that the conventional method is used for washing, i.e., the crystal is grown for 1 hour, filtered and then enters the washing stage: the first washing is performed with a mixed solvent of 20 mL of methanol + 80 mL of acetone, followed by a second washing with 100 mL of acetone, cold extraction for 1 hour, and a third washing with 100 mL of acetone at 20°C.

[0041] The preparation results of the above embodiments are shown in Table 1.

[0042] Table 1: Comparison of the effects of each solution 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 ]]> Comparative Example 3 86.4% 88.7% 97.1% <![CDATA[0.52g / cm 3 ]]>

[0043] Examples 1 to 8 respectively provide different refining conditions and compare the refining to prove that the washing method does have a great influence on the product quality. The difference between the refining effect parameters is mainly reflected in the product content and bulk density, and the reason for the difference is mainly due to the difference in solvent ratio and washing method.

[0044] The influence of different mixed solvent compositions is mainly manifested in reducing the solubility of impurities and reducing the residual acetone, which is specifically reflected in the product content. In particular, the influence of mixed solvents on the dissolution of crude ceftiofur hydrochloride is more significant.

[0045] Compared with Comparative Examples 1, 2, and 3, it can be seen that the washing method of this case can significantly increase the product content and improve the product color compared with the conventional washing method.

[0046] In the washing scheme of this case, the difference mainly lies in the different composition of the second washing. This is because: Examples 1 to 4 use mixed solvent washing, and the key lies in controlling the proportion of alcohol, which is specifically manifested as: the higher the proportion of alcohol, the higher the product content; the higher the proportion of acetone, the higher the product bulk density.

[0047] After the second washing, a cold draw is applied, which creates conditions for the third washing. In Examples 5-6, the cold draw process increases the bulk density of the product, and the third washing with alcohol can remove the acetone residue and increase the product content; while in Examples 7-8, the cold draw process prevents the third washing with acetone from having too high a residual, which affects the product content. The above-mentioned Examples 5-8 using the third washing all achieve an increase in the bulk density of the product.

[0048] Combined with the above embodiments and Table 1, Figure 1 It can be seen that the control uses a market product (manufacturer: Zhejiang Dongying Pharmaceutical Co., Ltd., model: 2408001), which is yellow and has a color grade of <Y6; while the product obtained in this application is pure white and has a color grade of <Y4. The product in this case has good color and a stable yield of more than 87%.

[0049] Example 6 is used as a representative of this case, and a quality comparison is made with a comparative market product (manufacturer: Zhejiang Dongying Pharmaceutical Co., Ltd., model: 2408001). The results are shown in Figure 2.

[0050] Table 2: Comparison of test data between the product in this application and the product on the market content Acetone residue Methanol soluble residue Isopropyl alcohol residue 2-Ethylhexanoic acid residue purity Bulk density Dissolution rate pH Yield This case 93.50% 0.6% 0.02% 0.09% 0.42% 99.2% <![CDATA[0.52 g / cm 3 ]]> 35 s 6.93 88.80% Comparison 87.10% 2.38% 0.35% / 1.68% 97.06% <![CDATA[0.51 g / cm 3 ]]> 34 s 6.61 86.10%

[0051] It can be seen from Table 2 that the content of the control market product is only 87.1%, the acetone soluble residue is as high as 2.38%, the methanol soluble residue is as high as 0.35%, the isooctanoic acid soluble residue is 1.68%, the purity is only 97.06%, and the yield is 86.1%.

[0052] However, this application can increase the content 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, which greatly reduces the difficult-to-remove acetone. Although 0.09% of isopropanol residue is introduced, it does not affect the product quality because isopropanol belongs to Class III solvents and the content is very small; the product purity is increased to 99.2%, and the yield is 88.8%, which reduces the impurity content of the product. The improvement in the performance of the above-mentioned products in this case has an impact on the use of ceftiofur sodium mainly in the form of increasing the effective content of the drug and reducing the potential risk of physiological toxicity.

[0053] The above-mentioned embodiments only express several feasible implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for refining ceftiofur sodium, characterized in that: Here are the steps: Step 1, dissolving the crude product of ceftiofur hydrochloride in a mixed solvent, adjusting the pH to 2-4, adding a desalting agent to precipitate salt, decolorizing, filtering, and retaining the filtrate, The mixed solvent is any one of a mixture of acetone and alcohol, a mixture of acetone and alkane, and a mixture of acetone, alcohol and alkane. The alcohol is one or a mixture of methanol, ethanol, isopropanol, or more. The alkane is one of n-hexane and cyclohexane or a mixture of the two; Step 2, dissolving the salt-forming agent in a mixed solvent, dripping the obtained solution into the filtrate of step 1, controlling the temperature to 20-25°C to form salt, growing crystals, filtering, washing, draining, and vacuum drying to obtain the finished product of ceftiofur sodium, The mixed solvent is a mixture of methanol and acetone, The washing comprises two washing steps, wherein the first washing step is washing with a mixture of methanol and acetone, and the second washing step is washing with acetone, a mixture of acetone and ethanol, or a mixture of acetone and isopropanol.

2. A method for refining ceftiofur sodium according to claim 1, characterized in that: In step 1, the desalting agent is any one of acetone, a mixture of methanol and acetone, a mixture of isopropanol and acetone, and a mixture of n-hexane and acetone.

3. A method for refining ceftiofur sodium according to claim 1, characterized in that: In step 1, the volume ratio of the alcohol added to acetone is 3-4:

1.

4. The method for refining ceftiofur sodium according to claim 1, characterized in that: In step 1, the volume ratio of the alkane to acetone is 0.5-1:

1.

5. The method for refining ceftiofur sodium according to claim 1, characterized in that: In step 1, the pH is adjusted by adding either sodium bicarbonate or sodium carbonate.

6. The method for refining ceftiofur sodium according to claim 1, characterized in that: In step 2, the vacuum drying temperature is 50-60°C.

7. The method for refining ceftiofur sodium according to claim 1, characterized in that: In step 2, the salt-forming agent is any one of sodium 2-ethylhexanoate and sodium lactate.

8. The method for refining ceftiofur sodium according to claim 1, characterized in that: In step 2, in the first washing, the volume ratio of methanol to acetone in the mixture of methanol and acetone is 1:3-4, and the washing temperature is 20-25°C.

9. The method for refining ceftiofur sodium according to claim 1, characterized in that: In step 2, in the second washing, the washing temperature is 30-35° C., in the mixture of acetone and ethanol, the mixing volume ratio of ethanol to acetone is 1:7-9; in the mixture of acetone and isopropanol, the mixing volume ratio of isopropanol to acetone is 1:15-50.

10. The method for refining ceftiofur sodium according to claim 1, characterized in that: In step 2, the washing further comprises a third washing step, wherein the third washing step is performed by washing with ethanol or isopropanol at a washing temperature of 30-35°C.

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