Crystallization method of ceftiofur acid
By neutralizing ceftiofur hydrochloride with sodium bicarbonate in methanol and acetone solvents, and by employing a method of simultaneous dropwise addition and stirring control, the problems of high cost, high pollution, and low crystallinity in the traditional ceftiofuric acid crystallization method were solved, achieving the preparation of high-purity and high-efficiency ceftiofuric acid crystals.
Patent Information
- Application Number
- CN202510956608.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-11
- Publication Date
- 2025-11-18
AI Technical Summary
Existing methods for cefotiformic acid crystallization suffer from high production costs, significant environmental pollution, high safety risks, and low product crystallinity.
Methanol and acetone were used as solvents, and sodium bicarbonate was used to neutralize ceftiofur hydrochloride. The mixture was crystallized in a crystallizer by simultaneous dropwise addition, combined with stirring and temperature control, to form high-purity ceftiofuric acid crystals.
This has enabled low-cost and environmentally friendly production of ceftiofuric acid, improved the crystallinity and purity of the crystals, simplified the production process, and reduced safety risks.
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Figure CN120965715A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of medicine and chemical industry, and particularly relates to a crystallization method of ceftiofur acid. BACKGROUND
[0002] Ceftiofur acid is a third generation of beta-lactam cefalosporin for livestock and poultry, and has the characteristics of strong antibacterial activity, excellent pharmacokinetic characteristics, small toxic and side effects, and low residue, and is one of the most widely used cefalosporin antibiotics at present. The structural formula of ceftiofur acid is as follows:
[0003]
[0004] The existing crystallization methods of ceftiofur acid include:
[0005] Method 1: hydrochloric acid ceftiofur is dissolved in a mixed solvent of organic solvent and water, HCL molecules are adsorbed by polyvinylpyridine resin, and then water is added for crystallization.
[0006] Method 2: taking ceftiofur acid as raw material, the transparent solution is prepared by dissolving ceftiofur acid in DMF / DMSO solvent, then a catalytic amount of crystal agent and surfactant are added in the solution, after fully stirring, the solution is added into water, and the solid is obtained by crystallization, filtration and drying to prepare the ceftiofur acid product.
[0007] Method 3: amorphous ceftiofur acid is dissolved in ethyl acetate to obtain an ethyl acetate solution of ceftiofur acid; an emulsifier is dissolved in deionized water to form an emulsion; the ethyl acetate solution of ceftiofur acid is added into the emulsion under vigorous stirring, and an emulsion is immediately formed, and the ethyl acetate is evaporated under heating and reduced pressure to obtain a solid suspension, which is filtered, the filter cake is washed with deionized water, and the obtained solid is dried under nitrogen in vacuum to obtain ceftiofur acid crystals.
[0008] Method 4: hydrochloric acid ceftiofur is dissolved in a mixed solvent of organic solvent and water, HCL molecules are neutralized by alkali, and then water is added for crystallization.
[0009] In the above method, wherein: method 1 uses ion exchange resin to treat cefftiofur hydrochloride, but the activation and regeneration of ion exchange resin needs to consume a large amount of hydrochloric acid, sodium hydroxide and deionized water, and the process produces a large amount of wastewater, which is not friendly to the environment, and the production cost is high. Method 2 uses cefftiofur acid as raw material, which increases the production process, uses high-boiling solvent, and the mother liquor is difficult to handle, which pollutes the environment, and the use of surfactants and the like causes residues in the product, affecting the quality of the product. Method 3 is complicated and has safety risks, and the obtained cefftiofur acid product has low crystallinity. Method 4 uses a relatively dangerous organic base or sodium hydroxide to neutralize HCL molecules, and at the same time generates a large amount of organic or inorganic salt dissolved in the solvent, which affects the quality of the crystal, and the cefftiofur acid solution cannot be ice bathed for a long time, which will cause damage. The cefftiofur acid prepared by this method is mainly used as an intermediate for preparing cefftiofur hydrochloride, so its quality is not controlled. At present, there are few related researches, therefore, it is urgent to develop a crystallization method of cefftiofur acid. SUMMARY
[0010] The purpose of the present application is to provide a crystallization method of cefftiofur acid.
[0011] The technical scheme adopted by the present application is as follows:
[0012] A crystallization method of cefftiofur acid, comprising the following steps: under the condition that methanol and acetone are present, adding sodium bicarbonate and cefftiofur hydrochloride, reacting for 15-30 min, supplementing acetone, filtering after 15-30 min, washing the filter cake with acetone, and keeping the filtrate in ice bath at 0 DEG C; adding methanol and acetone in a crystallizer, keeping the crystallizer in water bath at 20-80 DEG C, opening the stirring, adding seed crystals, then adding the filtrate and deionized water dropwise into the crystallizer, keeping for 15-45 min after dropping, filtering, washing the filter cake with water three times, and drying the filter cake at 40-60 DEG C under vacuum for 5-12 h to obtain cefftiofur acid.
[0013] Further provided is:
[0014] The filtrate and deionized water are added dropwise into the crystallizer, the dropping method is one of synchronous dropping, one-way positive dropping and one-way reverse dropping, and the synchronous dropping method is preferably adopted, which has the best effect.
[0015] The filtrate and deionized water are added dropwise into the crystallizer, and the dropping time is 0.5-3 h, preferably 1 h.
[0016] The concentration of cefftiofur hydrochloride is 0.01-0.1 g / mL, preferably 0.03 g / mL, and the crystallization effect is the best.
[0017] The stirring rate of the crystallizer is 200-500 rpm, preferably 400 rpm.
[0018] The temperature in the crystallizer is preferably 20-80°C, preferably 50°C.
[0019] The drying under vacuum is preferably vacuum drying at 40°C for 8h.
[0020] Particularly preferably, a crystallization method of ceftiofur acid comprises the following steps: adding 48.8 mL of methanol and 26.3 mL of acetone into a four-necked flask, keeping a 10°C water bath, starting stirring at 300 rpm, adding 0.7 g of sodium bicarbonate into the four-necked flask, then weighing 4.2 g of ceftiofur hydrochloride and slowly adding it into the four-necked flask, after 30 min of reaction, adding 48.4 mL of acetone, after 15 min, filtering, washing the filter cake with 16.2 mL of acetone, and keeping the filtrate in a 0°C ice bath. Then, 5 mL of methanol and 10 mL of acetone are added into a crystallizer, the crystallizer is kept in a 50°C water bath, stirring is started at 400 rpm, 0.1 g of crystal seeds are added, then the filtrate and 200 mL of deionized water are simultaneously added into the crystallizer, the dropping is kept for 1 h, after the dropping is completed, the stirring is adjusted to 200 rpm, the crystal is kept for 30 min, immediately filtered, and the filter cake is washed with water three times, each time with 100 mL of water, the filter cake is vacuum dried at 40°C for 8 h, 4 g of pure white dry product is obtained, the purity is 99.2%, and the yield is 90.9%.
[0021] Compared with the prior art, the present application has the following beneficial effects:
[0022] (1) Direct production of ceftiofur acid from ceftiofur hydrochloride reduces the production process.
[0023] (2) The use of sodium bicarbonate to neutralize HCL molecules is safer, avoids the use of ion exchange resin, saves production cost, and prevents the destruction of ceftiofur acid molecules.
[0024] (3) The use of conventional solvents (methanol, acetone) to dissolve ceftiofur hydrochloride and the subsequent addition of acetone to remove sodium chloride in the solution prevents the influence on the subsequent crystallization process, the mother liquor is easy to handle, and the environmental pollution is small.
[0025] (4) The bidirectional synchronous dropping in the solvent-out crystallization process not only avoids the destruction of ceftiofur acid molecules exposed to a high-temperature environment for a long time, but also makes the crystal crystallinity higher in the mild crystallization environment.
[0026] (5) The use of variable-speed stirring not only ensures that the crystal particle size is small and is beneficial to the preparation of suspension, but also overcomes the problem of difficult filtration, which is conducive to industrialized production. BRIEF DESCRIPTION OF DRAWINGS
[0027] Figure 1 The XRD pattern of ceftiofur acid prepared in Example 1 of the present application.
[0028] Figure 2Microscope picture of ceftriaxone prepared in Example 1 of the present application.
[0029] Figure 3 XRD picture of existing ceftriaxone product.
[0030] Figure 4 Microscope picture of existing ceftriaxone product.
[0031] Figure 5 XRD picture of product prepared in Example 3.
[0032] Figure 6 Microscope picture of product prepared in Example 4. DETAILED DESCRIPTION
[0033] The equipment and raw materials used in the following examples, except for special instructions, are known or commercially available, wherein the ceftriaxone commercially available used for comparison is from Zhejiang Dongying Pharmaceutical Co., Ltd.
[0034] Example 1
[0035] Into a four-necked flask, 48.8 mL of methanol and 26.3 mL of acetone were added, a water bath of 10 °C was kept, the stirring was started to 300 rpm, 0.7 g of sodium bicarbonate was added into the four-necked flask, then 4.2 g of ceftriaxone hydrochloride was weighed and slowly added into the four-necked flask, after 30 min of reaction, 48.4 mL of acetone was added, after 15 min, the filter cake was washed with 16.2 mL of acetone, and the filtrate was kept in 0 °C ice bath.
[0036] Then 5 mL of methanol and 10 mL of acetone were added into the crystallizer, a water bath of 50 °C was kept, the stirring was started to 400 rpm, 0.1 g of crystal seed was added, then the filtrate was synchronously added into the crystallizer with 200 mL of deionized water, the dropping was kept for 1 h, after the dropping, the stirring was adjusted to 200 rpm, the crystal was kept for 30 min, immediately filtered, and the filter cake was washed with water three times, each time with 100 mL of water, the filter cake was dried in vacuum at 40 °C for 8 h, 4 g of pure white dry product was obtained, the purity was 99.2%, and the yield was 90.9%.
[0037] Product characterization:
[0038] The product prepared in Example 1 was compared with the commercially available product, as shown in Figures 1-4
[0039] (1) XRD comparison:
[0040] Please refer to Figure 1 and Figure 3 as shown: Figure 1 XRD picture of ceftriaxone prepared in Example 1 of the present application, Figure 3 Comparing the XRD pattern of the ceftriaxone product prepared in the present application with that of the commercially available product, it can be found that the XRD diffraction peak intensity of the product prepared in the present application is obviously higher than that of the commercially available product, indicating that the product prepared by the present process has high crystallinity.
[0041] (2) Comparison of microscope images:
[0042] Please refer to Figure 2 and Figure 4 : Figure 2 the microscope image of the ceftriaxone prepared in Example 1 of the present application, Figure 4 the microscope image of the commercially available ceftriaxone product, comparing the two, it can be found that the polarized light intensity of the product prepared in the present application is obviously higher than that of the commercially available product, indicating that the product prepared by the present process has high crystallinity.
[0043] (3) Comparison table of data
[0044] The ceftriaxone prepared in Example 1 of the present application and the commercially available product were detected, and the data are shown in Table 1:
[0045] Table 1
[0046] Name Content Liquid phase Melting point Color grade Example 1 98.50％ 99.20％ 214℃ ＜Y6 Commercial product (Zhejiang Dongying Pharmaceutical) 95.80％ 98.40％ 208℃ ＜Y8 .
[0047] In summary, comparing the product prepared in the present application with the commercially available product, it can be found that the product prepared by the present process has high crystallinity, high content, high purity and good color grade.
[0048] Example 2-3
[0049] This example mainly investigates the influence of different dropping methods on the crystallization effect. The crystallization method is the same as that in Example 1, the difference lies in that the simultaneous dropping method in Example 1 is replaced by one-way positive dropping and one-way reverse dropping, and the influence of the dropping method on the crystallization effect of ceftriaxone is investigated, as shown in Table 2.
[0050] Table 2
[0051] Serial number Dropping method Purity Yield Filtration time Crystal quality Example 1 Synchronous dropping 99.2％ 90.9％ 3 min Good Example 2 One-way positive dropping 97.6％ 88.2％ 3 min Good Example 3 One-way reverse dropping 98.7％ 90.9％ 3 min Poor
[0052] In Table 2: one-way positive dropping means dropping water into the ceftriaxone solution, and one-way reverse dropping means dropping the ceftriaxone solution into water.
[0053] Analysis: As shown in Table 1, the dropping method has a great influence on the crystallization effect, and the trend is that when the one-way positive dropping is used, the ceftriaxone is decomposed seriously in the high-temperature environment for a long time, resulting in low product purity; when the one-way reverse dropping is used, the crystal crystallinity is poor, and the XRD peak type is not sharp (as shown in Figure 5 the XRD pattern of the product prepared in Example 3). When the simultaneous dropping is selected, the effect is the best.
[0054] Examples 4-6
[0055] This embodiment mainly investigates the effect of different solution concentrations on the crystallization effect. The crystallization method is the same as in Example 1, except that the amount of ceftiofur hydrochloride added in Example 1 is replaced with 1.4g, 12.6g, and 37.7g, and the effect on the crystallization effect of ceftiofuric acid is investigated, as shown in Table 2.
[0056] Table 2
[0057]
[0058] In Table 2: the solution concentration refers to the concentration of the filtrate before it is added to the crystallizer.
[0059] Analysis: As shown in Table 2, solution concentration has a significant impact on crystallization. The trend is that the lower the solution concentration, the higher the product purity; however, excessively low concentrations result in needle-like crystals (such as...). Figure 6 The image shown is a microscope image of Example 4. It is difficult to filter; too high a concentration leads to a decrease in purity and yield. The best results are achieved when the feed amount is 4.2g (0.03g / mL).
[0060] Examples 7-9
[0061] This embodiment mainly examines the effect of different stirring rates on crystallization. The crystallization method is the same as in Example 1, except that the initial stirring rate of 400 rpm in the crystallizer in Example 1 is replaced with 200 rpm, 300 rpm, and 500 rpm, and the effect on the crystallization effect of ceftiofuric acid is examined, as shown in Table 3.
[0062] Table 3
[0063] Serial number Stirring speed Purity Yield Filtration time Crystal quality Example 1 400 rpm 99.2％ 90.9％ 3 min Good Example 7 200 rpm 98.3％ 91.1％ 2 min Good Example 8 300 rpm 98.6％ 90.8％ 2 min Good Example 9 500 rpm 99.3％ 89.2％ 10 min Good .
[0064] Analysis: As shown in Table 3, the stirring rate has a significant impact on the crystallization effect. The trend is as follows: if the stirring rate is too fast, the filtration time increases; if the stirring rate is too slow, the product purity decreases. The effect is best when the stirring rate is 400 rpm.
[0065] Examples 10-13
[0066] This embodiment mainly examines the effect of different dropping times on the crystallization effect. The crystallization method is the same as in Example 1, except that the dropping time in Example 1 is replaced with 0.5h, 2h, and 3h, and the effect on the crystallization effect of ceftiofuric acid is examined, as shown in Table 4.
[0067] Table 4
[0068] Serial number Dropping time Purity Yield Filtration time Crystal quality Example 1 1h 99.2％ 90.9％ 3 min Good Example 10 0.5h 98.9％ 91.1％ 6 min Poor Example 12 2h 98.6％ 90.1％ 3 min Good Example 13 3h 97.3％ 88.2％ 5 min Good .
[0069] Analysis: As shown in Table 4, the drop time has a great influence on the crystallization effect, and the trend is that if the drop time is too short, the crystallization is insufficient, leading to poor quality; if the drop time is too long, cefetamet pivoxil decomposes, leading to a decrease in purity and yield, and when 1 h is selected, the effect is the best.
[0070] Examples 14-15
[0071] This example mainly investigates the influence of different temperatures on the crystallization effect, and the crystallization method is the same as that in Example 1, the difference is that the crystallization temperature in Example 1 is replaced by 20℃ and 80℃, and the influence of the crystallization temperature on the crystallization effect of cefetamet pivoxil is investigated, as shown in Table 5.
[0072] Table 5
[0073] Serial number Crystallization temperature Purity Yield Filtration time Crystal quality Example 1 50℃ 99.2％ 90.9％ 3 min Good Example 14 20℃ 98.8％ 91.5％ 20 min Poor Example 15 80℃ 96.1％ 87.2％ 3 min Good .
[0074] Analysis: As shown in Table 5, the crystallization temperature has a great influence on the crystallization effect, and the trend is that if the crystallization temperature is too low, no crystal can be formed; if the filtration time increases, the crystallization temperature is too high, leading to serious decomposition, and the purity and yield of the product decrease, and when 50℃ is selected, the effect is the best.
Claims
1. A method for crystallizing cefotiformin, characterized in that, Includes the following steps: In the presence of methanol and acetone, sodium bicarbonate and ceftiofur hydrochloride are added, and the reaction is carried out for 15-30 min. Acetone is added, and the mixture is filtered after 15-30 min. The filter cake is washed with acetone, and the filtrate is kept in an ice bath at 0°C. Add methanol and acetone to the crystallizer, keep the crystallizer in a water bath at 20-80℃, turn on the stirrer, add seed crystals, and then add the filtrate and deionized water dropwise to the crystallizer. After the dropwise addition is complete, grow the crystals for 15-45 minutes, filter, and wash the filter cake three times with water. Dry the filter cake under vacuum at 40-60℃ for 5-12 hours to obtain ceftiofuric acid.
2. The crystallization method of cefotiformin according to claim 1, characterized in that: The filtrate and deionized water are added dropwise to the crystallizer in one of the following ways: synchronous addition, unidirectional forward addition, or unidirectional reverse addition. The addition time is 0.5-3 hours.
3. The crystallization method of cefotiformin according to claim 1, characterized in that: The filtrate and deionized water are added dropwise to the crystallizer in a synchronous dropping manner, with a dropping time of 1 hour.
4. The crystallization method of cefotiformin according to claim 1, characterized in that: The concentration of ceftiofur hydrochloride is 0.01-0.1 g / mL.
5. The crystallization method of cefotiformin according to claim 4, characterized in that: The concentration of ceftiofur hydrochloride is 0.03 g / mL.
6. The crystallization method of cefotiformin according to claim 1, characterized in that: Stirring is started in the crystallizer at a speed of 200-500 rpm.
7. The crystallization method of cefotiformin according to claim 6, characterized in that: Stirring is started in the crystallizer at a speed of 400 rpm.
8. The crystallization method of cefotiformin according to claim 1, characterized in that: The temperature in the crystallizer is 20℃-80℃.
9. The crystallization method of cefotiformin according to claim 8, characterized in that: The temperature in the crystallizer is 50°C.
10. The crystallization method of cefotiformin according to claim 1, characterized in that: The vacuum drying is preferably carried out at 40°C for 8 hours.