Process for the preparation of high purity sodium clavulanate crystals

Abstract

The application discloses a preparation method of high-purity sodium clometocillin crystal. 6-amino penicillanic acid (6-APA) is used as a starting material, reacts with o-chloro acyl chloride, is subjected to acidification treatment, is subjected to extraction separation to obtain acid liquor for a salting reaction, a suitable salting agent is added into the acid liquor for the salting reaction to perform a salting reaction, and finally, through evaporation-coupling crystallization means, the sodium clometocillin crystal product with excellent powder performance and high purity is obtained. The preparation method particularly emphasizes the simplicity of operation, the high purity (the purity of anhydride is up to 97.6%) and excellent powder performance (particle size > 200 μm, angle of repose < 26.5°) of the product, and focuses on the optimization of product stability, so that the high quality and reliability of the product are ensured.

Description

Technical Field

[0001] This invention belongs to the fields of pharmaceutical and chemical technology, specifically relating to a method for preparing high-purity cloxacillin sodium crystals with good powder properties. Background Technology

[0002] Cloxacillin Sodium, also known as o-cloxacillin sodium, has the chemical name 6-[3-(2-chlorophenyl)-5-methyl-4-isozolamide]penicillin sodium, and the chemical formula C. 19 H 17 ClN3O5SNa·H2O, with a molar mass of 475.88, has the structural formula shown below. It is a white or off-white crystalline powder with hygroscopic properties. Clinically, it is mainly used to treat sepsis, endocarditis, respiratory tract infections, and skin and soft tissue infections caused by penicillinase-resistant Staphylococcus aureus.

[0003]

[0004] In the current pharmaceutical industry environment, one of the main challenges encountered in the preparation of domestically produced cloxacillin sodium is that the final product fails to meet the stringent standards of the Chinese Pharmacopoeia for clarity and purity, and the poor crystal flowability leads to difficulties in packaging. The core of this problem lies in the fact that cloxacillin sodium produced by traditional processes suffers from deficiencies such as small and uneven crystal size, easy aggregation, severe impurity inclusion, irregular appearance, and incomplete crystal habit. These factors collectively result in low product purity, serious solvent residue problems, and a yellow or yellow-green color.

[0005] The conventional production method of cloxacillin sodium involves dissolving o-chloroacyl chloride and 6-aminopenicillanic acid (6-APA) separately in acetone, mixing them, and then carrying out an acylation reaction. After the reaction, further acidification is required, and butyl acetate is used as an extractant to obtain a butyl acetate solution of cloxacillin. Subsequently, a butyl acetate solution containing sodium salt is added to this solution to promote the crystallization of cloxacillin sodium. After crystallization, the final product is obtained through washing and vacuum drying. However, this production process is affected by various factors such as reaction rate, diffusion rate, heat of reaction, and heat of phase transition, leading to a series of technical problems, including low liquid phase content, long filtration time, difficult drying, small and incomplete crystals, non-uniform particle size, large batch-to-batch variability, low yield, excessive visible foreign matter, and excessive solvent residue. These problems further increase production and post-processing costs, thus necessitating the development of a new high-purity cloxacillin sodium production technology.

[0006] Studies on the crystallization process of cloxacillin sodium both domestically and internationally (Li Zhonghua, "Synthesis of Cloxacillin Sodium", 2002) indicate that mixing a butyl acetate solution of cloxacillin acid with methanol, sodium isooctanoate, and butyl acetate can promote crystallization by heating and natural cooling. Although this method can achieve a certain yield and purity, it has significant drawbacks, such as accelerated degradation of cloxacillin sodium due to excessively high reaction temperatures, improper control of sodium isooctanoate dosage, and uneven crystal size and product agglomeration caused by static natural crystallization. These factors not only affect product quality but also limit the efficiency and economic viability of the process.

[0007] To address these challenges, future research and process improvements need to focus on improving crystal quality and morphology, reducing solvent residue, and increasing the overall purity and yield of the product. Further efforts should be made to develop new production technologies for cloxacillin sodium to achieve higher industrial application standards and economic benefits. Summary of the Invention

[0008] This invention discloses a novel evaporation-dissolution coupled crystallization method that starts with 6-aminopenicillanic acid (6-APA), reacts with o-chloroacyl chloride, acidifies, extracts, forms a salt, and finally crystallizes to produce high-purity cloxacillin sodium crystals. This method is simple to operate, produces high-purity and stable products, and the product crystals are large and complete flakes with a particle size >200μm and an angle of repose <26.2°. It is not prone to impurity inclusion, has low solvent residue, high conversion rate and high molar yield based on 6-APA, and is easy for industrial production.

[0009] The method for preparing cloxacillin sodium involved in this invention comprises the following characteristic steps:

[0010] Step 1: Add 6-APA and a certain proportion of solvent I and solvent II solutions to the crystallizer, control the temperature inside the crystallizer, adjust the pH of the system to a certain value, and stir to dissolve it into solution A.

[0011] Solution B is prepared by dissolving o-chloroacyl chloride in solvent II;

[0012] Solution B is added to the crystallizer at a certain flow rate and reacted with solution A for 0.5 to 2 hours;

[0013] Step 2: After the reaction is complete, solvent III is added to the crystallizer for extraction, the system is adjusted to a certain pH value, allowed to stand and separate phases, and the upper organic phase is taken into the crystallizer for later use.

[0014] Step 3: Control the temperature inside the crystallizer, and add a certain amount of salt-forming agent and solvent IV solution to the crystallizer at a certain flow rate to carry out the salt-forming reaction;

[0015] Step 4: Add a certain amount of solvent V to the crystallizer, and after crystallization, allow the crystals to grow for a period of time, then continue to add a certain amount of the same solvent.

[0016] Step 5: Start the vacuum pump and control the vacuum level in the crystallizer to a certain value. Stop the vacuum operation after the solid content in the crystallizer reaches a certain proportion, and continue crystal growth for a period of time.

[0017] Step 6: Perform solid-liquid separation, wash the filter cake, and place the obtained crystals in a drying oven to dry them to obtain the final product.

[0018] Preferably, solvent I is one of methanol, water, ethanol and dichloromethane, and solvent II is one of acetone, acetonitrile, isopropanol and dichloromethane.

[0019] Preferably, in step 1, the temperature is maintained at 0–10°C.

[0020] Preferably, in step 1, the mass ratio of solvent I to solvent II is 1:1 to 1:1.5.

[0021] In any of the above-mentioned preferred embodiments, the mass ratio of 6-APA to the mixed solvent (solvent I and solvent II) in step 1 is 1:5 to 1:15.

[0022] Preferably, in step 1, the pH value is controlled within the range of 4.0 to 9.0.

[0023] In any of the above-mentioned preferred embodiments, the pH adjustment in step 1 uses an inorganic base or inorganic acid, namely sodium hydroxide, sodium carbonate, sodium bicarbonate, and dilute sulfuric acid or hydrochloric acid.

[0024] Preferably, solvent II used in step 1 is one of acetone, acetonitrile, isopropanol and dichloromethane.

[0025] Preferably, in any of the above, the mass ratio of 6-APA to o-chloroacyl chloride used in step 1 is 1:1 to 1:1.3.

[0026] Preferably, in any of the above embodiments, the mass ratio of o-chloroacyl chloride to solvent II used in step 1 is 1:2 to 1:5.

[0027] In any of the above-mentioned preferred embodiments, the flow rate of solution B in step 1 is 2 to 6 mL / min.

[0028] In any of the above-mentioned preferred embodiments, solvent III in step 2 is an extractant, specifically one of ethyl acetate, butyl acetate, isopropyl acetate, and petroleum ether.

[0029] Preferably, in step 2, the mass ratio of solvent III to solvent I is 1.5:1 to 2.4:1.

[0030] Preferably, in step 2, the pH value is controlled within the range of 4.0 to 9.0.

[0031] In any of the above-mentioned preferred embodiments, the pH adjustment in step 2 uses an inorganic base or inorganic acid, namely sodium hydroxide, sodium carbonate, sodium bicarbonate, and dilute sulfuric acid or hydrochloric acid.

[0032] In any of the above-mentioned preferred embodiments, the temperature inside the crystallizer is controlled at 20-30°C in step 3.

[0033] In any of the above-mentioned preferred embodiments, the salt-forming agent in step 3 is one of sodium bicarbonate, sodium ethoxide, and sodium isooctanoate, and the molar ratio of its dosage to 6-APA is 1:1 to 1.2:1.

[0034] Preferably, the solvent IV used in step 3 is one of methanol, acetone, ethyl acetate and butyl acetate.

[0035] In any of the above-mentioned preferred embodiments, the ratio of solvent IV to salt-forming agent in step 3 is 1:1 to 2:1.

[0036] Preferably, in step 3, the flow rate of the salt-forming solution is 2 to 6 mL / min.

[0037] Preferably, in any of the above, the salt formation reaction time in step 3 is 0.5 to 1 hour.

[0038] In any of the above-mentioned preferred embodiments, the solvent V in step 4 is one of ethyl acetate, butyl acetate, isopropyl acetate, and petroleum ether.

[0039] In any of the above-mentioned preferred embodiments, the mass ratio of the total amount of solvent V to solvent III in step 4 is 1.5:1 to 3:1.

[0040] Preferably, in step 4, the flow rate of solvent V is controlled between 0.1 and 10 mL / min.

[0041] Preferably, in step 4, the crystal growth time is 0.5 to 2 hours.

[0042] In any of the above-mentioned preferred embodiments, the temperature inside the crystallizer in step 5 is controlled at 20–30°C.

[0043] Preferably, in step 5, the vacuum level inside the crystallizer is controlled to be -0.05 to -0.09 MPa.

[0044] In any of the above-mentioned preferred embodiments, the solvent evaporation rate in the crystallizer in step 5 is 5-10 mL / h (based on 10 g of 6-APA).

[0045] In any of the above-mentioned preferred embodiments, the evaporation and crystallization operation is stopped when the final solid content in step 5 reaches 15% to 30% (V / V).

[0046] Preferably, in step 5, the crystal growth time is 0.5 to 1 hour.

[0047] Preferably, in step 6, the detergent is one of acetone, acetonitrile, and ethanol.

[0048] In any of the above-mentioned preferred embodiments, the drying method in step 6 is blower drying, the drying temperature is 40-50℃, and the drying time is 8-16 hours.

[0049] Advantages and benefits of the present invention

[0050] (1) The present invention controls crystal growth by coupling the crystallization process, and the resulting product has uniform particle size, complete plate-like crystal structure, and rapid filtration.

[0051] (2) The powder prepared by this invention has excellent performance, the crystal product has a large particle size, >200μm, an angle of repose <26.5°, and good flow properties.

[0052] (3) The method of the present invention has good process controllability, short production cycle, small batch difference, and single-pass molar yield of over 80%.

[0053] (4) The product obtained by this method has low solvent residue, total impurities as low as 0.3%, and chloramphenicol sodium purity as high as 97.6% (based on anhydrous), with excellent stability.

[0054] (5) The product prepared by the present invention is clear after dissolution, with a pH of 5.8 to 6.1, which all meet the requirements of the Chinese Pharmacopoeia. Attached Figure Description

[0055] Figure 1a Microscopic image of the cloxacillin sodium product prepared in Example 1 of this invention.

[0056] Figure 1b TEM image of the cloxacillin sodium product prepared in Example 1 of this invention.

[0057] Figure 2 XRD patterns of cloxacillin sodium products prepared in Examples 1-7 of this invention.

[0058] Figure 3 TG / DSC chromatogram of cloxacillin sodium product prepared in Example 1 of this invention.

[0059] Figure 4 Raman spectra of cloxacillin sodium products prepared in Examples 1-7 of this invention. Detailed Implementation

[0060] The present invention will be described more clearly and completely through the following embodiments, but the described examples are only a part of the embodiments of the present invention, and not all of them. The embodiments are provided to help understand the present invention and should not be construed as limiting the scope of protection of the present invention.

[0061] Example 1:

[0062] A method for preparing high-purity cloxacillin sodium crystals, comprising the following steps:

[0063] Step 1: Dissolve 10g of 6-APA in a mixture of 25mL water and 32mL acetone at 5℃, and adjust the pH of the solution to approximately 8.2 using 2-3M sodium carbonate solution to obtain a 6-APA solution (denoted as A). Dissolve 12g of o-chloroacyl chloride in 40mL acetone at room temperature to obtain an o-chloroacyl chloride solution (denoted as B). Controlling the crystallizer temperature at 5℃, add solution B to the crystallizer at a rate of 4mL / min, and allow it to undergo a condensation reaction with solution A for 1 hour.

[0064] Step 2: Add 60 mL of ethyl acetate to the crystallizer for extraction and stir for 20 min. Adjust the pH of the solution to 4.0 using dilute sulfuric acid solution, let stand for 30 min, and collect the upper organic phase into the crystallizer.

[0065] Step 3: At 25°C, dissolve 10g of sodium isooctanoate in 10mL of ethyl acetate solution (denoted as solution C), start stirring, and add solution C into the crystallizer at a flow rate of 2mL / min to carry out the salt formation reaction for 0.5h.

[0066] Step 4: Add 110 mL of ethyl acetate dropwise into the crystallizer at a flow rate of 3 mL / min. After crystallization, allow the crystals to grow for 0.5 h. Then, continue adding the remaining ethyl acetate at a flow rate of 0.2 mL / min and allow the crystals to grow for another 1 h.

[0067] Step 5: Control the temperature inside the crystallizer to 25℃ and carry out the reduced pressure evaporation crystallization process at -0.05MPa. Evaporate 37mL of solution at a uniform rate within 5h. When the solid content in the crystallizer is about 25% (V / V), stop the reduced pressure evaporation and continue crystallization at this temperature and stirring rate for 0.5h.

[0068] Step 6: Perform solid-liquid separation and wash the sample with acetone. Place the washed solid sample in a forced-air drying oven, set the oven temperature to 45℃, and dry for 10 hours to obtain cloxacillin sodium product.

[0069] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2 As shown. The molar yield was 80.8%, the purity was 97.0% (anhydrous), the aqueous solution was colorless, clear and transparent, the acidity was 5.98, the product particle size was approximately 230 μm, and the angle of repose was 22.4°.

[0070] Example 2:

[0071] A method for preparing high-purity cloxacillin sodium crystals, comprising the following steps:

[0072] Step 1: Dissolve 10g of 6-APA in a mixture of 40mL methanol and 60mL acetonitrile at 5℃, and adjust the pH of the solution to approximately 4.0 using 2-3M dilute sulfuric acid solution to obtain a 6-APA solution (denoted as A). Dissolve 13g of o-chloroacyl chloride in 65mL acetonitrile at room temperature to obtain an o-chloroacyl chloride solution (denoted as B). Controlling the crystallizer temperature at 5℃, add solution B to the crystallizer at a rate of 6mL / min, and allow it to undergo a condensation reaction with solution A for 1 hour.

[0073] Step 2: Add 60 mL of ethyl acetate to the crystallizer for extraction and stir for 20 min. Adjust the pH of the solution to 8.5 using sodium carbonate solution, let it stand for 30 min, and collect the upper organic phase into the crystallizer.

[0074] Step 3: At 20°C, dissolve 11g of sodium isooctanoate in 22mL of ethyl acetate solution (denoted as solution C), start stirring, and add solution C into the crystallizer at a flow rate of 2mL / min to carry out the salt formation reaction for 1h.

[0075] Step 4: Add 90 mL of ethyl acetate dropwise into the crystallizer at a flow rate of 2 mL / min. After crystallization, allow the crystals to grow for 1 hour. Then, continue adding the remaining ethyl acetate at a flow rate of 0.1 mL / min and allow the crystals to grow for another hour.

[0076] Step 5: Control the temperature inside the crystallizer to 20℃ and carry out the reduced pressure evaporation crystallization process at -0.06MPa. Evaporate 27mL of solution at a uniform rate within 5h. When the solid content in the crystallizer is about 21% (V / V), stop the reduced pressure evaporation and continue crystallization at this temperature and stirring rate for 0.8h.

[0077] Step 6: Perform solid-liquid separation and wash the sample with acetone. Place the washed solid sample in a forced-air drying oven, set the oven temperature to 40℃, and dry for 8 hours to obtain cloxacillin sodium product.

[0078] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2As shown. The molar yield was 78.2%, the purity was 96.3% (anhydrous), the aqueous solution was colorless, clear and transparent, the acidity was 5.87, the product particle size was approximately 235 μm, and the angle of repose was 18.8°.

[0079] Example 3:

[0080] A method for preparing high-purity cloxacillin sodium crystals, comprising the following steps:

[0081] Step 1: Dissolve 10g of 6-APA in a mixed solvent of 70mL ethanol and 80mL isopropanol at 0℃, and adjust the pH of the solution to approximately 9.0 using 2-3M sodium bicarbonate solution to obtain a 6-APA solution (denoted as A). At room temperature, dissolve 11g of o-chloroacyl chloride in 22mL isopropanol to obtain an o-chloroacyl chloride solution (denoted as B). Maintaining the crystallizer temperature at 0℃, add solution B to the crystallizer at a rate of 2mL / min, and allow it to undergo a condensation reaction with solution A for 1 hour.

[0082] Step 2: Add 140 mL of butyl acetate to the crystallizer for extraction and stir for 20 min. Adjust the pH of the solution to 4.0 using hydrochloric acid solution, let stand for 30 min, and collect the upper organic phase into the crystallizer.

[0083] Step 3: At 30℃, dissolve 12g of sodium ethoxide in 20mL of butyl acetate solution (denoted as solution C), start stirring, and add solution C into the crystallizer at a flow rate of 4mL / min to carry out the salt formation reaction for 0.8h.

[0084] Step 4: Add 300 mL of butyl acetate dropwise into the crystallizer at a flow rate of 10 mL / min. After crystallization, it is necessary to maintain the crystals for 2 hours. Then, continue to add the remaining butyl acetate at a flow rate of 0.5 mL / min. Then, maintain the temperature in the crystallizer at 30°C and maintain the crystals for 0.5 hours.

[0085] Step 5: Control the temperature inside the crystallizer to 30℃ and carry out the reduced pressure evaporation crystallization process at -0.06MPa. Evaporate 50mL of solution at a uniform rate within 5h. When the solid content in the crystallizer is about 28% (V / V), stop the reduced pressure evaporation and continue crystallization for 1h at the same temperature and stirring rate.

[0086] Step 6: Perform solid-liquid separation and wash the sample with acetonitrile. Place the washed solid sample in a forced-air drying oven, set the oven temperature to 45℃, and dry for 16 hours to obtain cloxacillin sodium product.

[0087] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2As shown. The molar yield was 81.1%, the purity was 96.7% (anhydrous), the aqueous solution was colorless, clear and transparent, the acidity was 6.07, the product particle size was approximately 260 μm, and the angle of repose was 15.6°.

[0088] Example 4:

[0089] A method for preparing high-purity cloxacillin sodium crystals, comprising the following steps:

[0090] Step 1: Dissolve 10g of 6-APA in a mixture of 22mL dichloromethane and 28mL acetone at 3℃, and adjust the pH of the solution to approximately 7.5 using 2-3M sodium hydroxide solution to obtain a 6-APA solution (denoted as A). At room temperature, dissolve 10g of o-chloroacyl chloride in 40mL dichloromethane to obtain an o-chloroacyl chloride solution (denoted as B). Maintaining the crystallizer temperature at 3℃, add solution B to the crystallizer at a rate of 3mL / min, and allow it to undergo a condensation reaction with solution A for 1 hour.

[0091] Step 2: Add 40 mL of isopropyl acetate to the crystallizer for extraction and stir for 20 min. Adjust the pH of the solution to 6.0 using dilute sulfuric acid solution, let stand for 30 min, and collect the upper organic phase into the crystallizer.

[0092] Step 3: At 28℃, dissolve 10g of sodium bicarbonate in 15mL of methanol solution (denoted as solution C), start stirring, and add solution C into the crystallizer at a flow rate of 3mL / min to carry out the salt formation reaction for 1h.

[0093] Step 4: Add 120 mL of isopropyl acetate dropwise into the crystallizer at a flow rate of 8 mL / min. After crystallization, allow the crystals to grow for 1 hour. Then, continue adding the remaining ethyl acetate at a flow rate of 0.4 mL / min. Maintain the temperature inside the crystallizer at 28°C and allow the crystals to grow for another 2 hours.

[0094] Step 5: Control the temperature inside the crystallizer to 28℃ and carry out the reduced pressure evaporation crystallization process at -0.09MPa. Evaporate 47mL of solution at a uniform rate within 5h. When the solid content in the crystallizer is about 30% (V / V), stop the reduced pressure evaporation and continue crystallization at this temperature and stirring rate for 0.6h.

[0095] Solid-liquid separation was performed, and the sample was washed with ethanol. The washed solid sample was placed in a forced-air drying oven, and the oven temperature was set to 50℃ for 8 hours to obtain cloxacillin sodium product.

[0096] Step 6: The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2As shown. The molar yield was 80.1%, the purity was 96.1% (anhydrous), the aqueous solution was colorless, clear and transparent, the acidity was 5.78, the product particle size was approximately 290 μm, and the angle of repose was 15.3°.

[0097] Example 5:

[0098] A method for preparing high-purity cloxacillin sodium crystals, comprising the following steps:

[0099] Step 1: At 8°C, dissolve 10g of 6-APA in a mixture of 50mL dichloromethane and 50mL isopropanol, and adjust the pH of the solution to approximately 4.5 using 2-3M hydrochloric acid solution to obtain a 6-APA solution (denoted as A). At room temperature, dissolve 12g of o-chloroacyl chloride in 50mL isopropanol to obtain an o-chloroacyl chloride solution (denoted as B). Controlling the crystallizer temperature at 8°C, add solution B to the crystallizer at a rate of 5mL / min, and allow it to undergo a condensation reaction with solution A for 1 hour.

[0100] Step 2: Add 90 mL of petroleum ether to the crystallizer for extraction and stir for 20 min. Adjust the pH of the solution to 9.0 using sodium bicarbonate solution, let stand for 30 min, and collect the upper organic phase into the crystallizer.

[0101] Step 3: At 22℃, dissolve 11g of sodium isooctanoate in 10mL of acetone solution (denoted as solution C), start stirring, and add solution C into the crystallizer at a flow rate of 2mL / min to carry out the salt formation reaction for 0.5h.

[0102] Step 4: Add 135 mL of petroleum ether dropwise into the crystallizer at a flow rate of 6 mL / min. After crystallization, allow the crystals to grow for 0.5 h. Then, continue adding the remaining petroleum ether at a flow rate of 0.3 mL / min. Maintain the temperature inside the crystallizer at 22 °C and allow the crystals to grow for 1 h.

[0103] Step 5: Control the temperature inside the crystallizer to 22℃ and carry out the reduced pressure evaporation crystallization process at -0.07MPa. Evaporate 32mL of solution at a uniform rate within 5h. When the solid content in the crystallizer is about 18% (V / V), stop the reduced pressure evaporation and continue crystallization for 1h at the same temperature and stirring rate.

[0104] Step 6: Perform solid-liquid separation and wash the sample with ethanol. Place the washed solid sample in a forced-air drying oven, set the oven temperature to 45℃, and dry for 16 hours to obtain cloxacillin sodium product.

[0105] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2As shown. The molar yield was 79.2%, the purity was 96.2% (anhydrous), the aqueous solution was colorless, clear and transparent, the acidity was 5.84, the product particle size was approximately 205 μm, and the angle of repose was 26.3°.

[0106] Example 6:

[0107] A method for preparing high-purity cloxacillin sodium crystals, comprising the following steps:

[0108] Step 1: At 5°C, dissolve 10g of 6-APA in a mixture of 50mL ethanol and 72mL dichloromethane, and adjust the pH of the solution to approximately 8.0 using 2-3M sodium carbonate solution to obtain a 6-APA solution (denoted as A). At room temperature, dissolve 11.5g of o-chloroacyl chloride in 40mL dichloromethane to obtain an o-chloroacyl chloride solution (denoted as B). Maintaining the crystallizer temperature at 5°C, add solution B to the crystallizer at a rate of 4mL / min, and allow it to undergo a condensation reaction with solution A for 1 hour.

[0109] Step 2: Add 100 mL of butyl acetate to the crystallizer for extraction and stir for 20 min. Adjust the pH of the solution to 6.5 using dilute sulfuric acid solution, let stand for 30 min, and collect the upper organic phase into the crystallizer.

[0110] Step 3: At 20℃, dissolve 11.2g of sodium ethoxide in 20mL of butyl acetate solution (denoted as solution C), start stirring, and add solution C into the crystallizer at a flow rate of 6mL / min to carry out the salt formation reaction for 1h.

[0111] Step 4: Add 250 mL of butyl acetate dropwise into the crystallizer at a flow rate of 10 mL / min. After crystallization, allow the crystals to grow for 1.5 h. Then, continue adding the remaining butyl acetate at a flow rate of 0.5 mL / min. Maintain the temperature inside the crystallizer at 20 °C and allow the crystals to grow for another 1.5 h.

[0112] Step 5: Control the temperature inside the crystallizer to 20℃ and carry out the reduced pressure evaporation crystallization process at -0.09MPa. Evaporate 31mL of solution at a uniform rate within 5h. When the solid content in the crystallizer is about 18% (V / V), stop the reduced pressure evaporation and continue crystallization at the same temperature and stirring rate for 0.5h.

[0113] Step 6: Perform solid-liquid separation and wash the sample with acetonitrile. Place the washed solid sample in a forced-air drying oven, set the oven temperature to 45℃, and dry for 12 hours to obtain cloxacillin sodium product.

[0114] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2As shown. The molar yield was 78.8%, the purity was 95.9% (anhydrous), the aqueous solution was colorless, clear and transparent, the acidity was 5.88, the product particle size was approximately 240 μm, and the angle of repose was 19.4°.

[0115] Example 7:

[0116] A method for preparing high-purity cloxacillin sodium crystals, comprising the following steps:

[0117] Step 1: At 10℃, dissolve 10g of 6-APA in a mixture of 36mL water and 50mL acetonitrile, and adjust the pH of the solution to approximately 4.8 using 2-3M dilute sulfuric acid solution to obtain a 6-APA solution (denoted as A). At room temperature, dissolve 12.5g of o-chloroacyl chloride in 60mL acetonitrile to obtain an o-chloroacyl chloride solution (denoted as B). Maintaining the crystallizer temperature at 10℃, add solution B to the crystallizer at a rate of 6mL / min, and allow it to undergo a condensation reaction with solution A for 1 hour.

[0118] Step 2: Add 80 mL of isopropyl acetate to the crystallizer for extraction and stir for 20 min. Adjust the pH of the solution to 8.5 using sodium hydroxide solution, let it stand for 30 min, and collect the upper organic phase into the crystallizer.

[0119] Step 3: At 25°C, dissolve 12g of sodium isooctanoate in 10mL of acetone solution (denoted as solution C), start stirring, and add solution C into the crystallizer at a flow rate of 3mL / min to carry out the salt formation reaction for 0.6h.

[0120] Step 4: Add 120 mL of isopropyl acetate dropwise into the crystallizer at a flow rate of 7 mL / min. After crystallization, allow the crystals to mature for 0.5 h. Then, continue adding the remaining isopropyl acetate at a flow rate of 0.8 mL / min. Maintain the crystallizer temperature at 25 °C for 1 h.

[0121] Step 5: Control the temperature inside the crystallizer to 25℃ and carry out the reduced pressure evaporation crystallization process at -0.05MPa. Evaporate 50mL of solution at a uniform rate within 5h. When the solid content in the crystallizer is about 22% (V / V), stop the reduced pressure evaporation and continue crystallization at this temperature and stirring rate for 0.5h.

[0122] Step 6: Perform solid-liquid separation and wash the sample with acetonitrile. Place the washed solid sample in a forced-air drying oven, set the oven temperature to 50℃, and dry for 8 hours to obtain cloxacillin sodium product.

[0123] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2As shown. The molar yield was 81.7%, the purity was 96.5% (anhydrous), the aqueous solution was colorless, clear and transparent, the acidity was 5.95, the product particle size was approximately 320 μm, and the angle of repose was 13.8°.

[0124] Comparative Example 1:

[0125] The difference from Example 1 is that step 5 is omitted.

[0126] The final product is a white powder with a molar yield of 54.2% and a purity of 94.1% (anhydrous). The aqueous solution is colorless, clear, and transparent with an acidity of 5.61. The product particle size is approximately 75 μm and the angle of repose is 39.1°.

[0127] Comparative Example 2:

[0128] The difference from Example 1 lies in the synthesis method of cloxacillin sodium. Cloxacillin sodium is synthesized by acylation in a mixed solution of methanol and butyl acetate followed by direct reaction with sodium isooctanoate for crystallization. The subsequent evaporation-dissolution coupled crystallization steps are the same as in Example 1. The specific steps are as follows:

[0129] Step 1: Dissolve 10g of 6-APA in a mixed solution of 25mL methanol and 32mL butyl acetate at 5℃ to obtain a 6-APA solution (denoted as A). Dissolve 12g of o-chloroacyl chloride in 40mL butyl acetate at room temperature to obtain an o-chloroacyl chloride solution (denoted as B). Controlling the crystallizer temperature at 5℃, add solution B to the crystallizer at a rate of 4mL / min and allow it to undergo a condensation reaction with solution A for 1h to obtain a mixed solution of cloxacillin acid in methanol and butyl acetate.

[0130] Step 2: At 25℃, dissolve 10g of sodium isooctanoate in 10mL of butyl acetate solution (denoted as solution C), start stirring, and add solution C into the crystallizer at a flow rate of 2mL / min to carry out the salt formation reaction for 0.5h, forming a solid-liquid suspension of cloxacillin sodium.

[0131] Step 3: Add 110 mL of butyl acetate dropwise into the crystallizer at a flow rate of 3 mL / min. After the addition is complete, allow the crystals to grow for 1 hour.

[0132] Step 4: Control the temperature inside the crystallizer to 25℃ and carry out the reduced pressure evaporation crystallization process at -0.05MPa. Evaporate 37mL of solution at a uniform rate within 5h. When the solid content in the crystallizer is about 25% (V / V), stop the reduced pressure evaporation and continue crystallization at this temperature and stirring rate for 0.5h.

[0133] Step 5: Perform solid-liquid separation and wash the sample with acetone. Place the washed solid sample in a forced-air drying oven, set the oven temperature to 45℃, and dry for 10 hours to obtain cloxacillin sodium product.

[0134] The final product is a yellow powder with a molar yield of 75.8% and a purity of 91.2% (anhydrous). The aqueous solution is pale yellow and clear with an acidity of 5.37. The product particle size is approximately 31 μm and the angle of repose is 42.4°.

[0135] Chemical property testing

[0136] 1) The chemical stability of cloxacillin sodium prepared in Examples 1-7 and Comparative Examples 1-2 of this invention was investigated. During storage at 30±5℃ and 40±5%RH for 30 days, the color, purity, and morphology of the product did not change, indicating that the crystal has good chemical stability. The results are shown in Table 1.

[0137] Table 1. Chemical stability study of cloxacillin sodium in this invention.

[0138]

[0139] 2) The chemical stability of chloramphenicol sodium prepared in Examples 1-7 and Comparative Examples 1-2 of this invention, including its turbidity and acidity, was investigated. During storage at 30±5℃ and 40±5%RH for 30 days, the acidity and turbidity of the products remained essentially unchanged, indicating good crystal stability. The results are shown in Table 2.

[0140] Table 2. Stability Study of Nafcilin Sodium in This Invention (Turbidity, Acidity, etc.)

[0141]

[0142]

[0143] 3) The properties of the cloxacillin sodium crystal powders prepared in Examples 1-7 and Comparative Examples 1-2 of this invention were investigated. During storage at 30±5℃ and 40±5%RH for 30 days, the angle of repose and other properties of the products were examined, and no significant changes were observed, indicating that the crystal powder has good stability. The results are shown in Table 3.

[0144] Table 3. Stability Study of Nafcilin Sodium Powder of the Present Invention (±0.1°)

[0145]

[0146] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several modifications and improvements can be made without departing from the inventive concept, and these all fall within the protection scope of the present invention.

Claims

1. A method for preparing high-purity sodium clavulanic acid crystals, comprising the following steps: Step 1: adding 6-APA and a mixture of solvent I and solvent II in a mass ratio of 1:1 to 1:1.5 into a crystallizer, controlling the temperature in the crystallizer to be 0-10 ℃, adjusting the pH value to be 4.0-9.0, stirring to dissolve the 6-APA to prepare solution A, wherein the solvent I is one of methanol, water, ethanol and dichloromethane, and the solvent II is one of acetone, acetonitrile, isopropyl alcohol and dichloromethane; dissolving the o-chloro acyl chloride in the solvent II to prepare solution B; adding the solution B into the crystallizer at a certain flow rate, and acylating the solution A for 0.5-2 h, wherein the mass ratio of 6-APA to o-chloro acyl chloride is 1:1 to 1:1.3; Step 2: after the reaction is completed, adding solvent III into the crystallizer to extract, adjusting the pH value of the system to be 4.0-9.0, and standing to separate the phases, and taking the upper organic phase into the crystallizer for use; wherein the solvent III is one of ethyl acetate, butyl acetate, isopropyl acetate and petroleum ether; Step 3: controlling the temperature in the crystallizer to be 20-30 ℃, and adding a certain amount of a solution of a salting agent and solvent IV into the crystallizer at a certain flow rate to perform salting reaction for 0.5-1 h; wherein the salting agent is one of sodium bicarbonate, sodium ethoxide and sodium iso-octanoate, and the molar ratio of the salting agent to 6-APA is 1:1 to 1.2:1, and the solvent IV is one of methanol, acetone, ethyl acetate and butyl acetate; Step 4: adding a certain amount of solvent V into the crystallizer, and after crystallization, crystallizing for 0.5-2 h, and continuously adding a certain amount of the solvent V; wherein the solvent V is one of ethyl acetate, butyl acetate, isopropyl acetate and petroleum ether, and the mass ratio of the total amount of the solvent V to the solvent III is 1.5:1 to 3:1; Step 5: starting a vacuum pump, and controlling the vacuum degree in the crystallizer to be -0.05 to -0.09 MPa, stopping the vacuum operation when the solid content in the crystallizer reaches 15%-30% V / V, and continuously crystallizing for 0.5-1 h; Step 6: performing solid-liquid separation, washing the filter cake, and drying the obtained crystals in a drying box to obtain the final product, wherein the particle size is greater than 200 μm, and the rest angle is less than 26.5°.

2. The method for preparing high-purity sodium clavulanic acid crystals according to claim 1, wherein the mass ratio of 6-APA to the mixed solvent in step 1 is 1:5 to 1:15, and the mixed solvent is a mixture of the solvent I and the solvent II.

3. The method for preparing high-purity sodium clavulanic acid crystals according to claim 1, wherein the mass ratio of o-chloro acyl chloride to the solvent II used in step 1 is 1:2 to 1:

5.

4. The method for preparing high-purity sodium clavulanic acid crystals according to claim 1, wherein the flow rate of the solution B in step 1 is 2-6 mL / min.

5. The method for preparing high-purity sodium clavulanic acid crystals according to claim 1, wherein the mass ratio of the solvent III to the solvent I in step 2 is 1.5:1 to 2.4:

1. ​ 6. The method of claim 1, wherein the ratio of the solvent IV to the salting agent in step 3 is 1:1 to 2:

1.

7. The method of claim 1, wherein the flow rate of the salting solution in step 3 is 2 to 6 mL / min.

8. The method of claim 1, wherein the flow rate of the solvent V in step 4 is controlled to be 0.1 mL / min to 10 mL / min.

9. The method of claim 1, wherein the evaporation rate of the solvent in the crystallizer in step 5 is 5 to 10 mL / h, based on 10 g of 6-APA.

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