A coupled crystallization process for preparing dicloxacillin sodium prime

Abstract

The application belongs to the technical field of medicine separation, and discloses a coupled crystallization method for preparing dichloris sodium superior product, wherein 6-amino penicillanic acid (6-APA) is used as a starting raw material, after acylation reaction and salt formation, finally, through evaporation-solvent-out coupled crystallization means, the dichloris sodium superior product with regular crystal morphology, large particle size (>200 μm), high crystallinity, high purity (up to 99.4%), process yield ≥80% and good stability can be obtained. The required equipment is simple, the processing scale is large, the operation is simple, and the industrial production is easy, so that the method has good technical economy and high industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical separation technology, specifically relating to a coupled crystallization method for preparing superior grade dicloxacillin sodium. Background Technology

[0002] Dicloxacillin sodium, chemical formula C 19 H 16 Cl2N3NaO5S·H2O, with a relative molecular mass of 510.32, has the chemical name (2S,5R,6R)-3,3-dimethyl-6-[5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolecarbamoylamino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, and its structure is shown below. Commercially available products are white or pale yellow crystalline powders, readily soluble in water, methanol, and ethanol, and exhibit resistance to acids and enzymes.

[0003]

[0004] Dicloxacillin sodium is a β-lactam antibiotic with antibacterial activity against Staphylococcus and Gram-positive bacteria. Dicloxacillin sodium is the pharmaceutical form of dicloxacillin; it is stable under dry conditions but its stability decreases in the presence of water. Currently, dicloxacillin sodium is only available in clinical practice in solid dosage forms such as tablets, capsules, and dry suspensions. Dicloxacillin sodium has broad applications against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus epidermidis, viridans streptococci, agalactiae streptococci, and Neisseria meningitidis.

[0005] Currently, the preparation of dicloxacillin sodium solid products mainly employs a crystallization process involving the reaction of dicloxacillin acid with its sodium salt. However, this process results in dicloxacillin sodium solid products with problems such as high solvent residue, small particle size, low purity, and unsatisfactory morphology, severely impacting product quality and bioavailability, and hindering storage and transportation. Furthermore, the synthetic route for dicloxacillin sodium is lengthy, using a large amount of organic solvents. Dicloxacillin sodium readily forms solvent compounds with these organic solvents, leading to significant organic solvent residue. This residue is also difficult to separate and purify during post-processing, resulting in poor crystallinity, purity, color, acidity, turbidity, and stability of the dicloxacillin sodium product.

[0006] Chinese patent CN103687862A discloses a method for preparing isoxazolidin sodium salt, which involves reaction crystallization. However, the resulting crystals are mostly irregular flakes, small in size, and of low purity. While Chinese patent CN108659007A discloses a method for preparing dicloxacillin sodium columnar crystals, it yields regular columnar crystals, but the aspect ratio is too large, resulting in small particle size. This leads to high solvent residue, long filtration times, difficulty in drying, long production cycles, and low production capacity. To date, no method for preparing superior-grade dicloxacillin sodium has been reported.

[0007] Therefore, there is an urgent need to develop a method for preparing superior grade dicloxacillin sodium crystals to obtain crystals with low solvent residue, regular morphology, large particle size, easy post-processing such as filtration, washing, and drying, and high purity. Summary of the Invention

[0008] To address the aforementioned problems, this invention discloses a coupled crystallization method for preparing superior grade dicloxacillin sodium. By utilizing evaporation-dissolution coupled crystallization technology, superior grade dicloxacillin sodium with high crystallinity, high purity, and good stability can be obtained. The method is simple to operate, low in cost, and easy to industrialize.

[0009] The technical solution adopted by this invention to solve the technical problem is:

[0010] A coupled crystallization method for preparing superior grade dicloxacillin sodium, comprising the following steps:

[0011] Step 1: Add 6-APA (6-aminopenicillanic acid) and a certain proportion of solvent I and water 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.

[0012] Solution B is prepared by dissolving 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide in solvent II;

[0013] Solution B is added to the crystallizer at a certain flow rate and reacted with solution A for 0.5 to 2 hours. At the same time, the pH of the system is adjusted to a certain level to prepare dicloxacillin.

[0014] 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, and the phases are separated by standing. The upper organic phase is taken into the crystallizer for later use, which is a dicloxacillin solution.

[0015] Step 3: Control the temperature inside the crystallizer and add the salt-forming agent solution prepared with solvent IV into the crystallizer at a certain flow rate, so that it reacts with the dicloxacillin solution obtained in step 2 to obtain dicloxacillin sodium solution.

[0016] Step 4: Control the temperature inside the crystallizer to 5-40℃, the stirring speed to 100-500 rpm, add the solvent dropwise to the dicloxacillin sodium solution at a flow rate of 0.1-1.5 mL / min, the crystal growth time to 0.5-1 h, the vacuum degree to -0.01--0.09 MPa, the solvent evaporation rate to 10-30 mL / h, and the evaporation time to 2-8 h, and carry out evaporation-solution coupled crystallization to obtain the superior grade dicloxacillin sodium crystal slurry;

[0017] Step 5: Separate the crystal slurry obtained in Step 4 into solid and liquid phases, and dry it to obtain superior grade dicloxacillin sodium crystals.

[0018] Preferably, solvent I is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, and glycerol; solvent II is one or more of isopropanol, ethanol, methanol, acetone, isopropyl acetate, and ethyl acetate; solvent III is one or more of methyl formate, ethyl formate, methyl acetate, ethyl acetate, and isopropyl acetate; and solvent IV is one or more of methanol, ethanol, isopropanol, acetone, isopropyl acetate, and ethyl acetate.

[0019] Preferably, the temperature inside the crystallizer in step 1 is -5 to 15°C.

[0020] Preferably, the pH value in steps 1 and 2 is controlled within the range of 2.0 to 9.0. An inorganic base or inorganic acid is used to adjust the pH value of the solution; the inorganic base is one or more of sodium hydroxide, sodium carbonate, and sodium bicarbonate, and the inorganic acid is dilute sulfuric acid or hydrochloric acid.

[0021] Preferably, in step 1, the mass ratio of 6-APA (6-aminopenicillanic acid) to 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide is 0.5:1 to 1:1.3, the mass ratio of 6-aminopenicillanic acid, solvent I, and water is 1:5:5 to 1:3:3, and the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide to solvent II is 1:4 to 1:2.

[0022] Preferably, the flow rate of solution B in step 1 is 2 to 20 mL / min.

[0023] Preferably, the salt-forming agent in step 3 is one of sodium bicarbonate, sodium ethoxide, sodium isooctanoate, and sodium hydroxide, and the molar ratio of the salt-forming agent to 6-APA (6-aminopenicillanic acid) is 1:1 to 1.5:1.

[0024] Preferably, in step 3, the mass ratio of solvent IV to salt-forming agent is 1:1 to 2:1.

[0025] Preferably, the flow rate of the salt-forming agent solution in step 3 is 3 to 20 mL / min.

[0026] Preferably, the salt formation reaction time in step 3 is 0.5 to 1 hour.

[0027] Preferably, the temperature inside the crystallizer during the salt formation reaction in step 3 is controlled at 5–40°C.

[0028] Preferably, the stirring rate in step 3 is 100-500 rpm.

[0029] Preferably, the solvent used in the solvent-evaporation coupled crystallization process in step 4 is one or more of acetone, methyl acetate, isopropyl acetate, ethyl acetate, and isopropanol.

[0030] Preferably, the mass ratio of the solvent to the salt-forming agent used in the dissolution-evaporation coupled crystallization process in step 4 is 8:1 to 10:1.

[0031] Preferably, the drying temperature in step 5 is 45–80°C.

[0032] Preferably, the drying time in step 5 is 4 to 10 hours.

[0033] The advantages and beneficial effects of this invention are:

[0034] (1) The dicloxacillin sodium hydrate crystal provided by the present invention is simple to operate, has a stable process, consumes little energy, is economical, and the product has good chemical stability, making it suitable for the manufacture and long-term storage of pharmaceutical preparations.

[0035] (2) The present invention controls crystal growth by coupling the crystallization process, resulting in a product with uniform particle size, complete plate-like crystal structure, and rapid filtration.

[0036] (3) The crystal products prepared by this invention have a large particle size, >200μm;

[0037] (4) The method of the present invention has good process controllability, short production cycle, small batch difference, and single-pass molar yield of over 80%.

[0038] (5) The solvent selected in this invention is green and environmentally friendly, and the resulting product has low solvent residue, total impurities as low as 0.3%, sodium dicloxacillin purity of over 99%, and excellent stability.

[0039] (6) The product prepared by the present invention is clear after dissolution, with a pH of 5.5 to 6.5, which meets the requirements of the Chinese Pharmacopoeia. Attached Figure Description

[0040] Figure 1a This is a microscope image of the superior grade dicloxacillin sodium prepared in Example 1 of the present invention.

[0041] Figure 1b This is a microscopic image of the superior grade dicloxacillin sodium prepared in Comparative Example 1 of this invention.

[0042] Figure 2 The XRD patterns are of the superior grade dicloxacillin sodium prepared in Examples 1-6 of this invention.

[0043] Figure 3 The Raman chromatograms are of the superior grade dicloxacillin sodium prepared in Examples 1-6 of this invention. Detailed Implementation

[0044] 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.

[0045] Example 1

[0046] A coupled crystallization method for preparing superior grade dicloxacillin sodium, comprising the following steps:

[0047] Step 1: Add 6-APA to the methanol-water crystallizer and control the temperature inside the crystallizer to -5℃. Add sodium hydroxide solution dropwise to the system to adjust the pH to 9.0. Stir to dissolve the solution and prepare solution A. The mass ratio of 6-APA, methanol and water is 1:3:3.

[0048] Solution B is prepared by dissolving 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide (in a mass ratio of 1:1 to the 6-APA used) in isopropanol; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide to isopropanol is 1:4.

[0049] Solution B was added to the crystallizer at a flow rate of 2 mL / min and reacted with solution A for 1 h. Simultaneously, the pH of the system was adjusted to 7.0 with sodium hydroxide solution to prepare dicloxacillin. The mass ratio of solution A to solution B was 3:1.

[0050] Step 2: After the reaction is complete, add methyl formate to the crystallizer for extraction, adjust the pH of the system to 2.0 with dilute hydrochloric acid, let it stand for phase separation, and take the upper organic phase into the crystallizer for later use, which is dicloxacillin solution;

[0051] Step 3: Control the temperature inside the crystallizer to 40℃, the stirring speed to 100rpm, and add a salt-forming agent solution prepared with sodium ethoxide (the molar ratio of sodium ethoxide to 6-APA is 1.5:1) and methanol (the mass ratio of methanol to sodium ethoxide is 2:1) to the crystallizer at a flow rate of 3mL / min. After reacting with the dicloxacillin solution obtained in Step 2 for 1h, a dicloxacillin sodium solution is obtained.

[0052] Step 4: Control the temperature inside the crystallizer to 40℃, the stirring speed to 100rpm, and add acetone dropwise to the dicloxacillin sodium solution obtained in Step 3 at a flow rate of 1.5mL / min (the mass ratio of acetone to sodium ethoxide is 8:1). After crystallization, allow the crystals to grow for 1h, and then carry out evaporation-dissolution coupled crystallization for 8h under the same stirring rate and temperature and a vacuum of -0.01MPa, with an evaporation rate of 10mL / h, to obtain the superior grade dicloxacillin sodium crystal slurry.

[0053] Step 5: Separate the crystal slurry obtained in Step 4 into solid and liquid phases, dry it at 45°C for 10 hours, and obtain superior grade dicloxacillin sodium crystals after drying.

[0054] The final product appears as flaky white crystals, as shown in the microscope image. Figure 1a As shown, the X-ray powder diffraction pattern is as follows: Figure 2 As shown. Raman graph as follows. Figure 3 As shown. The molar yield was 80.8%, the purity was 99.4%, the aqueous solution was colorless, clear and transparent, the acidity was 6.0, and the product particle size was approximately 220 μm.

[0055] Example 2

[0056] A coupled crystallization method for preparing superior grade dicloxacillin sodium, comprising the following steps:

[0057] Step 1: Add 6-APA to the acetone-water crystallizer and control the temperature inside the crystallizer to 5°C. Add dilute sulfuric acid dropwise to the system to adjust the pH to 4.5. Stir to dissolve the solution and prepare solution A. The mass ratio of 6-APA, acetone and water is 1:4:4.

[0058] Solution B is prepared by dissolving 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide (in a mass ratio of 1.2:1 to the 6-APA used) in acetone; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide to acetone is 1:3.

[0059] Solution B was added to the crystallizer at a flow rate of 10 mL / min and reacted with solution A for 0.5 h. Simultaneously, the pH of the system was adjusted to 7 with sodium hydroxide solution to prepare dicloxacillin. The mass ratio of solution A to solution B was 3.5:1.

[0060] Step 2: After the reaction is complete, add isopropyl acetate to the crystallizer for extraction, adjust the pH of the system to 3.0 with dilute sulfuric acid, let it stand for phase separation, and take the upper organic phase into the crystallizer for later use, which is dicloxacillin solution;

[0061] Step 3: Control the temperature inside the crystallizer to 25℃, the stirring speed to 300rpm, and add a salt-forming agent solution prepared by sodium hydroxide (molar ratio of 6-APA to sodium hydroxide to 1.3:1) and isopropanol (mass ratio of sodium hydroxide to sodium hydroxide to 1:1) to the crystallizer at a flow rate of 7mL / min. After reacting with the dicloxacillin solution obtained in Step 2 for 0.5h, a dicloxacillin sodium solution is obtained.

[0062] Step 4: Control the temperature inside the crystallizer to 25℃, the stirring speed to 300rpm, and add isopropanol dropwise to the dicloxacillin sodium solution obtained in Step 3 at a flow rate of 0.8mL / min (the mass ratio of isopropanol to sodium hydroxide is 8:1). After crystallization, allow the crystals to grow for 0.5h, and then carry out evaporation-dissolution coupled crystallization for 5h under the same stirring rate and temperature and a vacuum of -0.05MPa, with an evaporation rate of 20mL / h, to obtain the superior grade dicloxacillin sodium crystal slurry.

[0063] Step 5: Separate the crystal slurry obtained in Step 4 into solid and liquid phases, dry it at 80℃ for 6 hours, and after drying, obtain superior grade dicloxacillin sodium crystals.

[0064] The final product appears as flaky white crystals, as shown in the microscope image. Figure 1b As shown, the X-ray powder diffraction pattern is as follows: Figure 2 As shown. Raman graph as follows. Figure 3 As shown. The molar yield was 80%, the purity was 99.2%, the aqueous solution was colorless, clear and transparent, the acidity was 6.2, and the product particle size was approximately 237 μm.

[0065] Example 3

[0066] A coupled crystallization method for preparing superior grade dicloxacillin sodium, comprising the following steps:

[0067] Step 1: Add 6-APA to the crystallizer of glycerol-water solution and control the temperature inside the crystallizer to 15℃. Add sodium bicarbonate solution dropwise to the system to adjust the pH of the system to 6.0, and stir to dissolve it to prepare solution A; the mass ratio of 6-APA, glycerol and water is 1:5:5.

[0068] Solution B was prepared by dissolving 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide (in a mass ratio of 1.3:1 to the 6-APA used) in ethyl acetate; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide to ethyl acetate was 1:2.

[0069] Solution B was added to the crystallizer at a flow rate of 20 mL / min and reacted with solution A for 1.5 h. At the same time, the pH of the system was adjusted to 7 with sodium bicarbonate solution to prepare dicloxacillin. The mass ratio of solution A to solution B was 4:1.

[0070] Step 2: After the reaction is complete, ethyl acetate is added to the crystallizer for extraction. The pH of the system is adjusted to 4.0 using dilute hydrochloric acid. The system is allowed to stand and separate into phases. The upper organic phase is collected in the crystallizer for later use and is a dicloxacillin solution.

[0071] Step 3: Control the temperature inside the crystallizer to 5℃, the stirring speed to 500rpm, and add a solution of sodium isooctanoate (molar ratio of 6-APA to sodium isooctanoate to ethyl acetate (mass ratio of sodium isooctanoate to sodium isooctanoate to 2:1) to the crystallizer at a flow rate of 20mL / min. After the solution reacts with the dicloxacillin solution obtained in Step 2 to form a salt for 0.5h, a dicloxacillin sodium solution is obtained.

[0072] Step 4: Control the temperature inside the crystallizer to 5℃, the stirring speed to 500rpm, and add methyl acetate dropwise to the dicloxacillin sodium solution obtained in Step 3 at a flow rate of 0.1mL / min (the mass ratio of methyl acetate to sodium isooctanoate is 8:1). After crystallization, allow the crystals to grow for 0.75h, and then carry out evaporation-dissolution coupled crystallization for 2h under the same stirring rate and temperature and a vacuum of -0.09MPa, with an evaporation rate of 10ml / h, to obtain the superior grade dicloxacillin sodium crystal slurry.

[0073] Step 5: Separate the crystal slurry obtained in Step 4 into solid and liquid phases, dry it at 60°C for 4 hours, and obtain superior grade dicloxacillin sodium crystals after drying.

[0074] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2 As shown. Raman graph as follows. Figure 3 As shown. The molar yield was 81.3%, the purity was 99.1%, the aqueous solution was colorless, clear and transparent, the acidity was 6.5, and the product particle size was approximately 230 μm.

[0075] Example 4

[0076] A coupled crystallization method for preparing superior grade dicloxacillin sodium, comprising the following steps:

[0077] Step 1: Add 6-APA to the isopropanol-water crystallizer and control the temperature inside the crystallizer to 0℃. Add sodium carbonate water dropwise to the system to adjust the pH to 7.0, and stir to dissolve it to prepare solution A; the mass ratio of 6-APA, isopropanol and water is 1:3:3.

[0078] Solution B is prepared by dissolving 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide (in a mass ratio of 1:0.5 to the 6-APA used) in isopropanol; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide to isopropanol is 1:4.

[0079] Solution B was added to the crystallizer at a flow rate of 2 mL / min and reacted with solution A for 2 h. Simultaneously, the pH of the system was adjusted to 7 with sodium carbonate solution to prepare dicloxacillin. The mass ratio of solution A to solution B was 3:1.

[0080] Step 2: After the reaction is complete, add methyl formate to the crystallizer for extraction, adjust the pH of the system to 4.0 with dilute sulfuric acid, let it stand for phase separation, and take the upper organic phase into the crystallizer for later use, which is dicloxacillin solution;

[0081] Step 3: Control the temperature inside the crystallizer to 40℃, the stirring speed to 100rpm, and add a solution of sodium ethoxide (molar ratio of sodium ethoxide to 6-APA is 1.5:1) and ethanol (mass ratio of sodium ethoxide to sodium ethoxide is 1.5:1) to the crystallizer at a flow rate of 10mL / min. After the solution reacts with the dicloxacillin solution obtained in Step 2 to form a salt for 0.5h, a dicloxacillin sodium solution is obtained.

[0082] Step 4: Control the temperature inside the crystallizer to 40℃, the stirring speed to 500rpm, and add ethyl acetate (the mass ratio of ethyl acetate to sodium ethoxide is 10:1) dropwise to the dicloxacillin sodium solution obtained in Step 3 at a flow rate of 1.5mL / min. After crystallization, allow the crystals to grow for 1h, and then carry out evaporation-dissolution coupled crystallization for 8h at the same stirring speed and temperature and a vacuum degree of -0.01MPa, with an evaporation rate of 10mL / h, to obtain the superior grade dicloxacillin sodium crystal slurry.

[0083] Step 5: Separate the crystal slurry obtained in Step 4 into solid and liquid phases, dry it at 45°C for 10 hours, and obtain superior grade dicloxacillin sodium crystals after drying.

[0084] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2 As shown. Raman graph as follows. Figure 3 As shown. The molar yield was 80.1%, the purity was 99.2%, the aqueous solution was colorless, clear and transparent, the acidity was 5.5, and the product particle size was approximately 215 μm.

[0085] Example 5

[0086] A coupled crystallization method for preparing superior grade dicloxacillin sodium, comprising the following steps:

[0087] Step 1: Add 6-APA to the methanol-water crystallizer and control the temperature inside the crystallizer to 5℃. Add sodium bicarbonate solution dropwise to the system to adjust the pH to 5.0. Stir to dissolve the solution and prepare solution A. The mass ratio of 6-APA, methanol and water is 1:4:4.

[0088] Solution B was prepared by dissolving 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide (in a mass ratio of 1.25:1 to the 6-APA used) in ethyl acetate; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide to ethyl acetate was 1:3.

[0089] Solution B was added to the crystallizer at a flow rate of 10 mL / min and reacted with solution A for 0.5 h. Simultaneously, the pH of the system was adjusted to 7 with sodium bicarbonate solution to prepare dicloxacillin. The mass ratio of solution A to solution B was 3.5:1.

[0090] Step 2: After the reaction is complete, add isopropyl acetate to the crystallizer for extraction, adjust the pH of the system to 9.0 with dilute hydrochloric acid, let it stand for phase separation, and take the upper organic phase into the crystallizer for later use, which is dicloxacillin solution;

[0091] Step 3: Control the temperature inside the crystallizer to 5℃, the stirring speed to 300rpm, and add a salt-forming agent solution prepared with sodium ethoxide (molar ratio of 6-APA to sodium ethoxide is 1.3:1) and ethyl acetate (mass ratio of sodium ethoxide to sodium ethoxide is 2:1) to the crystallizer at a flow rate of 15mL / min. After the salt-forming reaction with the dicloxacillin solution obtained in Step 2 is carried out for 0.5h, a dicloxacillin sodium solution is obtained.

[0092] Step 4: Control the temperature inside the crystallizer to 25℃, the stirring speed to 500rpm, and add ethyl acetate (the mass ratio of ethyl acetate to sodium ethoxide is 10:1) dropwise to the dicloxacillin sodium solution obtained in Step 3 at a flow rate of 0.8mL / min. After crystallization, allow the crystals to grow for 0.5h, and then carry out evaporation-dissolution coupled crystallization for 5h under the same stirring rate and temperature and a vacuum of -0.05MPa. The evaporation rate is 20ml / h, to obtain the superior grade dicloxacillin sodium crystal slurry.

[0093] Step 5: Separate the crystal slurry obtained in Step 4 into solid and liquid phases, and dry it at 80°C for 6 hours. After drying, dicloxacillin sodium premium grade crystals are obtained.

[0094] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2 As shown. Raman graph as follows. Figure 3 As shown. The molar yield was 80.6%, the purity was 99.3%, the aqueous solution was colorless, clear and transparent, the acidity was 6.3, and the product particle size was approximately 210 μm.

[0095] Example 6

[0096] A coupled crystallization method for preparing superior grade dicloxacillin sodium, comprising the following steps:

[0097] Step 1: Add 6-APA to the acetone-water crystallizer and control the temperature inside the crystallizer to 15℃. Add dilute hydrochloric acid dropwise to the system to adjust the pH to 2.0, and stir to dissolve it to prepare solution A; the mass ratio of 6-APA, acetone and water is 1:5:5.

[0098] Solution B was prepared by dissolving 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide (in a mass ratio of 1.3:1 to the 6-APA used) in ethyl acetate; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide to ethyl acetate was 1:2.

[0099] Solution B was added to the crystallizer at a flow rate of 20 ml / min and reacted with solution A for 2 h. At the same time, the pH of the system was adjusted to 7 with sodium bicarbonate solution to prepare dicloxacillin. The mass ratio of solution A to solution B was 4:1.

[0100] Step 2: After the reaction is complete, ethyl acetate is added to the crystallizer for extraction. Sodium carbonate is used to adjust the pH of the system to 7.5. The system is allowed to stand and separate into phases. The upper organic phase is collected in the crystallizer for later use and is a dicloxacillin solution.

[0101] Step 3: Control the temperature inside the crystallizer to 40℃, the stirring speed to 500rpm, and add a solution of sodium bicarbonate (molar ratio of sodium bicarbonate to 6-APA is 1:1) and acetone (mass ratio of acetone to sodium bicarbonate is 1.2:1) to the crystallizer at a flow rate of 5mL / min. After the solution of dicloxacillin obtained in step 2 undergoes a salt formation reaction for 0.5h, a sodium dicloxacillin solution is obtained.

[0102] Step 4: Control the temperature inside the crystallizer to 40℃, the stirring speed to 500rpm, and add isopropyl acetate (the mass ratio of isopropyl acetate to sodium bicarbonate is 10:1) dropwise to the dicloxacillin sodium solution obtained in Step 3 at a flow rate of 0.1mL / min. After crystallization, allow the crystals to grow for 0.75h, and then carry out evaporation-dissolution coupled crystallization for 2h at the same stirring speed and temperature and a vacuum degree of -0.09MPa, with an evaporation rate of 30ml / h, to obtain the superior grade dicloxacillin sodium crystal slurry.

[0103] Step 5: Separate the crystal slurry obtained in Step 4 into solid and liquid phases, and dry it at 60°C for 4 hours. After drying, dicloxacillin sodium premium grade crystals are obtained.

[0104] The final product is a plate-like white crystal, and its X-ray powder diffraction pattern is as follows. Figure 2 As shown. Raman graph as follows. Figure 3 As shown. The molar yield was 80.0%, the purity was 99.1%, the aqueous solution was colorless, clear and transparent, the acidity was 6.0, and the product particle size was approximately 208 μm.

[0105] Comparative Example 1

[0106] The difference from Example 1 is that the dissolution process in step 4 is omitted.

[0107] The final product is a white powder with a molar yield of 54.2% and a purity of 96.2%. The aqueous solution is colorless, clear, and transparent with an acidity of 5.61, and the product particle size is approximately 75 μm.

[0108] Comparative Example 2

[0109] The difference from Example 1 lies in the synthesis method of dicloxacillin sodium. This example uses a butyl acetate solvent system, while the evaporation-dissolution coupled crystallization steps are the same as in Example 1. The specific steps are as follows:

[0110] Step 1: Add 6-APA to the crystallizer of butyl acetate-water solution and control the temperature inside the crystallizer to -5℃. Add sodium hydroxide solution dropwise to the system to adjust the pH of the system to 9.0. Stir to dissolve the solution and prepare solution A. The mass ratio of 6-APA, butyl acetate and water is 1:3:3.

[0111] Solution B was prepared by dissolving 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide (in a mass ratio of 1:1 to the 6-APA used) in butyl acetate; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide to butyl acetate was 1:2.

[0112] Solution B was added to the crystallizer at a flow rate of 2 mL / min and reacted with solution A for 1 h. Simultaneously, the pH of the system was adjusted to 7.0 with sodium hydroxide solution to prepare dicloxacillin. The mass ratio of solution A to solution B was 3:1.

[0113] Step 2: After the reaction is complete, butyl acetate is added to the crystallizer for extraction. The pH of the system is adjusted to 2.0 using dilute hydrochloric acid. The system is allowed to stand and separate into phases. The upper organic phase is collected in the crystallizer for later use and is a dicloxacillin solution.

[0114] Step 3: Control the temperature inside the crystallizer to 40℃, the stirring speed to 100rpm, and add a solution of sodium isooctanoate (molar ratio of 6-APA to 6-APA is 1.5:1) and methanol (molar ratio of sodium isooctanoate to 6-APA is 2:1) to the crystallizer at a flow rate of 3mL / min. Let it react with the dicloxacillin solution obtained in Step 2 to form a salt for 1h to obtain a dicloxacillin sodium solution.

[0115] Step 4: Control the temperature inside the crystallizer to 40℃, the stirring speed to 100rpm, and add acetone dropwise to the dicloxacillin sodium solution obtained in Step 3 at a flow rate of 1.5mL / min (the mass ratio of acetone to sodium ethoxide is 8:1). After crystallization, allow the crystals to grow for 1h, and then carry out evaporation-dissolution coupled crystallization for 8h under the same stirring rate and temperature and a vacuum of -0.01MPa, with an evaporation rate of 10mL / h, to obtain the superior grade dicloxacillin sodium crystal slurry.

[0116] Step 5: Separate the crystal slurry obtained in Step 4 into solid and liquid phases, and dry it at 45°C for 10 hours. After drying, dicloxacillin sodium premium grade crystals are obtained.

[0117] The final product is a yellow powder with a molar yield of 77.6% and a purity of 95.1%. The aqueous solution is pale yellow, clear, and transparent with an acidity of 5.65. The product particle size is approximately 20 μm, and it exhibits severe agglomeration.

[0118] Chemical property testing

[0119] 1) The chemical stability of the superior grade dicloxacillin sodium prepared in Examples 1-6 and Comparative Examples 1-2 of this invention was investigated. During storage at 25℃±5℃ and RH40±5% for 30 days, the color, purity, and morphology of the superior grade dicloxacillin sodium prepared in Examples 1-6 did not change, indicating that the crystal has good chemical stability. The results are shown in Table 1.

[0120] Table 1. Chemical stability study of dicloxacillin sodium hydrate crystals according to the present invention.

[0121]

[0122]

[0123] 2) The chemical stability of the dicloxacillin sodium hydrates prepared in Examples 1-6 and Comparative Examples 1-2 was investigated, including their turbidity and other properties. During storage at 25℃±5℃ and RH40±5% for 30 days, the turbidity of the products in Examples 1-6 remained essentially unchanged, indicating good chemical stability of the crystal. The results are shown in Table 2.

[0124] Table 2. Chemical stability study of dicloxacillin sodium hydrate crystals according to the present invention.

[0125]

[0126] The method for preparing superior grade dicloxacillin sodium disclosed and proposed in this invention can be implemented by those skilled in the art by appropriately modifying the raw materials, process parameters, and other aspects, based on the content of this document. The method and product of this invention have been described through preferred embodiments. Those skilled in the art can obviously modify or appropriately change and combine the methods and products described herein without departing from the content, spirit, and scope of this invention to achieve the technical requirements of this invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the spirit, scope, and content of this invention.

Claims

1. A coupled crystallization method for preparing superior grade dicloxacillin sodium, characterized in that, The steps are as follows: Step 1: Add 6-aminopenicillanic acid, solvent I, and water 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; Solution B is prepared by dissolving 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide in solvent II; Solution B is added to the crystallizer at a certain flow rate and reacted with solution A for 0.5 to 2 hours. At the same time, the pH of the system is adjusted to a certain level to prepare dicloxacillin. 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, and the phases are separated by standing. The upper organic phase is taken into the crystallizer for later use, which is a dicloxacillin solution. Step 3: Control the temperature inside the crystallizer and add the salt-forming agent solution prepared with solvent IV into the crystallizer at a certain flow rate, so that it reacts with the dicloxacillin solution obtained in step 2 to obtain dicloxacillin sodium solution. Step 4: Control the temperature inside the crystallizer to 5~40 ℃, the stirring speed to 100~500 rpm, add the solvent dropwise to the dicloxacillin sodium solution at a flow rate of 0.1~1.5 mL / min, the crystal growth time to 0.5~1 h, the vacuum degree to -0.01~-0.09 MPa, the solvent evaporation rate to 10~30 mL / h, and the evaporation time to 2~8 h, and carry out evaporation-solution coupled crystallization to obtain the superior grade dicloxacillin sodium crystal slurry; Step 5: The crystal slurry obtained in Step 4 is subjected to solid-liquid separation and dried to obtain superior grade dicloxacillin sodium crystals. The product has uniform particle size, the crystals are in the form of complete flakes, it can be filtered quickly, the particle size is >200μm, and the purity of dicloxacillin sodium is over 99%. Wherein, solvent I is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, and glycerol; solvent II is one or more of isopropanol, ethanol, methanol, acetone, isopropyl acetate, and ethyl acetate; solvent III is one or more of methyl formate, ethyl formate, methyl acetate, ethyl acetate, and isopropyl acetate; solvent IV is one or more of methanol, ethanol, isopropanol, acetone, isopropyl acetate, and ethyl acetate; the salt-forming agent is one or more of sodium bicarbonate, sodium ethoxide, sodium isooctanoate, and sodium hydroxide; and the solvent used in the dissolution-evaporation coupled crystallization process in step 4 is one or more of acetone, methyl acetate, isopropyl acetate, ethyl acetate, and isopropanol.

2. The coupled crystallization method according to claim 1, wherein the temperature inside the crystallizer in step 1 is -5 ~ 15 ℃.

3. The coupled crystallization method according to claim 1, wherein in step 1, the mass ratio of 6-aminopenicillanic acid to 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide is 0.5:1 to 1:1.3, the mass ratio of 6-aminopenicillanic acid, solvent I, and water is 1:5:5 to 1:3:3, and the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazoleformamide to solvent II is 1:4 to 1:

2.

4. In the coupled crystallization method according to claim 1, the flow rate of solution B in step 1 is 2 to 20 mL / min.

5. The coupled crystallization method according to claim 1, wherein the pH value in steps 1 and 2 is 2.0 to 9.0, and the pH value of the solution is adjusted using an inorganic base or an inorganic acid, wherein the inorganic base is one or more of sodium hydroxide, sodium carbonate, and sodium bicarbonate, and the inorganic acid is dilute sulfuric acid or hydrochloric acid.

6. The coupled crystallization method according to claim 1, wherein the molar ratio of the salt-forming agent to 6-aminopenicillanic acid in step 3 is 1:1 to 1.5:1; and the mass ratio of solvent IV to the salt-forming agent is 1:1 to 2:

1.

7. The coupled crystallization method according to claim 1, wherein in step 3, the temperature inside the crystallizer during the salt formation reaction is 5~40 ℃, the flow rate of the salt-forming agent solution is 3~20 mL / min, the salt formation reaction time is 0.5~1 h, and the stirring rate is controlled at 100~500 rpm.

8. In the coupled crystallization method according to claim 1, the drying temperature in step 5 is 45~80 ℃ and the drying time is 4~10 h.

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