Coupling crystallization method for preparing dicloxacillin sodium superior product

Abstract

The invention belongs to the technical field of medicine separation, and discloses a coupling crystallization method for preparing a dicloxacillin sodium premium-grade product, which comprises the following steps: taking 6-aminopenicillanic acid (6-APA) as an initial raw material, carrying out acylation reaction and salt forming reaction, and finally carrying out evaporation-elution coupling crystallization to obtain the dicloxacillin sodium premium-grade product. The dicloxacillin sodium premium-grade product with regular crystal morphology, large particle size (greater than 200 [mu] m), high crystallinity, high purity (up to 99.4%), process yield greater than or equal to 80% and good stability can be obtained. The method is simple in required equipment, large in treatment scale, simple and convenient to operate and easy for industrial production, and has better technical economy and higher industrial application value.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical separation, and particularly relates to a coupled crystallization method for preparing a superior grade of dicloxacillin sodium. Background Art

[0002] Dicloxacillin sodium, chemical formula is C 19 H 16 Cl2N3NaO5S·H2O, relative molecular mass 510.32, chemical name (2S,5R,6R)-3,3-dimethyl-6-[5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate sodium, its structure is shown below. The commercial product is a white or light yellow crystalline powder, easily soluble in water, methanol, ethanol, and has the characteristics of acid resistance and enzyme resistance.

[0003]

[0004] Dicloxacillin sodium is a β-lactam antibiotic with antibacterial activity against staphylococci and gram-positive bacteria. Dicloxacillin sodium is a drug form of dicloxacillin, which is stable under dry conditions and has reduced stability when water is present. Currently, only solid preparations such as tablets, capsules, and dry suspensions of dicloxacillin sodium are used in clinical practice. Dicloxacillin sodium has a wide range of applications in the antibacterial treatment of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus epidermidis, Streptococcus viridans, Streptococcus agalactiae, and Neisseria meningitidis.

[0005] At present, the preparation of dicloxacillin sodium solid products mainly adopts the reaction crystallization process of dicloxacillin acid and sodium salt. The obtained dicloxacillin sodium solid products have problems such as large solvent residue, small particle size, low purity, and unsatisfactory morphology, which seriously affect its product quality and bioavailability, and are not conducive to the storage and transportation of the product. At the same time, due to the long synthesis process of dicloxacillin sodium, more organic solvents are used, and dicloxacillin sodium easily forms solvent compounds with organic solvents, resulting in more organic solvent residues, and it is not easy to separate and purify during post-processing, resulting in poor crystallinity, purity, color, acidity, turbidity and stability of dicloxacillin sodium products.

[0006] Chinese patent CN103687862A discloses a method for preparing isoxazolyl penicillin sodium salt, and the crystals prepared by reaction crystallization are mostly irregular flakes, small in particle size, and low in purity; although the preparation method of dicloxacillin sodium columnar crystals disclosed in Chinese patent CN108659007A obtains regular columnar crystals, the aspect ratio of the crystals is too large and the particle size is small, which also leads to a large residual solvent content of dicloxacillin sodium crystals, a long filtration time, and difficulty in drying, a long product production cycle, and low production capacity. So far, there is no report on the preparation method of dicloxacillin sodium superior product.

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

[0008] In view of the above problems, the present invention discloses a coupled crystallization method for preparing a superior grade of dicloxacillin sodium. The superior grade of dicloxacillin sodium with high crystallinity, high purity and good stability can be obtained by utilizing the evaporation-solution coupled crystallization technology. The method has the advantages of simple operation, low cost and easy industrial production.

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

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

[0011] Step 1: Add 6-APA (6-aminopenicillanic acid) and a certain proportion of solvent I and water into a crystallizer, control the temperature in the crystallizer, adjust the pH of the system to a certain pH value, and stir to dissolve it to form solution A;

[0012] 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide is dissolved in solvent II to prepare solution B;

[0013] Solution B is added to the crystallizer at a certain flow rate to react with solution A for 0.5 to 2 hours, and the pH of the system is adjusted to a certain pH to prepare dicloxacillin acid;

[0014] Step 2: After the reaction is completed, solvent III is added to the crystallizer for extraction, the system is adjusted to a certain pH value, the phases are allowed to stand for separation, and the upper organic phase is taken from the crystallizer for standby use to obtain a dicloxacillin acid solution;

[0015] Step 3: controlling the temperature in the crystallizer, and adding a salt-forming agent solution prepared by a salt-forming agent and solvent IV into the crystallizer at a certain flow rate, so that the salt-forming agent reacts with the dicloxacillin acid solution obtained in step 2 to obtain a dicloxacillin sodium solution;

[0016] Step 4: Control the temperature in the crystallizer to 5-40° C., the stirring rate to 100-500 rpm, the solvent is added dropwise to the dicloxacillin sodium solution at a flow rate of 0.1-1.5 mL / min, the crystal growing time is 0.5-1 h, the vacuum degree is -0.01-0.09 MPa, the solvent evaporation rate is controlled to 10-30 mL / h, the evaporation time is controlled to 2-8 h, and evaporation-solution coupled crystallization is performed to obtain a superior grade dicloxacillin sodium crystal slurry;

[0017] Step 5: The slurry obtained in step 4 is subjected to solid-liquid separation and dried to obtain high-quality crystals of dicloxacillin sodium.

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

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

[0020] Preferably, the pH value in step 1 and step 2 is controlled in the range of 2.0 to 9.0. An inorganic base or an inorganic acid is used to adjust the pH value of the solution, 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.

[0021] Preferably, the mass ratio of 6-APA (6-aminopenicillanic acid) to 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide used in step 1 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-methylisoxazolecarboxamide 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, in step 3, the salt-forming agent 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 3-20 mL / min.

[0026] Preferably, the salt-forming reaction time in step 3 is 0.5 to 1 h.

[0027] Preferably, the temperature in the crystallizer during the salt-forming 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 elution-evaporation coupled crystallization process in step 4 is one or more of acetone, methyl acetate, isopropyl acetate, ethyl acetate and isopropanol.

[0030] Preferably, in the dissolution-evaporation coupled crystallization process in step 4, the mass ratio of the dissolution agent to the salt-forming agent 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 the present invention are:

[0034] (1) The dicloxacillin sodium hydrate crystals provided by the present invention are simple to operate, stable in process, low in energy consumption, high in economy, and the product has good chemical stability, and is suitable for the manufacture and long-term storage of pharmaceutical preparations;

[0035] (2) The present invention controls crystal growth by coupling the crystallization process, and the resulting product has uniform particle size, complete flakes, and fast filtration;

[0036] (3) The crystal product prepared by the present invention has a relatively large particle size, which is greater than 200 μm;

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

[0038] (5) The solvent selected by the present invention is green and environmentally friendly, the obtained product has low solvent residue, total impurities as low as 0.3%, the purity of dicloxacillin sodium is more than 99%, and the stability is excellent;

[0039] (6) The product prepared by the present invention is clear after dissolution, and the pH value is 5.5 to 6.5, which meets the requirements of the Chinese Pharmacopoeia. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

[0042] Figure 2 This is the XRD diagram of the superior grade of dicloxacillin sodium prepared in Examples 1 to 6 of the present invention.

[0043] Figure 3 This is the Raman spectrum of the superior dicloxacillin sodium prepared in Examples 1 to 6 of the present invention. DETAILED DESCRIPTION

[0044] The present invention is described more clearly and completely through the following examples, but the examples described are only part of the embodiments of the present invention, not all of them. The embodiments are to help understand the present invention and should not be used to limit the scope of protection of the present invention.

[0045] Example 1

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

[0047] Step 1: Add 6-APA to a crystallizer of a methanol-water solution, and control the temperature in the crystallizer to -5°C, drop sodium hydroxide aqueous solution into the system to adjust the pH of the system to 9.0, and stir to dissolve it to prepare solution A; the mass ratio of 6-APA, methanol, and water is 1:3:3;

[0048] 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide (with a mass ratio of 1:1 to 6-APA used) was dissolved in isopropanol to prepare solution B; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide to isopropanol was 1:4;

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

[0050] Step 2: After the reaction is completed, methyl formate is added to the crystallizer for extraction, and the pH of the system is adjusted to 2.0 with dilute hydrochloric acid. The phases are allowed to stand for phase separation, and the upper organic phase is taken from the crystallizer for standby use to obtain a dicloxacillin acid solution;

[0051] Step 3: Control the temperature in the crystallizer to 40° C., the stirring speed to 100 rpm, and add a salt-forming agent solution prepared by sodium ethoxide (the molar ratio of sodium ethoxide to 6-APA is 1.5:1) and methanol (the mass ratio of the amount to the amount of sodium ethoxide is 2:1) to the crystallizer at a flow rate of 3 mL / min, and react the solution with the dicloxacillin acid solution obtained in step 2 for 1 hour to obtain a dicloxacillin sodium solution;

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

[0053] Step 5: The slurry obtained in step 4 is subjected to solid-liquid separation, and dried at 45° C. for 10 h. After drying, high-quality crystals of dicloxacillin sodium are obtained.

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

[0055] Example 2

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

[0057] Step 1: Add 6-APA to the crystallizer of acetone-water solution, and control the temperature in the crystallizer to 5°C, drop dilute sulfuric acid into the system to adjust the pH of the system to 4.5, and stir to dissolve it to prepare solution A; the mass ratio of 6-APA, acetone and water is 1:4:4;

[0058] 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide (with a mass ratio of 1.2:1 to 6-APA used) was dissolved in acetone to prepare solution B; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide to acetone was 1:3;

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

[0060] Step 2: After the reaction is completed, isopropyl acetate is added to the crystallizer for extraction, and the pH of the system is adjusted to 3.0 with dilute sulfuric acid. The phases are allowed to stand for phase separation, and the upper organic phase is taken from the crystallizer for standby use to obtain a dicloxacillin acid solution;

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

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

[0063] Step 5: The slurry obtained in step 4 is subjected to solid-liquid separation, and dried at 80° C. for 6 h. After drying, high-quality crystals of dicloxacillin sodium are obtained.

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

[0065] Example 3

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

[0067] Step 1: Add 6-APA to a crystallizer of glycerol-water solution, and control the temperature in the crystallizer to 15°C, drop sodium bicarbonate aqueous solution into 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] 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide (with a mass ratio of 1.3:1 to 6-APA used) was dissolved in ethyl acetate to prepare solution B; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide to ethyl acetate was 1:2;

[0069] Solution B was added to the crystallizer at a flow rate of 20 mL / min, and acylated 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 acid. The mass ratio of solution A to solution B was 4:1.

[0070] Step 2: After the reaction is completed, ethyl acetate is added to the crystallizer for extraction, and the pH of the system is adjusted to 4.0 with dilute hydrochloric acid. The phases are allowed to stand for phase separation, and the upper organic phase is taken and placed in the crystallizer for standby use to obtain a dicloxacillin acid solution;

[0071] Step 3: Control the temperature in the crystallizer to 5°C, the stirring speed to 500rpm, and add a solution prepared by sodium isooctanoate (the molar ratio of the amount to 6-APA is 1:1) and ethyl acetate (the mass ratio of the amount to sodium isooctanoate is 2:1) to the crystallizer at a flow rate of 20mL / min, and react the solution with the dicloxacillin acid solution obtained in step 2 for 0.5h to obtain a dicloxacillin sodium solution;

[0072] Step 4: Control the temperature in the crystallizer to 5°C, 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, grow the crystal for 0.75h, and carry out evaporation-solution coupled crystallization for 2h at the stirring rate and temperature under a vacuum degree of -0.09Mpa, and the evaporation rate is 10ml / h to obtain a superior grade crystal slurry of dicloxacillin sodium;

[0073] Step 5: The slurry obtained in step 4 is subjected to solid-liquid separation, and dried at 60° C. for 4 h. After drying, high-quality crystals of dicloxacillin sodium are obtained.

[0074] The final product is white flaky crystals, and the X-ray powder diffraction spectrum is as follows: Figure 2 As shown. The Raman spectrum is Figure 3 The molar yield is 81.3%, the purity is 99.1%, the aqueous solution is colorless, clear and transparent, the acidity is 6.5, and the product particle size is about 230 μm.

[0075] Example 4

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

[0077] Step 1: Add 6-APA to the crystallizer of isopropanol-water solution, and control the temperature in the crystallizer to 0°C, add sodium carbonate aqueous solution to the system to adjust the pH of the system 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] 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide (with a mass ratio of 1:0.5 to 6-APA used) was dissolved in isopropanol to prepare solution B; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide to isopropanol was 1:4;

[0079] Solution B was added into the crystallizer at a flow rate of 2 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 carbonate solution to prepare dicloxacillin acid. The mass ratio of solution A to solution B was 3:1.

[0080] Step 2: After the reaction is completed, methyl formate is added to the crystallizer for extraction, and the system is adjusted to pH = 4.0 with dilute sulfuric acid, and the phases are allowed to stand for separation, and the upper organic phase is taken from the crystallizer for standby use to obtain a dicloxacillin acid solution;

[0081] Step 3: Control the temperature in the crystallizer to 40° C., the stirring speed to 100 rpm, and add a solution prepared by sodium ethoxide (the molar ratio of sodium ethoxide to 6-APA is 1.5:1) and ethanol (the mass ratio of the amount to the amount of sodium ethoxide is 1.5:1) to the crystallizer at a flow rate of 10 mL / min, and react it with the dicloxacillin acid solution obtained in step 2 for 0.5 h to obtain a dicloxacillin sodium solution;

[0082] Step 4: Control the temperature in the crystallizer to 40° C., the stirring speed to 500 rpm, and add ethyl acetate (the mass ratio of ethyl acetate to sodium ethoxide is 10:1) to the dicloxacillin sodium solution obtained in step 3 at a flow rate of 1.5 mL / min. After crystallization, grow the crystal for 1 hour, and carry out evaporation-solution coupled crystallization for 8 hours at the stirring rate and temperature under a vacuum degree of -0.01 MPa, and the evaporation rate is 10 mL / h to obtain a superior grade crystal slurry of dicloxacillin sodium;

[0083] Step 5: The slurry obtained in step 4 is subjected to solid-liquid separation, and dried at 45° C. for 10 h. After drying, high-quality crystals of dicloxacillin sodium are obtained.

[0084] The final product is white flaky crystals, and the X-ray powder diffraction spectrum is as follows: Figure 2 As shown. The Raman spectrum is Figure 3 The molar yield is 80.1%, the purity is 99.2%, the aqueous solution is colorless, clear and transparent, the acidity is 5.5, and the product particle size is about 215 μm.

[0085] Example 5

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

[0087] Step 1: Add 6-APA to a crystallizer of a methanol-water solution, and control the temperature in the crystallizer to 5°C, drop sodium bicarbonate aqueous solution into the system to adjust the pH of the system to 5.0, and stir to dissolve it to prepare solution A; the mass ratio of 6-APA, methanol, and water is 1:4:4;

[0088] 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide (with a mass ratio of 1.25:1 to 6-APA used) was dissolved in ethyl acetate to prepare solution B; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide to ethyl acetate was 1:3;

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

[0090] Step 2: After the reaction is completed, isopropyl acetate is added to the crystallizer for extraction, and the pH of the system is adjusted to 9.0 with dilute hydrochloric acid. The phases are allowed to stand for phase separation, and the upper organic phase is taken from the crystallizer for standby use to obtain a dicloxacillin acid solution;

[0091] Step 3: Control the temperature in the crystallizer to 5°C, the stirring speed to 300rpm, and add a salt-forming agent solution prepared by sodium ethoxide (the molar ratio of the amount to 6-APA is 1.3:1) and ethyl acetate (the mass ratio of the amount to the amount of sodium ethoxide is 2:1) to the crystallizer at a flow rate of 15mL / min, and react the salt with the dicloxacillin acid solution obtained in step 2 for 0.5h to obtain a dicloxacillin sodium solution;

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

[0093] Step 5: The slurry obtained in step 4 is subjected to solid-liquid separation, and dried at 80° C. for 6 h. After drying, high-quality crystals of dicloxacillin sodium are obtained.

[0094] The final product is white flaky crystals, and the X-ray powder diffraction spectrum is as follows: Figure 2 As shown. The Raman spectrum is Figure 3 The molar yield is 80.6%, the purity is 99.3%, the aqueous solution is colorless, clear and transparent, the acidity is 6.3, and the product particle size is about 210 μm.

[0095] Example 6

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

[0097] Step 1: Add 6-APA to the crystallizer of acetone-water solution, and control the temperature in the crystallizer to 15°C, drop dilute hydrochloric acid into the system to adjust the pH of the system 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] 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide (with a mass ratio of 1.3:1 to 6-APA used) was dissolved in ethyl acetate to prepare solution B; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide to ethyl acetate was 1:2;

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

[0100] Step 2: After the reaction is completed, ethyl acetate is added to the crystallizer for extraction, and the pH of the system is adjusted to 7.5 using sodium carbonate. The mixture is allowed to stand for phase separation, and the upper organic phase is taken and placed in the crystallizer for standby use to obtain a dicloxacillin acid solution;

[0101] Step 3: Control the temperature in the crystallizer to 40°C, the stirring speed to 500rpm, and add a solution prepared by sodium bicarbonate (the molar ratio of sodium bicarbonate to 6-APA is 1:1) and acetone (the mass ratio of the amount to the amount of sodium bicarbonate is 1.2:1) to the crystallizer at a flow rate of 5mL / min, and react the solution with the dicloxacillin acid solution obtained in step 2 for 0.5h to obtain a dicloxacillin sodium solution;

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

[0103] Step 5: The slurry obtained in step 4 is subjected to solid-liquid separation, and dried at 60° C. for 4 h. After drying, high-quality crystals of dicloxacillin sodium are obtained.

[0104] The final product is white flaky crystals, and the X-ray powder diffraction spectrum is as follows: Figure 2 As shown. The Raman spectrum is Figure 3 The molar yield is 80.0%, the purity is 99.1%, the aqueous solution is colorless, clear and transparent, the acidity is 6.0, and the product particle size is about 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 in the form of white powder, with a molar yield of 54.2%, a purity of 96.2%, a colorless, clear and transparent aqueous solution, an acidity of 5.61, and a product particle size of about 75 μm.

[0108] Comparative Example 2

[0109] The difference from Example 1 is that the synthesis method of dicloxacillin sodium is different, a butyl acetate solvent system is used, and the evaporation-solution coupled crystallization steps are the same as those of Example 1. The specific steps are as follows:

[0110] Step 1: Add 6-APA to a crystallizer of butyl acetate-water solution, and control the temperature in the crystallizer to -5°C, add sodium hydroxide aqueous solution to the system to adjust the pH of the system to 9.0, and stir to dissolve it to prepare solution A; the mass ratio of 6-APA, butyl acetate and water is 1:3:3;

[0111] 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide (with a mass ratio of 1:1 to 6-APA used) was dissolved in butyl acetate to prepare solution B; the mass ratio of 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide to butyl acetate was 1:2;

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

[0113] Step 2: After the reaction is completed, butyl acetate is added to the crystallizer for extraction, and the pH of the system is adjusted to 2.0 with dilute hydrochloric acid. The mixture is allowed to stand for phase separation, and the upper organic phase is taken and placed in the crystallizer for standby use to obtain a dicloxacillin acid solution;

[0114] Step 3: Control the temperature in the crystallizer to 40°C, the stirring speed to 100 rpm, and add a solution prepared by sodium isooctanoate (the molar ratio of the amount to 6-APA is 1.5:1) and methanol (the molar ratio of the amount to sodium isooctanoate is 2:1) to the crystallizer at a flow rate of 3 mL / min, and react the solution with the dicloxacillin acid solution obtained in step 2 for 1 hour to obtain a dicloxacillin sodium solution;

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

[0116] Step 5: The slurry obtained in step 4 is subjected to solid-liquid separation, and dried at 45° C. for 10 h. After drying, high-quality crystals of dicloxacillin sodium are obtained.

[0117] The final product is in the form of yellow powder, with a molar yield of 77.6% and a purity of 95.1%. The aqueous solution is light yellow, clear and transparent, with an acidity of 5.65. The product particle size is about 20 μm and has severe agglomeration.

[0118] Chemical property testing

[0119] 1) The chemical stability of the dicloxacillin sodium premium products prepared in Examples 1-6 and Comparative Examples 1-2 of the present invention was investigated. The color, purity and morphology of the dicloxacillin sodium premium products prepared in Examples 1-6 did not change during storage for 30 days at 25°C ± 5°C and RH 40 ± 5%, indicating that the crystal had good chemical stability. The investigation results are shown in Table 1.

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

[0121]

[0122]

[0123] 2) The chemical stability of the turbidity and other properties of the dicloxacillin sodium superior hydrate prepared in Examples 1-6 of the present invention and Comparative Examples 1-2 was investigated. During storage for 30 days at 25°C ± 5°C and RH 40 ± 5%, the turbidity of the product in Examples 1-6 remained substantially unchanged, indicating that the crystal had good chemical stability. The investigation results are shown in Table 2.

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

[0125]

[0126] The preparation method of the superior grade of dicloxacillin sodium disclosed and proposed in the present invention can be realized by those skilled in the art by referring to the content of this article and appropriately changing the raw materials, process parameters and other links. The method and product of the present invention have been described through preferred embodiments, and relevant technical personnel can obviously modify or appropriately change and combine the method and product described herein without departing from the content, spirit and scope of the present invention to realize the technology of the present invention. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the spirit, scope and content of the present invention.

Claims

1. A coupled crystallization method for preparing a superior grade of dicloxacillin sodium, characterized in that: Here are the steps: Step 1: Add 6-aminopenicillanic acid, solvent I and water into a crystallizer, control the temperature in the crystallizer, adjust the pH of the system to a certain pH value, and stir to dissolve it to prepare solution A; 3-(2,6-dichlorophenyl)-5-methylisoxazolecarboxamide is dissolved in solvent II to prepare solution B; Solution B is added to the crystallizer at a certain flow rate to react with solution A for 0.5 to 2 hours, and the pH of the system is adjusted to a certain pH to prepare dicloxacillin acid; Step 2: After the reaction is completed, solvent III is added to the crystallizer for extraction, the system is adjusted to a certain pH value, the phases are allowed to stand for separation, and the upper organic phase is taken from the crystallizer for standby use to obtain a dicloxacillin acid solution; Step 3: controlling the temperature in the crystallizer, and adding a salt-forming agent solution prepared by a salt-forming agent and solvent IV into the crystallizer at a certain flow rate, so that the salt-forming agent reacts with the dicloxacillin acid solution obtained in step 2 to obtain a dicloxacillin sodium solution; Step 4: Control the temperature in the crystallizer to 5-40° C., the stirring rate to 100-500 rpm, the solvent is added dropwise to the dicloxacillin sodium solution at a flow rate of 0.1-1.5 mL / min, the crystal growing time is 0.5-1 h, the vacuum degree is -0.01-0.09 MPa, the solvent evaporation rate is controlled to 10-30 mL / h, the evaporation time is controlled to 2-8 h, and evaporation-solution coupled crystallization is performed to obtain a superior grade dicloxacillin sodium crystal slurry; Step 5: The slurry obtained in step 4 is subjected to solid-liquid separation and dried to obtain high-quality crystals of dicloxacillin sodium.

2. The coupled crystallization method according to claim 1, wherein the solvent I is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, and glycerol; the solvent II is one or more of isopropanol, ethanol, methanol, acetone, isopropyl acetate, and ethyl acetate; the solvent III is one or more of methyl formate, ethyl formate, methyl acetate, ethyl acetate, and isopropyl acetate; the solvent IV is one or more of methanol, ethanol, isopropanol, acetone, isopropyl acetate, and ethyl acetate.

3. The coupled crystallization method according to claim 1, wherein the temperature in the crystallizer in step 1 is -5 to 15°C.

4. 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-methylisoxazolecarboxamide 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-methylisoxazolecarboxamide to solvent II is 1:4 to 1:

2.

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

6. The coupled crystallization method according to claim 1, wherein the pH value in step 1 and step 2 is 2.0 to 9.0, and an inorganic base or an inorganic acid is used to adjust the pH value of the solution, 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.

7. The coupled crystallization method according to claim 1, wherein the salt-forming agent in step 3 is one or more of sodium bicarbonate, sodium ethoxide, sodium isooctanoate, and sodium hydroxide, and the molar ratio of the salt-forming agent to 6-aminopenicillanic acid is 1:1 to 1.5:1; the mass ratio of the solvent IV used to the salt-forming agent is 1:1 to 2:

1.

8. According to the coupled crystallization method of claim 1, during the salt-forming reaction in step 3, the temperature in the crystallizer is 5 to 40°C, the flow rate of the salt-forming agent solution is 3 to 20 mL / min, the salt-forming reaction time is 0.5 to 1 h, and the stirring rate is controlled to be 100 to 500 rpm.

9. The coupled crystallization method according to claim 1, wherein the solvent used in the elution-evaporation coupled crystallization process in step 4 is one or more of acetone, methyl acetate, isopropyl acetate, ethyl acetate, and isopropyl alcohol.

10. The coupled crystallization method according to claim 1, wherein in step 5, the drying temperature is 45-80°C and the drying time is 4-10 hours.

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