Preparation method of cefoperazone sodium

Abstract

The invention discloses a preparation method of cefoperazone sodium, which comprises the following steps: S1, adding cefoperazone acid into a first solvent system, and dropwise adding a sodium salt-forming agent aqueous solution for reaction to obtain a first reaction solution; s2, adding the first reaction solution into a second solvent system, and filtering to obtain an amorphous cefoperazone sodium wet product; s3, the amorphous cefoperazone sodium wet product is added into a third solvent system for suspension pulping, the crystal transformation temperature is controlled, and crystalline cefoperazone sodium is obtained; the high-purity cefoperazone sodium is obtained by salifying and crystallizing cefoperazone acid and then carrying out suspension crystal transformation, so that the molecular space structure of the cefoperazone sodium can be changed, and N-nitrosamine genotoxic impurities such as NDMA embedded into the crystal can be effectively separated.

Description

Technical Field

[0001] The present invention relates to a preparation method of cefoperazone sodium, belonging to the field of pharmaceutical technology. Background Art

[0002] The chemical name of cefoperazone sodium is (6R,7R)-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarbonylamino)-2-p-hydroxyphenyl-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt. It is a white to slightly yellowish powder or crystalline powder, readily soluble in water, slightly soluble in methanol, very slightly soluble in ethanol, and insoluble in acetone or ethyl acetate. Its structural formula is as follows:

[0003]

[0004] In recent years, trace amounts of N-nitrosamine genotoxic impurities have been successively found in sartan drugs and ranitidine, which has attracted extensive attention from domestic and foreign pharmaceutical companies and regulatory authorities. The N-nitrosamine impurities in sartan APIs are considered to originate from the synthesis process of the tetrazole ring in the structure, and cefoperazone sodium also contains a tetrazole structure. Li Qian pointed out in "Quality Evaluation of Cefoperazone Sodium for Injection" that there is a risk of introducing such impurities during the raw material production process of cefoperazone sodium for injection.

[0005] Currently, there are mainly two methods for preparing cefoperazone sodium at home and abroad: one is the solvent crystallization method, and the other is the freeze-drying crystallization method. Since the product obtained by the freeze-drying crystallization method is an amorphous substance, impurities are wrapped in the product, resulting in low product purity and poor stability. Therefore, most domestic and foreign literature reports and actual production in enterprises use the solvent crystallization method to prepare cefoperazone sodium.

[0006] Patent CN114621254A discloses a method for reducing the formation of cefoperazone sodium solvates and reducing solvent residues. By using solvent replacement and dissociation, the problem of high solvent residues in cefoperazone sodium affecting product stability is solved, but it cannot solve the problem of N-nitrosamine genotoxic impurities.

[0007] Patent CN116143803A discloses a method for preparing large particle spherical crystals of cefoperazone sodium. The obtained cefoperazone sodium is large particle spherical crystals with a particle size of more than 350 μm, which is more unfavorable for removing impurities inside the particles.

[0008] In the existing cefoperazone sodium preparation technology, there is no effective control for N-nitrosamine genotoxic impurities. Summary of the Invention

[0009] To solve the above technical problems, the present invention provides a method for preparing cefoperazone sodium. Cefoperazone acid is salted and crystallized, and then suspension transformation crystallization is carried out to obtain high-purity cefoperazone sodium, which can change the molecular spatial structure of cefoperazone sodium and effectively separate N-nitrosamine genotoxic impurities such as NDMA embedded inside the crystal.

[0010] To solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0011] A method for preparing cefoperazone sodium, comprising the following steps:

[0012] S1: Add cefoperazone acid to the first solvent system, and dropwise add an aqueous solution of a sodium salting agent for reaction to obtain a first reaction solution;

[0013] S2: Add the first reaction solution to the second solvent system, and filter to obtain wet amorphous cefoperazone sodium;

[0014] S3: Add the wet amorphous cefoperazone sodium to the third solvent system for suspension pulping, and control the transformation crystallization temperature to obtain crystalline cefoperazone sodium.

[0015] A further improvement of the technical solution of the present invention lies in that: in S1, the aqueous solution of the sodium salting agent is an aqueous solution of sodium bicarbonate, and the mass concentration is 9-11%.

[0016] A further improvement of the technical solution of the present invention lies in that: in S1, the reaction temperature is controlled at 15-20 °C, and the addition amount of the aqueous solution of the sodium salting agent is adjusted to make the pH of the reaction system 6.5-7.5.

[0017] A further improvement of the technical solution of the present invention lies in that: in S1, the first solvent system is acetone, and the mass-volume ratio of cefoperazone acid to the first solvent system is 1 g:(10-15) ml.

[0018] A further improvement of the technical solution of the present invention lies in that: in S2, the second solvent system is one or more of acetone, methanol, isopropanol, and ethanol, and the volume ratio of the first solvent system to the second solvent system is 1:(8-12).

[0019] A further improvement of the technical solution of the present invention lies in that: in S3, the third solvent system is a mixture of one or more of ethanol, isopropanol, ethyl formate, and methyl acetate and water, and the volume ratio of the first solvent system to the third solvent system is 1:(2-4).

[0020] A further improvement of the technical solution of the present invention lies in that: the transformation crystallization temperature in S3 is 40 °C to 50 °C.

[0021] Due to the adoption of the above technical solution, the technical progress achieved by the present invention is:

[0022] By suspending and transforming the crystal molecular spatial structure of cefoperazone sodium, the present invention converts it from an amorphous form to a crystalline form, enabling the release of N-nitrosamine genotoxic impurities originally embedded inside the cefoperazone sodium crystal. Then, by reducing the polarity of the solvent and weakening the hydrogen bonds or van der Waals forces between the N-nitrosamine genotoxic impurities and cefoperazone sodium, the separation of impurities and the purification of the product are achieved. The prepared cefoperazone sodium crystals are regular, in the form of needle-shaped crystals, with high purity and are not prone to occluding impurities, thus greatly reducing the safety risk of N-nitrosamine genotoxic impurities.

[0023] Meanwhile, the preparation process of cefoperazone sodium is simple and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is the crystal morphology diagram of cefoperazone sodium of the present invention, which is in the form of needle-shaped crystals. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0025] A preparation method of cefoperazone sodium includes the following steps:

[0026] S1: Cefoperazone acid is added to the first solvent system, and an aqueous solution of a sodium salt-forming agent is added dropwise for reaction to obtain a first reaction solution;

[0027] S2: The first reaction solution is added to the second solvent system, and filtered to obtain wet amorphous cefoperazone sodium;

[0028] S3: The wet amorphous cefoperazone sodium is added to the third solvent system for suspension and pulping, and the crystal transformation temperature is controlled to obtain crystalline cefoperazone sodium.

[0029] The principle of the present invention is that during the crystal transformation process, the decrease in solvent polarity leads to a weakened binding force between N-nitrosamine impurities and cefoperazone sodium, reducing the interaction between impurity molecules and cefoperazone sodium, thereby achieving the separation of impurities. And by controlling the crystal transformation temperature to optimize the crystal growth environment, it promotes the orderly arrangement of cefoperazone sodium molecules to form a regular and high-purity crystal structure. This process not only improves the purity of the product but also effectively reduces the safety risk of N-nitrosamine impurities.

[0030] Among them, in S1, the sodium salt-forming agent is sodium bicarbonate, which is added dropwise in the form of an aqueous solution of sodium bicarbonate with a mass concentration of 9-11%, and the addition amount is controlled to adjust the pH of the reaction system to 6.5-7.5.

[0031] The advantages of using sodium bicarbonate as the sodium salt-forming agent are reflected in its ability to effectively adjust the pH value, providing a stable environment for the synthesis process of cefoperazone sodium; its moderate solubility, facilitating preparation and operation; the harmless reaction by-products, showing environmental friendliness; and its low cost, helping to reduce the preparation cost and improve economic benefits.

[0032] And the first solvent system is acetone, and the mass-to-volume ratio of cefoperazone acid to the first solvent system is 1 g : (10 - 15) ml.

[0033] Acetone exhibits excellent dissolving ability and can efficiently dissolve cefoperazone acid, thus ensuring the full progress of the reaction.

[0034] In S2, the second solvent system is one or more of acetone, methanol, isopropanol, and ethanol, and the volume ratio of the first solvent system to the second solvent system is 1 : (8 - 12).

[0035] In the preparation process of sodium cefoperazone, the second solvent system plays a crucial role. This system not only promotes the dissolution, dispersion, and reaction of the drug, but also can regulate the polarity of the whole system. In addition, it plays a key role in controlling the crystallization process, has a significant impact on the crystal morphology and particle size, and thus improves the purity and quality of the product. By carefully selecting one or more solvents from acetone, methanol, isopropanol, and ethanol and precisely adjusting their volume ratios, the preparation process of sodium cefoperazone can be optimized, thereby obtaining the desired product.

[0036] In S3, the third solvent system is a mixture of one or more of ethanol, isopropanol, ethyl formate, and methyl acetate and water, and the volume ratio of the first solvent system to the third solvent system is 1 : (2 - 4).

[0037] The third solvent system plays a crucial role in the preparation process of sodium cefoperazone. This system can not only dissolve cefoperazone acid and its salts, but also cooperate with the first solvent system to jointly regulate the properties of the reaction medium, ensuring the stability of the reaction process. In addition, the third solvent system has a significant impact on the precipitation rate of the product and the crystal growth process, and can control the crystal morphology and particle size, thereby optimizing the quality and performance of the product. By carefully selecting a mixture of one or more of ethanol, isopropanol, ethyl formate, and methyl acetate and water as the third solvent and precisely controlling its volume ratio to the first solvent, fine control of the preparation process of sodium cefoperazone can be achieved, and thus high-quality products can be obtained.

[0038] The present invention limits the transformation temperature to 40°C - 50°C, and the setting of this temperature plays a decisive role. By maintaining the transformation temperature within the range of 40°C to 50°C, the stable growth of crystals can be ensured, thus forming an ideal crystal morphology and particle size. If the temperature exceeds this range, it will have a negative impact on the crystal quality and yield. Therefore, precisely regulating the temperature is crucial for optimizing the crystal structure, improving the product quality and performance, and is the key to achieving the preparation of high-quality sodium cefoperazone.

[0039] The following further elaborates on the present invention with reference to the embodiments:

[0040] Example 1

[0041] Take a four-necked flask, add 50 ml of acetone and 5 g of cefoperazone acid, dropwise add 9% sodium bicarbonate aqueous solution until the pH of the reaction system is 6.5, and control the reaction temperature at 15°C. Add the above reaction solution to a mixed solution system of 360 ml of acetone and 40 ml of isopropanol, and filter to obtain amorphous cefoperazone sodium wet powder; the wet powder is added to a mixed solution system of 80 ml of ethanol, 15 ml of isopropanol and 5 ml of purified water for suspension pulping, control the recrystallization temperature at 40°C, filter and dry to obtain cefoperazone sodium with a needle-shaped crystal form, and the crystal morphology diagram is as Figure 1 shown.

[0042] Example 2

[0043] Take a four-necked flask, add 75 ml of acetone and 5 g of cefoperazone acid, dropwise add 11% sodium bicarbonate aqueous solution until the pH of the reaction system is 7.5, and control the reaction temperature at 20°C. Add the above reaction solution to a mixed solution system of 860 ml of acetone and 40 ml of isopropanol, and filter to obtain amorphous cefoperazone sodium wet powder; the wet powder is added to a mixed solution system of 260 ml of ethanol, 30 ml of ethyl formate and 10 ml of purified water for suspension pulping, control the recrystallization temperature at 50°C, filter and dry to obtain cefoperazone sodium with a needle-shaped crystal form.

[0044] Example 3

[0045] Take a four-necked flask, add 62 ml of acetone and 5 g of cefoperazone acid, dropwise add 10% sodium bicarbonate aqueous solution until the pH of the reaction system is 7.0, and control the reaction temperature at 17°C. Add the above reaction solution to 620 ml of acetone, and filter to obtain amorphous cefoperazone sodium wet powder; the wet powder is added to a mixed solution system of 180 ml of ethanol and 6 ml of purified water for suspension pulping, control the recrystallization temperature at 45°C, filter and dry to obtain cefoperazone sodium with a needle-shaped crystal form.

[0046] Comparative Example 1 (Example 1 of a preparation method of cefoperazone sodium in CN114621254A)

[0047] Add 280 ml of acetone and 100 g of cefoperazone acid into a 3000 ml reaction flask, stir, and dropwise add the pre-prepared 10% sodium bicarbonate solution at a reaction temperature of 15 - 18°C to adjust the pH of the system to 6.9. After the reaction is complete, filter. First, add 130 ml of acetone and then add 0.3 g of seed crystals to induce crystallization. Control the system temperature at 20 - 24°C for crystal cultivation for 1 h. Dropwise add 1400 ml of acetone for crystallization. After the crystal cultivation is completed, filter to obtain the wet product. Add 150 g of isopropyl alcohol and 15 g of water to the wet product for slurry replacement and then filter. Filter the filter cake under reduced pressure and displace it with dry nitrogen for a total of 1.5 h. The residual of the mixed solvent is 0.48% by on-line gas chromatography control. Vacuum dry at 45 - 50°C for 1 h. The residual of acetone is 0.24% by on-line gas chromatography control. After passing the inspection, discharge the product to obtain 98.0 g of dry cefoperazone sodium product.

[0048] Comparative Example 2 (Example 1 of the preparation method of a large particle cefoperazone sodium spherical crystal in CN116143803A)

[0049] ① Prepare a cefoperazone acid solution: At 20°C, dissolve 1 kg of cefoperazone acid in 4 kg of acetone, and filter through a 0.22 μm organic filter element to obtain a cefoperazone acid solution;

[0050] ② Prepare a sodium bicarbonate aqueous dispersion: At 20°C, dissolve 0.16 kg of sodium bicarbonate in 0.8 kg of deionized water, then add 0.04 g of hydroxypropyl cellulose thereto, stir and dissolve, and filter through a 0.22 μm organic filter element,

[0051] to obtain a sodium bicarbonate aqueous dispersion;

[0052] ③ Prepare a cefoperazone sodium seed crystal suspension: At 20°C, add 0.096 kg of the sodium bicarbonate aqueous dispersion obtained in step ② and 0.5 kg of the cefoperazone acid solution obtained in step ① to the first seed crystal kettle, start stirring and insert the ultrasonic rod below the liquid level. Set the ultrasonic on time to 2 s and the ultrasonic off time to 2 s, and operate in an alternating intermittent manner. After 5 minutes, when solid cefoperazone acid seed crystals are generated in the system, turn off the ultrasonic equipment and keep stirring for crystal cultivation for 15 minutes to obtain a cefoperazone sodium seed crystal suspension;

[0053] ④ Prepare a cefoperazone sodium crystal suspension: Sequentially add the remaining cefoperazone acid solution obtained in step ① and the cefoperazone sodium seed crystal suspension obtained in step ③ to the second seed crystal kettle, start stirring, and dropwise add the remaining sodium bicarbonate aqueous dispersion obtained in step ② to the second seed crystal kettle. Then lower the temperature of the second seed crystal kettle to 3°C and carry out crystal cultivation at this temperature for 1 h to obtain a cefoperazone sodium crystal suspension;

[0054] Filter the cefoperazone sodium crystal suspension obtained in step ④, wash the filter cake with 3 kg of acetone, and vacuum dry at 80°C for 5 h to obtain large particle cefoperazone sodium spherical crystals.

[0055] Comparative Example 3: (Based on Example 1, process parameters are outside the scope of the claims)

[0056] Take a four-necked flask, add 150 ml of acetone and 5 g of cefoperazone acid, and dropwise add 9% aqueous sodium bicarbonate solution until the pH of the reaction system is 7.5, and control the reaction temperature at 35°C. Add the above reaction solution to a mixed solution system of 360 ml of acetone and 40 ml of isopropanol, and filter to obtain wet amorphous cefoperazone sodium powder; add the wet powder to a suspension and pulping system of a mixed solution of 150 ml of isopropanol and 5 ml of purified water, control the recrystallization temperature at 20°C, and filter and dry to obtain cefoperazone sodium.

[0057] Comparative Example 4: (Based on Example 1, without the recrystallization process)

[0058] Take a four-necked flask, add 50 ml of acetone and 5 g of cefoperazone acid, and dropwise add 9% aqueous sodium bicarbonate solution until the pH of the reaction system is 6.5, and control the reaction temperature at 15°C. Add the above reaction solution to a mixed solution system of 360 ml of acetone and 40 ml of isopropanol, and filter and dry to obtain cefoperazone sodium.

[0059] Comparative Example 5: (Based on Example 1, other solvents are selected for the second solvent system)

[0060] Take a four-necked flask, add 50 ml of acetone and 5 g of cefoperazone acid, and dropwise add 9% aqueous sodium bicarbonate solution until the pH of the reaction system is 6.5, and control the reaction temperature at 15°C. Add the above reaction solution to 400 ml of acetonitrile, and filter to obtain wet amorphous cefoperazone sodium powder; add the wet powder to a suspension and pulping system of a mixed solution of 80 ml of ethanol, 15 ml of isopropanol and 5 ml of purified water, control the recrystallization temperature at 40°C, and filter and dry to obtain cefoperazone sodium.

[0061] Comparative Example 6: (Based on Example 1, other solvents are selected for the third solvent system)

[0062] Take a four-necked flask, add 50 ml of acetone and 5 g of cefoperazone acid, and dropwise add 9% aqueous sodium bicarbonate solution until the pH of the reaction system is 6.5, and control the reaction temperature at 15°C. Add the above reaction solution to a mixed solution system of 360 ml of acetone and 40 ml of isopropanol, and filter to obtain wet amorphous cefoperazone sodium powder; add the wet powder to a suspension and pulping system of a mixed solution of 80 ml of n-butanol, 15 ml of cyclohexane and 5 ml of purified water, control the recrystallization temperature at 40°C, and filter and dry to obtain cefoperazone sodium.

[0063] Refer to the detection method recorded in the reference "Quality Evaluation of Cefoperazone Sodium for Injection", and the detection results are shown in Table 1:

[0064] Table 1 Detection Results of N-Nitrosodimethylamine (NDMA) in Experimental Samples

[0065] Batch number Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Results (LOD = 6 ppb) Not detected Not detected Not detected 5.66 4.98 Batch number Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Results (LOD = 6 ppb) 5.66 5.73 5.56 5.69

[0066] As can be seen from Table 1, within the scope of the claims, the nitrite index in the product meets the requirements and there is no risk of exceeding the standard.

[0067] Table 2 Detection Results of Related Substances

[0068] Batch number Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Impurity A (%) 0.06 0.06 0.05 0.13 0.15 Other impurities (%) 0.07 0.08 0.10 0.18 0.22 Total other impurities (%) 0.13 0.15 0.16 0.31 0.35 Batch number Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Impurity A (%) 0.17 0.23 0.21 0.18 Other impurities (%) 0.19 0.27 0.23 0.25 Total other impurities (%) 0.29 0.52 0.44 0.46

[0069] As can be seen from Table 2, within the scope of the claims, the related substance index in the product meets the requirements.

Claims

1. A preparation method of cefoperazone sodium, characterized in that, It includes the following steps: S1: Cefoperazone acid is added to the first solvent system, and an aqueous solution of a sodium salt-forming agent is added dropwise for reaction to obtain a first reaction solution; S2: The first reaction solution is added to the second solvent system, and an amorphous cefoperazone sodium wet product is obtained by filtration; S3: The amorphous cefoperazone sodium wet product is added to the third solvent system for suspension and pulping, and the crystal transformation temperature is controlled to obtain crystalline cefoperazone sodium.

2. The preparation method of cefoperazone sodium according to claim 1, wherein: In S1, the aqueous solution of the sodium salt-forming agent is an aqueous solution of sodium bicarbonate with a mass concentration of 9-11%.

3. The preparation method of cefoperazone sodium according to claim 2, characterized in that: In S1, the reaction temperature is controlled at 15-20°C, and the addition amount of the aqueous solution of the sodium salt-forming agent is adjusted to make the pH of the reaction system reach 6.5-7.

5.

4. The preparation method of cefoperazone sodium according to claim 1, characterized in that: In S1, the first solvent system is acetone, and the mass-volume ratio of cefoperazone acid to the first solvent system is 1 g:(10-15) ml.

5. The preparation method of cefoperazone sodium according to claim 1, characterized in that: In S2, the second solvent system is one or more of acetone, methanol, isopropanol, and ethanol, and the volume ratio of the first solvent system to the second solvent system is 1:(8-12).

6. The preparation method of cefoperazone sodium according to claim 1, characterized in that: In S3, the third solvent system is a mixture of one or more of ethanol, isopropanol, ethyl formate, and methyl acetate and water, and the volume ratio of the first solvent system to the third solvent system is 1:(2-4).

7. The preparation method of cefoperazone sodium according to claim 6, characterized in that: In S3, the crystal transformation temperature is 40°C to 50°C.

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