Method for purifying cefazolin acid

Abstract

The invention discloses a method for purifying cefazolin acid, which belongs to the technical field of medicine, and comprises the following steps: mixing a material A, water and triethylamine, dissolving, controlling the temperature, and filtering to obtain a solution A; the material A accounting for 10% of the weight of the solution A, the water accounting for 10% of the weight of the solution A and the triethylamine accounting for 5% of the weight of the solution A are mixed, stirred, dissolved and filtered; rapidly stirring the filtered solution under a 40HZ ultrasonic condition, rapidly adding a hydrochloric acid solution, adjusting the pH value to be less than 3, and controlling the temperature; then reducing the stirring speed, and stirring again to prepare a seed crystal mixed solution; simultaneously adding the solution A and the hydrochloric acid solution into the seed crystal mixed solution, and controlling the pH value to be less than 3; after the solution A is added, growing crystals, continuously adding a hydrochloric acid solution, and stabilizing the pH value to be less than 2; growing the crystal again; filtering, washing and drying to obtain high-purity cefazolin acid powder. The high-purity cefazolin acid powder is prepared by adopting a stable number of crystal nucleuses and an equal low-concentration crystallization technology.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, in particular to a method for purifying cefazolin acid. Background Art

[0002] Cefazolin sodium, also known as cephalosporin V, Pioneer 5, etc., is a semi-synthetic first-generation cephalosporin with strong effects on Gram-positive bacteria and Gram-negative bacteria, especially Klebsiella pneumoniae. Cefazolin acid has obvious advantages over the first-generation cephalosporins, with enzyme resistance, high efficiency, low toxicity, and a wide range of clinical indications. It is mainly used for respiratory tract, urogenital system, cholecystitis, liver abscess, endocarditis, sepsis, ear and soft tissue infections caused by sensitive bacteria, with good therapeutic effects.

[0003] The clinically used cefazolin sodium is an injectable powder, which is usually prepared by freeze-drying, where cefazolin acid and sodium bicarbonate are directly freeze-dried into sodium salt. The finished cefazolin sodium prepared by this method is directly in the form of a preparation, so the quality requirements for cefazolin acid are relatively high, requiring the content of cefazolin acid to be ≥98%, the maximum unknown single impurity to be ≤0.2%, and the color grade to be ≤3. # However, the quality of cefazolin acid synthesized in actual production does not meet this requirement; the quality of some cefazolin sodium also does not meet the requirements.

[0004] The conventional crystallization method of cefazolin acid is: adding hydrochloric acid solution to the crystallization solution in stages, adjusting the pH value for crystallization. In this method, the concentration of the crystallization solution is high at the beginning of crystallization, which makes it difficult to control the crystal output, resulting in too much or too little crystal output at one time. Too much results in fine powder and poor product fluidity. Too little results in secondary crystallization and uneven powder particle size. In addition, too much or too little will cause crystal agglomeration, encapsulate impurities, and affect product quality.

[0005] Therefore, it is necessary to provide a method for purifying cefazolin acid to overcome the above problems. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a method for purifying cefazolin acid, which adopts ultrafine equal-size seed crystal preparation technology and equal-low concentration crystallization technology to effectively control the number of crystal nuclei, crystal growth rate and crystal quality, so that the crystallization process is easy to control and implement, and the product quality is excellent; the product quality is effectively improved, and a high-purity cefazolin acid powder is prepared.

[0007] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0008] A method for purifying cefazolin acid comprises the following steps:

[0009] Step 1, preparation of solution A: mixing material A, water and triethylamine, dissolving, controlling the temperature, and filtering to obtain solution A;

[0010] Step 2, preparation of a seed mixture: 10% by weight of material A in solution A, 10% by weight of water in solution A and 5% by weight of triethylamine in solution A are mixed, stirred to dissolve, and filtered; the filtered solution is rapidly stirred under 40HZ ultrasonic conditions, hydrochloric acid solution is quickly added, the pH value is adjusted to less than 3, and the temperature is controlled; then the stirring speed is reduced, and stirring is continued to obtain a seed mixture;

[0011] Step 3, crystallization: adding solution A and hydrochloric acid solution to the seed mixture at the same time, controlling the pH value to be less than 3; after adding solution A, growing crystals, continuing to add hydrochloric acid solution, and stabilizing the pH to less than 2; growing crystals again; filtering, washing, and drying to obtain high-purity cefazolin acid powder.

[0012] A further improvement of the technical solution of the present invention is that in step 1, material A is cefazolin sodium whose quality does not meet the requirements.

[0013] The further improvement of the technical solution of the present invention is that: in solution A, the mass volume ratio of material A to water is 1:12; the mass volume ratio of triethylamine to water is 1:100.

[0014] A further improvement of the technical solution of the present invention is that in step 1, material A is a crude product of cefazolin acid.

[0015] The further improvement of the technical solution of the present invention is that: in solution A, the mass volume ratio of material A to water is 1:12; and the mass volume ratio of triethylamine to water is 1:75.

[0016] A further improvement of the technical solution of the present invention is that in step 1, the temperature is controlled at 0-10°C.

[0017] The further improvement of the technical solution of the present invention is that: in step 2, the concentration of the hydrochloric acid solution is 20%; the pH value is adjusted to 1.5-2.0; the temperature is controlled at 10-20° C.; and the stirring speed is reduced and then stirred for another 30 minutes.

[0018] The further improvement of the technical solution of the present invention is that: in step 3, the concentration of the hydrochloric acid solution is 20%; and the pH value is controlled to be 1.5-2.0.

[0019] A further improvement of the technical solution of the present invention is that in step 3, after adding solution A, the crystal is grown for 30 minutes.

[0020] The further improvement of the technical solution of the present invention is that: in step 3, the hydrochloric acid solution is continuously added for 30-60 minutes until the pH value is stabilized to 1.5; and the crystal is then grown for 30 minutes.

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

[0022] 1. The present invention adopts ultrafine equal-size seed preparation technology and equal-low concentration crystallization technology to effectively control the number of crystal nuclei, crystal growth rate and crystal quality, making the crystallization process easy to control and implement, and the product quality is excellent; the product quality is effectively improved, and high-purity cefazolin acid powder is prepared.

[0023] 2. In the present invention, ultrafine equal-size crystal seeds are realized by controlling the preparation process of the seed mixture, and rapid stirring is performed under the support of ultrasound to achieve efficient mass transfer and heat transfer. The feed liquid is quickly mixed and the crystals are concentrated. At the same time, by controlling the concentration of the liquid to be crystallized, the number of crystal nuclei is controlled while avoiding crystal nucleus agglomeration.

[0024] 3. In the present invention, crystallization is carried out under low supersaturation conditions, which effectively controls crystal growth, ensures the perfection of crystals and product quality, and the content of cefazolin acid in the prepared high-purity cefazolin acid powder is ≥98%, the maximum unknown single impurity is ≤0.2%, and the color grade is ≤3. # . BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative work.

[0026] Figure 1 The present invention provides a flow chart of a method for purifying cefazolin acid. DETAILED DESCRIPTION

[0027] It should be noted that the terms "including" and "having" and any variations thereof in the specification and claims of the present invention and the above-mentioned drawings are intended to cover non-exclusive inclusions. For example, a process, method, system, product or apparatus comprising a series of steps or units is not necessarily limited to those steps or units clearly listed, but may include other steps or units that are not clearly listed or inherent to these processes, methods, products or apparatus.

[0028] The present invention is further described in detail below with reference to the accompanying drawings and embodiments:

[0029] like Figure 1 As shown, a method for purifying cefazolin acid comprises the following steps:

[0030] Step 1, preparation of solution A: 50 g of crude cefazolin sodium or cefazolin acid that does not meet the quality requirements is mixed with 600 ml of water and 6 g or 8 g of triethylamine, dissolved, the temperature is controlled at 0-10° C., and filtered to obtain a cefazolin sodium solution or a cefazolin acid solution to obtain solution A.

[0031] Step 2, preparation of seed mixture: 5g of crude cefazolin sodium or cefazolin acid that does not meet the quality requirements is mixed with 60ml of water and 0.3g or 0.4g of triethylamine, stirred to dissolve, and filtered; the filtered solution is rapidly stirred under 40HZ ultrasonic conditions, and a quantitative 20% hydrochloric acid solution is quickly added, the pH value is adjusted to 1.5-2.0, and the temperature is controlled at 10-20°C; then the stirring speed is reduced and stirred for another 30min.

[0032] Step 3, crystallization: adding solution A and 20% hydrochloric acid solution to the seed mixture at the same time, controlling the pH value to 1.5-2.0; after adding solution A, growing the crystal for 30 minutes, continuing to add 20% hydrochloric acid solution for 30-60 minutes, and the pH value stabilizes to 1.5; growing the crystal for another 30 minutes; filtering, washing, and drying to obtain high-purity cefazolin acid powder.

[0033] After testing, the high-purity cefazolin acid powder obtained has a cefazolin acid content of ≥98%, a maximum unknown single impurity of ≤0.2%, and a color grade of ≤3. # .

[0034] Example 1

[0035] A method for purifying cefazolin acid comprises the following steps:

[0036] Step 1, preparation of solution A: 50 g of cefazolin sodium that does not meet the quality requirements is mixed with 600 ml of water and 6 g of triethylamine, dissolved, the temperature is controlled at 0° C., and filtered to obtain a cefazolin sodium solution to obtain solution A.

[0037] Step 2, preparation of seed mixture: 5g of cefazolin sodium that does not meet the quality requirements is mixed with 60ml of water and 0.3g of triethylamine, stirred to dissolve, and filtered; the filtered solution is rapidly stirred under 40HZ ultrasonic conditions, and a quantitative 20% hydrochloric acid solution is quickly added, the pH value is adjusted to 1.5, and the temperature is controlled at 10°C; then the stirring speed is reduced and stirred for another 30min.

[0038] Step 3, crystallization: adding solution A and 20% hydrochloric acid solution to the seed mixture at the same time, controlling the pH value to 1.5; after adding solution A, growing the crystal for 30 minutes, continuing to add 20% hydrochloric acid solution, it takes 30 minutes, and the pH stabilizes to 1.5; growing the crystal for another 30 minutes; filtering, washing, and drying to obtain high-purity cefazolin acid powder.

[0039] Example 2

[0040] A method for purifying cefazolin acid comprises the following steps:

[0041] Step 1, preparation of solution A: 50 g of cefazolin sodium that does not meet the quality requirements is mixed with 600 ml of water and 6 g of triethylamine, dissolved, the temperature is controlled at 5° C., and filtered to obtain a cefazolin sodium solution to obtain solution A.

[0042] Step 2, preparation of seed mixture: 5g of cefazolin sodium that does not meet the quality requirements is mixed with 60ml of water and 0.3g of triethylamine, stirred to dissolve, and filtered; the filtered solution is rapidly stirred under 40HZ ultrasonic conditions, and a quantitative 20% hydrochloric acid solution is quickly added, the pH value is adjusted to 1.8, and the temperature is controlled at 15°C; then the stirring speed is reduced and stirred for another 30min.

[0043] Step 3, crystallization: adding solution A and 20% hydrochloric acid solution to the seed mixture at the same time, controlling the pH value to 1.8; after adding solution A, growing the crystal for 30 minutes, continuing to add 20% hydrochloric acid solution, it takes 45 minutes, and the pH stabilizes to 1.5; growing the crystal for another 30 minutes; filtering, washing, and drying to obtain high-purity cefazolin acid powder.

[0044] Example 3

[0045] A method for purifying cefazolin acid comprises the following steps:

[0046] Step 1, preparation of solution A: 50 g of cefazolin sodium that does not meet the quality requirements is mixed with 600 ml of water and 6 g of triethylamine, dissolved, the temperature is controlled at 10° C., and filtered to obtain a cefazolin sodium solution to obtain solution A.

[0047] Step 2, preparation of seed mixture: 5g of cefazolin sodium that does not meet the quality requirements is mixed with 60ml of water and 0.3g of triethylamine, stirred to dissolve, and filtered; the filtered solution is rapidly stirred under 40HZ ultrasonic conditions, and a quantitative 20% hydrochloric acid solution is quickly added, the pH value is adjusted to 2.0, and the temperature is controlled at 20°C; then the stirring speed is reduced and stirred for another 30min.

[0048] Step 3, crystallization: adding solution A and 20% hydrochloric acid solution to the seed mixture at the same time, controlling the pH value to 2.0; after adding solution A, growing the crystal for 30 minutes, continuing to add 20% hydrochloric acid solution for 60 minutes, and stabilizing the pH to 1.5; growing the crystal for another 30 minutes; filtering, washing, and drying to obtain high-purity cefazolin acid powder.

[0049] Example 4

[0050] A method for purifying cefazolin acid comprises the following steps:

[0051] Step 1, preparation of solution A: 50 g of crude cefazolin acid was mixed with 600 ml of water and 8 g of triethylamine, dissolved, the temperature was controlled at 0° C., and the cefazolin acid solution was filtered to obtain solution A.

[0052] Step 2, preparation of seed mixture: 5g of crude cefazolin acid is mixed with 60ml of water and 0.4g of triethylamine, stirred to dissolve, and filtered; the filtered solution is rapidly stirred under 40HZ ultrasonic conditions, and a quantitative 20% hydrochloric acid solution is quickly added, the pH value is adjusted to 1.5, and the temperature is controlled at 10°C; then the stirring speed is reduced and stirred for another 30min.

[0053] Step 3, crystallization: adding solution A and 20% hydrochloric acid solution to the seed mixture at the same time, controlling the pH value to 1.5; after adding solution A, growing the crystal for 30 minutes, continuing to add 20% hydrochloric acid solution, it takes 30 minutes, and the pH stabilizes to 1.5; growing the crystal for another 30 minutes; filtering, washing, and drying to obtain high-purity cefazolin acid powder.

[0054] Example 5

[0055] A method for purifying cefazolin acid comprises the following steps:

[0056] Step 1, preparation of solution A: 50 g of crude cefazolin acid was mixed with 600 ml of water and 8 g of triethylamine, dissolved, the temperature was controlled at 5° C., and the cefazolin acid solution was filtered to obtain solution A.

[0057] Step 2, preparation of seed mixture: 5g of crude cefazolin acid is mixed with 60ml of water and 0.4g of triethylamine, stirred to dissolve, and filtered; the filtered solution is rapidly stirred under 40HZ ultrasonic conditions, and a quantitative 20% hydrochloric acid solution is quickly added, the pH value is adjusted to 1.8, and the temperature is controlled at 15°C; then the stirring speed is reduced and stirred for another 30min.

[0058] Step 3, crystallization: adding solution A and 20% hydrochloric acid solution to the seed mixture at the same time, controlling the pH value to 1.8; after adding solution A, growing the crystal for 30 minutes, continuing to add 20% hydrochloric acid solution, it takes 45 minutes, and the pH stabilizes to 1.5; growing the crystal for another 30 minutes; filtering, washing, and drying to obtain high-purity cefazolin acid powder.

[0059] Example 6

[0060] A method for purifying cefazolin acid comprises the following steps:

[0061] Step 1, preparation of solution A: 50 g of crude cefazolin acid was mixed with 600 ml of water and 8 g of triethylamine, dissolved, the temperature was controlled at 10° C., and the cefazolin acid solution was filtered to obtain solution A.

[0062] Step 2, preparation of seed mixture: 5g of crude cefazolin acid is mixed with 60ml of water and 0.4g of triethylamine, stirred to dissolve, and filtered; the filtered solution is rapidly stirred under 40HZ ultrasonic conditions, and a quantitative 20% hydrochloric acid solution is quickly added, the pH value is adjusted to 2.0, and the temperature is controlled at 20°C; then the stirring speed is reduced and stirred for another 30min.

[0063] Step 3, crystallization: adding solution A and 20% hydrochloric acid solution to the seed mixture at the same time, controlling the pH value to 2.0; after adding solution A, growing the crystal for 30 minutes, continuing to add 20% hydrochloric acid solution for 60 minutes, and stabilizing the pH to 1.5; growing the crystal for another 30 minutes; filtering, washing, and drying to obtain high-purity cefazolin acid powder.

[0064] In addition, the upper and lower limits and interval values ​​of the process parameters (such as time, pH value, temperature, etc.) of the present invention can all realize the present invention, and the embodiments are not listed one by one here.

[0065] Comparative Example 1

[0066] A method for purifying cefazolin acid comprises the following steps:

[0067] 50 g of cefazolin sodium that does not meet the quality requirements is mixed with 600 ml of water and 6 g of triethylamine, dissolved, the temperature is controlled at 5-20° C., and filtered to obtain a cefazolin sodium solution.

[0068] At 5-20° C., add 20% hydrochloric acid solution to the cefazolin sodium solution, slowly adjust the pH to 3.4-3.8 over 30-40 minutes to produce crystals, stop adding acid, and grow the crystals for 30 minutes; then adjust the pH to 1.5±0.1 with 20% hydrochloric acid, grow the crystals for 60 minutes, filter, wash, and dry to obtain cefazolin acid powder.

[0069] Comparative Example 2

[0070] A method for purifying cefazolin acid comprises the following steps:

[0071] 50 g of crude cefazolin acid was mixed with 600 ml of water and 8 g of triethylamine, dissolved, the temperature was controlled at 5-20° C., and the cefazolin acid solution was obtained by filtration.

[0072] At 5-20°C, add 20% hydrochloric acid solution to the cefazolin acid solution, slowly adjust the pH to 3.4-3.8 over 30-40 minutes to produce crystals, stop adding acid, and grow the crystals for 30 minutes; then adjust the pH to 1.5±0.1 with 20% hydrochloric acid, grow the crystals for 60 minutes, filter, wash, and dry to obtain cefazolin acid powder.

[0073] The cefazolin acid powders prepared in Examples 1-6 and Comparative Examples 1-2 were tested respectively, and the results are shown in Table 1 below:

[0074] Table 1 Comparison table of test results of cefazolin acid powder prepared in Examples and Comparative Examples

[0075]

[0076] As can be seen from Table 1 above, the content of cefazolin acid in the cefazolin acid powder prepared by the purification method of cefazolin acid provided by the present invention is all greater than 98%, the maximum unknown single impurity is all less than 0.2%, and the color grade is all less than 3. # , and the powders are shiny and not agglomerated. However, since the ultrafine equal-size seed crystal preparation technology and equal-low-concentration crystallization technology were not used in Comparative Examples 1 and 2, the quality of the prepared cefazolin acid powders was significantly lower than that of the cefazolin acid powders prepared in Examples 1-6.

[0077] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for purifying cefazolin acid, characterized in that: The following steps are involved: Step 1, preparation of solution A: mixing material A, water and triethylamine, dissolving, controlling the temperature, and filtering to obtain solution A; Step 2, preparation of seed mixture: 10% by weight of material A in solution A, 10% by weight of water in solution A and 5% by weight of triethylamine in solution A are mixed, stirred to dissolve, and filtered; the filtered solution is rapidly stirred under 40HZ ultrasonic conditions, hydrochloric acid solution is quickly added, the pH value is adjusted to less than 3, and the temperature is controlled; Then, the stirring speed is reduced and the mixture is stirred again to obtain a seed crystal mixture; Step 3, Crystallization: Add solution A and hydrochloric acid solution to the seed mixture at the same time, and control the pH value to be less than 3; After adding solution A, grow crystals, continue to add hydrochloric acid solution until the pH value is stabilized to less than 2; grow crystals again; filter, wash and dry to obtain high-purity cefazolin acid powder.

2. A method for purifying cefazolin acid according to claim 1, characterized in that: In step 1, material A is cefazolin sodium which does not meet the quality requirements.

3. A method for purifying cefazolin acid according to claim 2, characterized in that: In step 1, the mass volume ratio of material A to water is 1:12; the mass volume ratio of triethylamine to water is 1:

100.

4. A method for purifying cefazolin acid according to claim 1, characterized in that: In step 1, material A is crude cefazolin acid.

5. A method for purifying cefazolin acid according to claim 4, characterized in that: In solution A, the mass volume ratio of material A to water is 1:12; the mass volume ratio of triethylamine to water is 1:

75.

6. A method for purifying cefazolin acid according to claim 1, characterized in that: In step 1, the temperature is controlled at 0-10°C.

7. A method for purifying cefazolin acid according to claim 1, characterized in that: In step 2, the concentration of the hydrochloric acid solution is 20%; the pH value is adjusted to 1.5-2.0; the temperature is controlled at 10-20° C.; the stirring speed is reduced and the stirring is continued for another 30 minutes.

8. A method for purifying cefazolin acid according to claim 1, characterized in that: In step 3, the concentration of the hydrochloric acid solution is 20%; the pH value is controlled to be 1.5-2.

0.

9. A method for purifying cefazolin acid according to claim 1, characterized in that: In step 3, after adding solution A, the crystal was grown for 30 minutes.

10. The method for purifying cefazolin acid according to claim 1, characterized in that: In step 3, continue to add hydrochloric acid solution for 30-60 minutes until the pH stabilizes to 1.5; then grow the crystal for another 30 minutes.

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