Refining method of biapenem crude product

Abstract

The invention relates to a biapenem crude product refining method, which comprises: adding a biapenem crude product into water for injection, stirring to dissolve, adding an acetic acid aqueous solution, adding active carbon, decolorizing, filtering, adding a seed crystal, crystallizing, filtering, washing, and drying under reduced pressure to obtain a biapenem refined product. The prepared product is short in redissolution time, low in residual solvent content, high in purity, good in stability and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a method for refining crude biapenem. Background Art

[0002] Biapenem, English name: biapenem, is a 1β-methylcarbapenem antibiotic. It was developed by Lederle Company of Japan and Cyanamid Company of the United States in 1989, and was jointly launched in Japan by Lederle Company of Japan and Meiji Co., Ltd. of Japan in March 2002. It was first launched in China in 2008. Clinically, it is widely used in the treatment of acute and chronic infections caused by Gram-negative aerobic bacteria and Gram-positive aerobic bacteria. Its activity against Gram-negative bacteria is superior to that of imipenem, and its activity against Gram-positive bacteria is similar to that of imipenem. It has good curative effects on orthopedic surgery infections, gynecological infections and otorhinolaryngological infections.

[0003] The chemical name of biapenem is: (-)-6-[(4R,5S,6S)-2-thiol-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-3-yl]-thio-[6,7-dihydro-5H-pyrazolo[1,2-a]]-[1,2,4]triazolium inner salt, and its structural formula is as follows:

[0004]

[0005] Currently, the commonly used method for preparing biapenem is to dissolve the crude biapenem in purified water and precipitate the biapenem solid using ethanol or acetone. However, these methods have problems such as long product redissolution time, low product purity, and inconvenient operation.

[0006] Patent CN201110424832.2 discloses a method for preparing biapenem crystals. In Example 3, 10 g of crude biapenem was put into 500 ml of injection water (temperature controlled at 5-15°C), stirred, and completely dissolved. Then, 2 g of activated carbon was added, and the mixture was stirred and decolorized for 40 min. After filtering the solution, 3000 ml of a mixed solution of ethanol:acetone = 2:1 was added under stirring, and the temperature was controlled at (5-15°C) for crystallization for 3 h, and then dried to obtain white crystals. The product prepared by this method has a relatively long redissolution time. At a concentration of 0.15 g / ml, it takes 90-120 s to completely dissolve.

[0007] Patent CN201310586616.7 discloses a preparation process of biapenem. In step 5 of Example 1, the purification method of biapenem is disclosed: in a sterile environment, 60 ml of deionized water and 8.0 g of biapenem are added to a 100 ml round-bottom flask, heated with stirring until dissolved, 0.5 g of activated carbon is added for decolorization, dissolved, filtered while hot, and then filtered through a 0.22 μm organic filter membrane. The filtrate is cooled to room temperature, stirred, 30 ml of ethanol is added for crystallization, and cooled in an ice bath. Filtered, the solid is washed with a small amount of frozen ethanol, and dried in vacuo at 50 °C to obtain 5.80 g of refined biapenem product with a yield of 72.5%. The yield of the refined biapenem product prepared by this method is low, which is not conducive to cost control.

[0008] Patent WO2014097221A1 discloses a purification method of biapenem. Example 1 discloses the purification method of biapenem: 12 g of biapenem is added to 300 ml of water at 65 °C, stirred for 5 min, cooled to 30 °C in 10 min, 0.6 g of activated carbon is added, stirred for 10 - 15 min, and the temperature is maintained at 25 - 30 °C. The reaction mixture is filtered through a fluidized bed and washed with 36 ml of water. The filtrate is filtered through a 0.45 μm filter membrane, and the pH is adjusted to 5.5 with 5% sodium hydroxide solution at a temperature of 5 - 10 °C. 336 ml of acetone is added, stirred for 3 h, filtered, washed with 60 ml of acetone, and dried under reduced pressure at 30 - 35 °C to obtain a white crystalline product. The dissolution temperature of this method is relatively high, which easily causes product degradation, thereby reducing the product purity.

[0009] In order to overcome the problems existing in the prior art, it is necessary to further optimize the purification process of biapenem, improve the yield and purity of biapenem, and at the same time maintain good stability of the product to meet the pharmaceutical requirements. Summary of the Invention

[0010] Aiming at the deficiencies of the prior art, the present invention provides a purification method for crude biapenem. By adopting the methods of reverse precipitation and staged crystallization, the prepared product has small crystal particle size, less solvent residue, short redissolution time, high yield and high purity.

[0011] To solve the above technical problems, the present invention provides the following technical solutions:

[0012] The present invention provides a purification method for crude biapenem, including the following steps:

[0013] S1. Temperature control: Add crude biapenem to water for injection and stir to dissolve.

[0014] S2. Temperature control: Add acetic acid aqueous solution to the solution, then add activated carbon, and stir for decolorization for 30 min.

[0015] S3. Filter through a 0.22 μm filter membrane, and cool the filtrate for standby.

[0016] S4. Add seed crystals to the crystallization solvent, control the temperature, slowly add the above-mentioned filtrate, with the addition time being 60 - 120 min, and keep warm for crystallization after addition.

[0017] S5. After the crystallization is completed, continue to slowly add the crystallization solvent, with the addition time being 20 - 60 min, and control the temperature for crystallization after addition.

[0018] S6. Filter, wash, and dry under reduced pressure to obtain the refined product of biapenem.

[0019] Preferably, in step S1, the mass - to - volume ratio of the crude biapenem to water for injection is 1:30 - 70 g / ml, preferably 1:60 g / ml; the temperature of the water for injection is 10 - 35°C; the stirring and dissolving time is 30 min.

[0020] Preferably, in step S2, the mass ratio of activated carbon to the crude biapenem is 0.05 - 0.15:1, the concentration of the acetic acid aqueous solution is 2.2%; keep the temperature of the feed liquid at 10 - 35°C.

[0021] Preferably, in step S3, the temperature of the filtrate is controlled at 5 - 20°C.

[0022] Preferably, in step S4, the crystallization solvent is one of acetone and absolute ethanol. Further preferably, the crystallization solvent in step S4 is absolute ethanol; the volume - to - mass ratio of the crystallization solvent to the crude biapenem is 20 - 50:1 ml / g. Further preferably, the volume - to - mass ratio of the crystallization solvent to the crude biapenem in step S4 is 35:1 ml / g; control the crystallization temperature at 10 - 25°C; control the crystallization time at 60 - 90 min.

[0023] Preferably, in step S5, the crystallization solvent is one of acetone and absolute ethanol. Further preferably, the crystallization solvent in step S5 is absolute ethanol; the volume - to - mass ratio of the crystallization solvent to the crude biapenem is 50 - 150:1 ml / g; control the crystallization temperature at 10 - 25°C; control the crystallization time at 60 - 90 min.

[0024] Compared with the prior art, the present invention has the following beneficial technical effects:

[0025] (1) By optimizing the refining process of biapenem, the present invention adopts a reverse crystallization method of slowly adding the feed liquid to the crystallization solvent, with staged crystallization, which is easy to control the crystal morphology. The obtained product has small crystal particle size, can reduce the solvent residue of the product, and improve the product purity.

[0026] (2) The product prepared by the method of the present invention has a short re - dissolution time, high purity, and good stability, and is suitable for industrial production. Specific embodiments

[0027] The following further elaborates on the content of the present invention through specific embodiments, but does not limit the content of the present invention thereby.

[0028] Source of the crude biapenem raw material: selected from the products of Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co., Ltd.

[0029] The method for preparing the seed crystal in the embodiment is prepared by the method of Example 1.

[0030] Example 1

[0031] S1. While controlling the temperature at 10 - 35°C, add 5 g of the crude biapenem to 300 ml of water for injection and stir for 30 min until the solid is completely dissolved;

[0032] S2. While controlling the temperature at 10 - 35°C, add 5 ml of 2.2% aqueous acetic acid solution to the solution, then add 0.25 g of activated carbon, and stir for decolorization for 30 min;

[0033] S3. Filter through a 0.22 - μm filter membrane, and cool the filtrate to 5 - 20°C for standby;

[0034] S4. Add 0.02 g of seed crystal to 175 ml of absolute ethanol, control the temperature at 10 - 15°C, slowly add the above - mentioned filtrate, and the addition time is 60 - 120 min. After adding, keep the temperature at 10 - 15°C for crystallization for 60 min;

[0035] S5. After the crystallization is completed, continue to slowly add 525 ml of absolute ethanol, and the addition time is 20 - 60 min. After adding, control the temperature at 10 - 15°C for crystallization for 60 min;

[0036] S6. After the crystallization is completed, filter, wash the filter cake with 300 ml of absolute ethanol, collect the filter cake and dry it to obtain 4.1 g of refined biapenem, with a yield of 82.0% and a purity of 99.82%.

[0037] Example 2

[0038] S1. While controlling the temperature at 10 - 35°C, add 8 g of the crude biapenem to 240 ml of water for injection and stir for 30 min until the solid is completely dissolved;

[0039] S2. While controlling the temperature at 10 - 35°C, add 8 ml of 2.2% aqueous acetic acid solution to the solution, then add 1.2 g of activated carbon, and stir for decolorization for 30 min;

[0040] S3. Filter through a 0.22 - μm filter membrane, and cool the filtrate to 5 - 20°C for standby;

[0041] S4. Add 0.04 g of seed crystals to 160 ml of absolute ethanol, control the temperature at 20 - 25 °C, slowly add the above filtrate over 60 - 120 min, and after addition, keep the temperature at 20 - 25 °C for crystallization for 90 min;

[0042] S5. After crystallization, continue to slowly add 400 ml of absolute ethanol over 20 - 60 min, and after addition, control the temperature at 20 - 25 °C for crystallization for 90 min;

[0043] S6. After crystallization, filter, wash the filter cake with 500 ml of absolute ethanol, collect the filter cake and dry it to obtain 6.9 g of faropenem sodium refined product, with a yield of 86.3% and a purity of 99.91%.

[0044] Example 3

[0045] S1. Control the temperature at 10 - 35 °C, add 10 g of faropenem sodium crude product to 700 ml of water for injection, and stir for 30 min until the solid is completely dissolved;

[0046] S2. Control the temperature at 10 - 35 °C, add 11 ml of 2.2% acetic acid aqueous solution to the solution, then add 1.0 g of activated carbon, and stir for decolorization for 30 min;

[0047] S3. Filter through a 0.22 μm filter membrane, and cool the filtrate to 5 - 20 °C for standby;

[0048] S4. Add 0.05 g of seed crystals to 500 ml of absolute ethanol, control the temperature at 15 - 20 °C, slowly add the above filtrate over 60 - 120 min, and after addition, keep the temperature at 15 - 20 °C for crystallization for 90 min;

[0049] S5. After crystallization, continue to slowly add 1500 ml of absolute ethanol over 20 - 60 min, and after addition, control the temperature at 15 - 20 °C for crystallization for 90 min;

[0050] S6. After crystallization, filter, wash the filter cake with 600 ml of absolute ethanol, collect the filter cake and dry it to obtain 8.6 g of faropenem sodium refined product, with a yield of 86.0% and a purity of 99.81%.

[0051] Example 4

[0052] S1. Control the temperature at 10 - 35 °C, add 5 g of faropenem sodium crude product to 300 ml of water for injection, and stir for 30 min until the solid is completely dissolved;

[0053] S2. Control the temperature at 10 - 35 °C, add 5 ml of 2.2% acetic acid aqueous solution to the solution, then add 0.25 g of activated carbon, and stir for decolorization for 30 min;

[0054] S3. Filter through a 0.22 μm filter membrane, and cool the filtrate to 5 - 20 °C for standby;

[0055] S4. Add 0.02 g of seed crystals to 175 ml of acetone, control the temperature at 10 - 15 °C, slowly add the above-mentioned filtrate, with the addition time taking 60 - 120 min. After adding, keep the temperature at 10 - 15 °C for crystallization for 60 min;

[0056] S5. After the crystallization is completed, continue to slowly add 525 ml of acetone, with the addition time taking 20 - 60 min. After adding, control the temperature at 10 - 15 °C for crystallization for 60 min;

[0057] S6. After the crystallization is completed, filter, wash the filter cake with 300 ml of acetone, collect the filter cake and dry it to obtain 3.92 g of faropenem sodium refined product, with a yield of 78.4% and a purity of 99.96%.

[0058] Test Example 1: Comparison of reconstitution time

[0059] Table 1 Results of comparison of reconstitution time

[0060]

[0061] The test results show that the reconstitution time of the sample prepared by the present invention is greatly shortened.

[0062] Test Example 2: Comparison of related substances

[0063] Table 2 Results of comparison of related substances

[0064]

[0065] Note: "N.D." represents not detected, and " / " represents not tested.

[0066] The test results show that the total impurity content and solvent residue of the product prepared by the present invention are relatively low.

[0067] Test Example 3: Stability test

[0068] The impurity situation of the faropenem sodium refined product prepared in Example 1 of the present invention after being placed at high temperature (40 °C) for 6 months is as follows in Table 3:

[0069] Table 3 Results of stability test

[0070]

[0071] The test results show that the product prepared by the present invention has high stability.

[0072] The embodiments described above are some, but not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claims of the present invention, but merely represents selected embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention.

Claims

1. A method for refining crude faropenem, characterized in that, It includes the following steps: S1. Control the temperature and add the crude product of biapenem into water for injection and stir to dissolve; S2. Control the temperature, add acetic acid aqueous solution into the solution, then add activated carbon, and stir for decolorization for 30 min; S3. Filter through a 0.22 μm filter membrane, and cool the filtrate for standby; S4. Add crystal seeds into the crystallization solvent, control the temperature, slowly add the above-mentioned filtrate, with the addition time of 60 - 120 min, and keep warm for crystallization after adding; S5. After the crystallization is completed, continue to slowly add the crystallization solvent, with the addition time of 20 - 60 min, and control the temperature for crystallization after adding; S6. Filter, wash, and dry under reduced pressure to obtain the refined product of biapenem.

2. The refining method according to claim 1, wherein In step S1, the mass - volume ratio of the crude product of biapenem to water for injection is 1:30 - 70 g / ml; the temperature of the water for injection is 10 - 35°C; the stirring and dissolving time is 30 min.

3. According to the refining method described in claim 2, the mass - volume ratio of the crude product of biapenem to water for injection in step S1 is 1:60 g / ml.

4. The refining method according to claim 1, characterized in that, In step S2, the mass ratio of the activated carbon to the crude product of biapenem is 0.05 - 0.15:1; the concentration of the acetic acid aqueous solution is 2.2%; keep the temperature of the material liquid at 10 - 35°C.

5. The refining method according to claim 1, wherein, In step S3, control the temperature of the filtrate to 5 - 20°C.

6. The refining method according to claim 1, wherein, In step S4, the crystallization solvent is one of acetone or absolute ethanol; the volume - mass ratio of the crystallization solvent to the crude product of biapenem is 20 - 50:1 ml / g; control the crystallization temperature to 10 - 25°C; the crystallization time is 60 - 90 min.

7. The refining method according to claim 6, characterized in that, In step S4, the crystallization solvent is absolute ethanol.

8. The refining method according to claim 6, characterized in that, In step S4, the volume - mass ratio of the crystallization solvent to the crude product of biapenem is 35:1 ml / g.

9. The refining method according to claim 1, characterized in that, In step S5, the crystallization solvent is one of acetone or absolute ethanol; the volume - mass ratio of the crystallization solvent to the crude product of biapenem is 50 - 150:1 ml / g; control the crystallization temperature to 10 - 25°C; control the crystallization time to 60 - 90 min.

10. The refining method according to claim 9, characterized in that, In step S5, the crystallization solvent is absolute ethanol.

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