CN110857307A - Preparation method of cefuroxime sodium for injection - Google Patents
Preparation method of cefuroxime sodium for injection Download PDFInfo
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- CN110857307A CN110857307A CN201810975640.2A CN201810975640A CN110857307A CN 110857307 A CN110857307 A CN 110857307A CN 201810975640 A CN201810975640 A CN 201810975640A CN 110857307 A CN110857307 A CN 110857307A
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- cefuroxime
- solution
- sodium
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- URDOHUPGIOGTKV-JTBFTWTJSA-M Cefuroxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 URDOHUPGIOGTKV-JTBFTWTJSA-M 0.000 title claims abstract description 59
- 229960000534 cefuroxime sodium Drugs 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000002347 injection Methods 0.000 title claims abstract description 20
- 239000007924 injection Substances 0.000 title claims abstract description 20
- 229960001668 cefuroxime Drugs 0.000 claims abstract description 60
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 claims abstract description 60
- 239000000243 solution Substances 0.000 claims abstract description 52
- 239000012296 anti-solvent Substances 0.000 claims abstract description 25
- 239000012043 crude product Substances 0.000 claims abstract description 19
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 239000000047 product Substances 0.000 claims abstract description 14
- 239000000725 suspension Substances 0.000 claims abstract description 10
- 239000012266 salt solution Substances 0.000 claims abstract description 5
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 5
- 230000001376 precipitating effect Effects 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 44
- 239000002904 solvent Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 9
- 229920001993 poloxamer 188 Polymers 0.000 claims description 9
- 229940044519 poloxamer 188 Drugs 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 6
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 6
- 230000007613 environmental effect Effects 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- URDOHUPGIOGTKV-BWTUWSSMSA-M sodium;(6r,7r)-3-(carbamoyloxymethyl)-7-[[2-(furan-2-yl)-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)C(=NOC)C1=CC=CO1 URDOHUPGIOGTKV-BWTUWSSMSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of cefuroxime sodium for injection, which comprises the following steps: converting the cefuroxime sodium crude product into a cefuroxime acid solution; precipitating the cefuroxime acid solution by a solvent-antisolvent to obtain a cefuroxime acid suspension; filtering the cefuroxime acid suspension to obtain a cefuroxime acid wet product; and dissolving the cefuroxime acid wet product, adding a sodium salt solution, adjusting the pH value, crystallizing and filtering to obtain the cefuroxime sodium for injection.
Description
Technical Field
The invention belongs to the technical field of medicine; relates to a preparation method of cefuroxime sodium, in particular to a preparation method of cefuroxime sodium for injection.
Background
Cefuroxime sodium is a second generation cephalosporin. The chemical name of cefuroxime sodium is: (6R,7R) -7- [ (2-Furan-2-yl) -2- (methoxyimino) acetamido ] -3-carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt having a molecular weight of 446.3. Cefuroxime sodium is white to pale yellow solid or crystalline powder, and is easily soluble in water. Cefuroxime sodium for injection and cefuroxime sodium raw materials have been collected in the second part of the pharmacopoeia of China, 2010 edition and 2015 edition.
Cefuroxime sodium has broad-spectrum antibacterial activity, is quite stable to β -lactamase generated by staphylococcus and gram-negative bacillus, 1-2mg/L can inhibit all staphylococcus aureus sensitive and resistant to penicillin, has stronger antibacterial activity to haemophilus influenzae, is sensitive to the cefuroxime sodium, escherichia coli and the like, has better distribution in various body fluids and tissue fluids, and can enter inflammatory cerebrospinal fluid.
However, cefuroxime sodium raw material is easily affected by environmental factors (pH value, temperature and illumination), and is easily degraded and polymerized after being stored for a long time or being placed, so that color change is caused, and impurities such as related substances and cefuroxime polymer are generated. In the mainstream view, these impurities are allergens causing allergic reactions of cefuroxime sodium drugs. Therefore, various means have been adopted to improve the purity of cefuroxime sodium as a raw material. Mainly comprises a dissolution crystallization method, a trans-acid and re-salt method and the like.
For example, the chinese patent application CN 101054386A discloses a method for purifying a cefuroxime sodium crude product, which comprises decolorizing an aqueous solution of cefuroxime sodium, and then precipitating crystals by dropping acetone, wherein the yield is 85%. However, the method has not strict control on the process conditions, and the purity of the cefuroxime sodium is not high.
Zhengyulin, et al (China journal of medicine 2009, 40, 34-36) disclose a trans-acid re-salting method. The method firstly changes the cefuroxime sodium crude product into cefuroxime acid, and then salifies to obtain the cefuroxime sodium. Active carbon is used for decoloring in the two-step reaction process, and cefuroxime sodium with qualified color can be obtained. However, the method has long operation time, low production efficiency and low yield. Meanwhile, the method adopts a distilled solvent and a high-temperature means in the process of preparing the cefuroxime acid, so that the cefuroxime sodium is easy to degrade and polymerize, and the purity is still not high.
However, the above-mentioned means still cannot solve the problem of impurities generated by environmental factors after long-term storage or storage of cefuroxime sodium.
According to the literature, the degradation and polymerization behavior of cefuroxime sodium is closely related to the temperature and time during the crystallization process of cefuroxime sodium or its intermediate.
On the other hand, there are increasing reports of microchannel reactors in the preparation of nanoparticles. Compared with the conventional reaction system, the microchannel reactor has incomparable advantages of high mass transfer rate, rapid and uniform mixing, narrow residence time distribution and the like. However, the microchannel reactor is mainly used to control the size of nanoparticles and their distribution, and is less reported to be used in a purification process of drugs.
Therefore, there is a need to find a method for preparing cefuroxime sodium for injection, which can further reduce the operation temperature and time during the purification process of the cefuroxime sodium crude product, thereby improving the yield and purity of cefuroxime sodium.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of cefuroxime sodium for injection, which has high yield and purity.
In order to achieve the above objects, in one aspect, the present invention provides a method for preparing cefuroxime sodium for injection, which comprises:
(1) converting the cefuroxime sodium crude product into a cefuroxime acid solution;
(2) precipitating the cefuroxime acid solution by a solvent-antisolvent to obtain a cefuroxime acid suspension;
(3) filtering the cefuroxime acid suspension to obtain a cefuroxime acid wet product; and the number of the first and second groups,
(4) dissolving the cefuroxime acid wet product, adding a sodium salt solution, adjusting the pH value, crystallizing and filtering to obtain the cefuroxime sodium for injection.
The preparation method comprises the following steps of (1): dissolving the cefuroxime sodium crude product in acetone to prepare a solution of 1.5-4.5 mg/mL; adding acid to adjust the pH value to 1.5-3.0; adding 0.4-1.8wt% of activated carbon into the solution, and keeping the temperature at room temperature for decoloring for 15-60 min; filtering to obtain the cefuroxime acid solution.
According to the preparation method of the present invention, the HPLC purity of the cefuroxime sodium crude product is not less than 97.0%, preferably not less than 97.5%, and more preferably not less than 98.0%. The acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid, preferably selected from the group consisting of hydrochloric acid and sulfuric acid, more preferably selected from the group consisting of hydrochloric acid.
In the present invention, room temperature means 20 to 30 ℃, preferably 22 to 28 ℃, and more preferably 23 to 27 ℃.
In a specific embodiment, room temperature represents 25 ℃.
Preferably, step (1) is: dissolving the cefuroxime sodium crude product in acetone to prepare a solution of 2.0-4.0 mg/mL; adding acid to adjust the pH value to 1.8-2.6; adding 0.6-1.6wt% of activated carbon into the solution, and keeping the temperature at room temperature for decoloring for 20-50 min; filtering to obtain the cefuroxime acid solution.
More preferably, step (1) is: dissolving the cefuroxime sodium crude product in acetone to prepare a solution of 2.5-3.5 mg/mL; adding acid to adjust the pH value to 2.0-2.4; adding 0.8-1.2wt% of activated carbon into the solution, and keeping the temperature at room temperature for decoloring for 25-45 min; filtering to obtain the cefuroxime acid solution.
In a specific embodiment, step (1) is: dissolving the cefuroxime sodium crude product in acetone to prepare a solution of 3 mg/mL; adding acid to adjust the pH value to 2.2; adding 1.0wt% of activated carbon into the solution, and keeping the temperature and decoloring for 30min at room temperature; filtering to obtain the cefuroxime acid solution.
The preparation method of the invention, wherein the step (2) is carried out by using a Y-type micromixer.
The preparation method of the invention is characterized in that the specification of the Y-shaped micro mixer is L =50 mm; w =1 mm; h =0.5mm and the inlet angle is 60 °.
In one specific embodiment, the Y-type micromixer is from guizhou micromechelon co.
The preparation method of the invention, wherein the solvent in step (2) is the cefuroxime acid solution in step (1).
The preparation method provided by the invention is characterized in that the antisolvent in the step (2) is 0.1-0.6mg/mL of poloxamer 188 aqueous solution. Preferably, the antisolvent in step (2) is 0.2-0.5mg/mL of poloxamer 188 in water. More preferably, the antisolvent in step (2) is 0.3-0.4mg/mL of poloxamer 188 in water.
In a specific embodiment, the antisolvent of step (2) is 0.35mg/mL of poloxamer 188 in water.
The preparation method comprises the following steps (2): the flow rate of the solvent is 6-18mL/min, and the flow rate ratio of the solvent to the anti-solvent is 1 (12-20).
Preferably, the flow rate of the solvent is 8-16mL/min, and the flow rate ratio of the solvent to the anti-solvent is 1 (14-18). More preferably, the flow rate of the solvent is 10-14mL/min, and the flow rate ratio of the solvent to the anti-solvent is 1 (15-17).
In a specific embodiment, the solvent flow is 12mL/min and the ratio of solvent to anti-solvent flow is 1: 16.
The production method according to the present invention, wherein the step (2) is carried out at a temperature of 0 to 25 ℃.
Preferably, step (2) is carried out at a temperature of 1-20 ℃. More preferably, step (2) is carried out at a temperature of 2-8 ℃.
In a particular embodiment, step (2) is carried out at a temperature of 5 ℃.
The preparation method comprises the following steps (3): the suspension of cefuroxime acid is filtered and washed with water several times to obtain a wet cefuroxime acid product.
According to the preparation method of the invention, in the step (4), the cefuroxime acid wet product is dissolved by using acetone to obtain 5-10mg/L of cefuroxime acid solution. Preferably, the cefuroxime acid wet product is dissolved by using acetone to obtain a cefuroxime acid solution of 6-9 mg/L. More preferably, the wet cefuroxime acid solution is dissolved in acetone to obtain 7-8mg/L of cefuroxime acid solution.
In a specific embodiment, in step (4), the cefuroxime acid wet product is dissolved by using acetone to obtain 7.5mg/L of cefuroxime acid solution.
The preparation method is characterized in that the sodium salt solution is a solution of sodium isooctanoate in 1:1 acetone and isopropanol.
The preparation method according to the present invention, wherein, in the step (4), the pH is 6.5 to 8.5. Preferably, the pH value is 6.5-8.0; more preferably, the pH is 6.5-7.5.
In a specific embodiment, in step (4), the pH is 7.0.
The inventor finds that when a Y-type micro mixer is used for solvent-antisolvent precipitation, the obtained cefuroxime acid has high yield, the purity of cefuroxime sodium is obviously improved, and the content of related substances is reduced. Without wishing to be bound by any theory, the micromixing process used in the present invention and the particular solvent and anti-solvent have a significant effect on the improvement of cefuroxime acid yield and purity of the present invention. The content of impurities generated after the cefuroxime sodium for injection is subjected to the action of environmental factors after being stored and placed for a long time is still within an allowable range.
Compared with the prior art, the invention has the following beneficial technical effects:
i) the cefuroxime sodium for injection has higher yield and purity.
ii) the content of the related substances produced by the cefuroxime sodium for injection after long-term storage and standing under the action of environmental factors is still within the allowable range.
iii) the preparation method is simple and easy to implement, has good repeatability, and does not need other auxiliary materials; the equipment cost is low and no pollution is caused; can generate huge social benefit and economic benefit, and is suitable for being widely popularized and used.
Detailed Description
The invention will be further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications can be made by those skilled in the art after reading the contents of the present invention, and those equivalents also fall within the scope of the invention defined by the appended claims.
The following examples will aid understanding of the present invention, but are not intended to limit the scope of the present invention. In each example, the water used was purified water, and the purity of the starting material was not indicated as being chromatographically pure.
Example 1:
the HPLC purity of the cefuroxime sodium crude product is 98.0%. Dissolving the cefuroxime sodium crude product in acetone to prepare a solution of 3 mg/mL; adding hydrochloric acid to adjust the pH value to 2.2; adding 1.0wt% of activated carbon into the solution, and keeping the temperature at 25 ℃ for decoloring for 30 min; filtering to obtain the cefuroxime acid solution. The cefuroxime acid solution is used as a solvent, and poloxamer 188 aqueous solution of 0.35mg/mL is used as an antisolvent, and the solvent-antisolvent precipitation is carried out in a Y-type micromixer of a Guizhou micromechelon Co. The specification of the Y-shaped micro mixer is L =50 mm; w =1 mm; h =0.5mm and the inlet angle is 60 °. The flow rate of the solvent is 12mL/min, and the flow rate ratio of the solvent to the anti-solvent is 1: 16; at a temperature of 5 ℃. Then, the suspension of cefuroxime acid was filtered and washed with water several times to obtain a wet cefuroxime acid product. Subsequently, the wet cefuroxime acid solution was dissolved in acetone to obtain a 7.5mg/L solution of cefuroxime acid. Adding a solution of sodium isooctanoate in 1:1 acetone and isopropanol, adjusting the pH value to 7.0 by using sodium acetate, crystallizing and filtering to obtain the cefuroxime sodium for injection.
Example 2:
the HPLC purity of the cefuroxime sodium crude product is 98.2%. Dissolving the cefuroxime sodium crude product in acetone to prepare a solution of 2.5 mg/mL; adding hydrochloric acid to adjust the pH value to 2.0; adding 1.2wt% of activated carbon into the solution, and keeping the temperature at 25 ℃ for decoloring for 30 min; filtering to obtain the cefuroxime acid solution. The cefuroxime acid solution is used as a solvent, and poloxamer 188 aqueous solution with the concentration of 0.4mg/mL is used as an antisolvent, and the solvent-antisolvent precipitation is carried out in a Y-type micromixer with the model of MCT micromixer of Guizhou Minichi technology Co. The specification of the Y-shaped micro mixer is L =50 mm; w =1 mm; h =0.5mm and the inlet angle is 60 °. The flow rate of the solvent is 14mL/min, and the flow rate ratio of the solvent to the anti-solvent is 1: 17; at a temperature of 5 ℃. Then, the suspension of cefuroxime acid was filtered and washed with water several times to obtain a wet cefuroxime acid product. Subsequently, the wet cefuroxime acid solution was dissolved in acetone to obtain an 8mg/L solution of cefuroxime acid. Adding a solution of sodium isooctanoate in 1:1 acetone and isopropanol, adjusting the pH value to 6.6 by using sodium acetate, crystallizing and filtering to obtain the cefuroxime sodium for injection.
Example 3:
the HPLC purity of the cefuroxime sodium crude product is 98.1%. Dissolving the cefuroxime sodium crude product in acetone to prepare a solution of 3.5 mg/mL; adding hydrochloric acid to adjust the pH value to 2.7; adding 1.0wt% of activated carbon into the solution, and keeping the temperature at 25 ℃ for decoloring for 30 min; filtering to obtain the cefuroxime acid solution. The cefuroxime acid solution is used as a solvent, and poloxamer 188 aqueous solution with the concentration of 0.3mg/mL is used as an antisolvent, and the solvent-antisolvent precipitation is carried out in a Y-type micromixer with the model of MCT micromixer of Guizhou Minichi technology Co. The specification of the Y-shaped micro mixer is L =50 mm; w =1 mm; h =0.5mm and the inlet angle is 60 °. The flow rate of the solvent is 10mL/min, and the flow rate ratio of the solvent to the anti-solvent is 1: 15; at a temperature of 5 ℃. Then, the suspension of cefuroxime acid was filtered and washed with water several times to obtain a wet cefuroxime acid product. Subsequently, the wet cefuroxime acid solution was dissolved in acetone to obtain a 7mg/L solution of cefuroxime acid. Adding a solution of sodium isooctanoate in 1:1 acetone and isopropanol, adjusting the pH value to 7.4 by using sodium acetate, crystallizing and filtering to obtain the cefuroxime sodium for injection.
Comparative example 1:
the solvent-anti-solvent precipitation was performed in a 500mL beaker, and the conditions were the same as in example 1.
Comparative example 2:
the same procedure as in example 1 was repeated except that the 0.35mg/mL aqueous solution of poloxamer 188 as used in example 1 was replaced with an equal amount of deionized water.
The cefuroxime sodium for injection of examples 1-3 and comparative examples 1-2 was used to determine the content of the related substances according to the test method of the second part of the pharmacopoeia 2015, page 261 and 263.
The results of the relevant tests are shown in tables 1 and 2 below:
TABLE 1 Performance index at day 0
| Yield/% | Maximum single impurity/%) | Total impurity content/%) | |
| Example 1 | 96 | 0.13 | 0.47 |
| Example 2 | 94 | 0.13 | 0.53 |
| Example 3 | 94 | 0.14 | 0.56 |
| Comparative example 1 | 81 | 0.26 | 0.74 |
| Comparative example 2 | 92 | 0.19 | 0.61 |
TABLE 2 Performance index at day 10
| Maximum single impurity/%) | Total impurity content/%) | |
| Example 1 | 0.22 | 0.62 |
| Example 2 | 0.24 | 0.65 |
| Example 3 | 0.27 | 0.71 |
| Comparative example 1 | 0.43 | 0.97 |
| Comparative example 2 | 0.31 | 0.86 |
As can be seen from tables 1 and 2, the cefuroxime sodium for injection of examples 1 to 3 of the present invention has higher yield and purity than those of comparative examples 1 to 2; and the content of the related substances generated after being subjected to the action of environmental factors after being stored and placed for a long time is still within the allowable range.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (10)
1. A method for preparing cefuroxime sodium for injection, which comprises the following steps:
(1) converting the cefuroxime sodium crude product into a cefuroxime acid solution;
(2) precipitating the cefuroxime acid solution by a solvent-antisolvent to obtain a cefuroxime acid suspension;
(3) filtering the cefuroxime acid suspension to obtain a cefuroxime acid wet product; and the number of the first and second groups,
(4) dissolving the cefuroxime acid wet product, adding a sodium salt solution, adjusting the pH value, crystallizing and filtering to obtain the cefuroxime sodium for injection.
2. The production method according to claim 1, wherein the step (1) is: dissolving the cefuroxime sodium crude product in acetone to prepare a solution of 1.5-4.5 mg/mL; adding acid to adjust the pH value to 1.5-3.0; adding 0.4-1.8wt% of activated carbon into the solution, and keeping the temperature at room temperature for decoloring for 15-60 min; filtering to obtain the cefuroxime acid solution.
3. The preparation method according to claim 2, wherein the HPLC purity of the cefuroxime sodium crude product is not less than 97.0%.
4. The production method according to claim 1, wherein the step (2) is performed using a Y-type micromixer.
5. The preparation method according to claim 4, wherein the specification of the Y-type micromixer is L =50 mm; w =1 mm; h =0.5mm and the inlet angle is 60 °.
6. The preparation method according to claim 1, wherein the solvent of step (2) is the cefuroxime acid solution of step (1); the antisolvent is 0.1-0.6mg/mL poloxamer 188 aqueous solution.
7. The preparation method according to claim 6, wherein the flow rate of the solvent is 6-18mL/min, and the flow rate ratio of the solvent to the anti-solvent is 1 (12-20).
8. The process according to claim 1, wherein in the step (4), the cefuroxime acid wet product is dissolved in acetone to obtain 5-10mg/L of cefuroxime acid solution.
9. The method of claim 1, wherein the sodium salt solution is a solution of sodium isooctanoate in 1:1 acetone and isopropanol.
10. The method according to claim 1, wherein the pH is 6.5 to 8.5.
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