CN111777625A - Preparation method of ceftizoxime sodium for injection - Google Patents
Preparation method of ceftizoxime sodium for injection Download PDFInfo
- Publication number
- CN111777625A CN111777625A CN202010506830.7A CN202010506830A CN111777625A CN 111777625 A CN111777625 A CN 111777625A CN 202010506830 A CN202010506830 A CN 202010506830A CN 111777625 A CN111777625 A CN 111777625A
- Authority
- CN
- China
- Prior art keywords
- ceftizoxime
- sodium
- preparation
- solution
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960000636 ceftizoxime sodium Drugs 0.000 title claims abstract description 72
- ADLFUPFRVXCDMO-LIGXYSTNSA-M ceftizoxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=CCS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 ADLFUPFRVXCDMO-LIGXYSTNSA-M 0.000 title claims abstract description 72
- 238000002347 injection Methods 0.000 title claims abstract description 49
- 239000007924 injection Substances 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 56
- 239000000243 solution Substances 0.000 claims abstract description 54
- 239000013078 crystal Substances 0.000 claims abstract description 42
- 229960001991 ceftizoxime Drugs 0.000 claims abstract description 40
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 claims abstract description 40
- 239000002253 acid Substances 0.000 claims abstract description 39
- 239000000843 powder Substances 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 24
- 239000008213 purified water Substances 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000011780 sodium chloride Substances 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 239000007853 buffer solution Substances 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 238000004806 packaging method and process Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims abstract description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 18
- 239000001632 sodium acetate Substances 0.000 claims description 18
- 235000017281 sodium acetate Nutrition 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000007974 sodium acetate buffer Substances 0.000 claims description 9
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000002425 crystallisation Methods 0.000 description 16
- 230000008025 crystallization Effects 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000007599 discharging Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000011146 sterile filtration Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010005940 Bone and joint infections Diseases 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- -1 methoxyimino Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000019206 urinary tract infection Diseases 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
-
- 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 relates to a preparation method of ceftizoxime sodium for injection, belonging to the technical field of medicines. The method comprises the following steps: (a) reducing the temperature of the purified water to 0-5 ℃; adding ceftizoxime acid into purified water, and adding a buffer solution; (b) adding a salt forming agent into the solution obtained in the step (a), controlling the temperature to be 0-5 ℃, and stirring until the solution is clear; (c) adding sodium chloride into the solution obtained in the step (b), and stirring until the solution is clear; (d) adding activated carbon into the filtrate obtained in the step (c) for decoloring, and filtering after decoloring; (e) controlling the temperature of the solution obtained in the step (d) to be 13-15 ℃, adding ethanol for the first time, then adding ceftizoxime sodium seed crystal, growing crystals, adding ethanol again after a large amount of crystals are produced, cooling, continuing to grow crystals, filtering, washing and drying to obtain ceftizoxime sodium powder; (f) and (e) aseptically packaging the ceftizoxime powder obtained in the step (e) to obtain the ceftizoxime sodium powder injection for injection. The product is easy for packaging powder injection.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of ceftizoxime sodium for injection.
Background
Ceftizoxime sodium was first marketed in japan in 1982 under the trade name Ceftizox, the third generation of cephalosporin antibiotics developed by japan tenuzolk chemical industries, ltd. It is commonly used as third generation cephalosporin antibiotics. The traditional Chinese medicine composition is clinically used for treating lower respiratory tract infection, urinary tract infection, abdominal cavity infection, pelvic cavity infection, septicemia, skin soft tissue infection, bone and joint infection, meningitis caused by streptococcus pneumoniae or haemophilus influenzae and simple gonorrhea caused by sensitive bacteria. The chemical name is as follows: (6R,7R) -7- [ [2, 3-dihydro-2-imino-4-thiazolyl) (methoxyimino) acetyl ] amino ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt. The structural formula is as follows:
the synthesis preparation of ceftizoxime sodium and the purification process of the product are more, but the sterile crystallization preparation process of ceftizoxime sodium for injection is not introduced much, and the methods introduced in the patent and literature mainly comprise the following steps:
the patent "a method for refining ceftizoxime sodium" (CN109553626A) provides ceftizoxime sodium prepared by adding concentrated hydrochloric acid and sodium bicarbonate into ceftizoxime acid, the product has poor color grade, and various solvents are used in the crystallization process, so that the solvents are not beneficial to recycling; the patent of new ceftizoxime sodium crystal form for reducing anaphylactic reaction and a preparation thereof (CN105622635A) also has the problem that the crystallization of various solvents is difficult to recover.
The ceftizoxime sodium product prepared by the patents of a ceftizoxime sodium preparation and refining method (CN102911186A) and a ceftizoxime sodium preparation method (CN102807573A) also has the problem of poor color grade; meanwhile, the product purity is low, and the medication safety is influenced.
The patent (CN102079750A) provides a method for converting ceftizoxime sodium into ceftizoxime acid and then converting the ceftizoxime acid into ceftizoxime sodium, and the method has the advantages of complex process and high production cost. The same patent of high-purity ceftizoxime sodium and a preparation method thereof (CN101348492A) also has the problem of complex process.
A process for preparing ceftizoxime sodium (CN102603771A) features that sodium hydroxide is used as salt-forming agent, and the dissolving procedure is performed at high pH value to destroy the structure of product and influence its quality, resulting in high content of impurities.
Disclosure of Invention
The invention aims to provide a preparation method of ceftizoxime sodium for injection, which is a method for preparing ceftizoxime sodium for injection by using single solvent crystallization.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of ceftizoxime sodium for injection comprises the following steps:
(a) reducing the temperature of the purified water to 0-5 ℃; adding ceftizoxime acid into purified water, and adding a buffer solution;
(b) adding a salt forming agent into the solution obtained in the step (a), controlling the temperature to be 0-5 ℃, and stirring until the solution is clear;
(c) adding sodium chloride into the solution obtained in the step (b), and stirring until the solution is clear;
(d) adding activated carbon into the solution obtained in the step (c) for decoloring, and filtering after decoloring;
(e) controlling the temperature of the filtrate obtained in the step (d) to be 13-15 ℃, adding ethanol for the first time, then adding ceftizoxime sodium seed crystal, growing crystals, adding ethanol again after a large amount of crystals are produced, cooling, continuing to grow crystals, filtering, washing and drying to obtain ceftizoxime sodium powder;
(f) and (e) aseptically packaging the ceftizoxime sodium powder obtained in the step (e) to obtain the ceftizoxime sodium powder injection for injection.
The technical scheme of the invention is further improved as follows: in the step (a), the amount of the purified water is 2.0-2.5 times of the weight of the ceftizoxime acid.
The technical scheme of the invention is further improved as follows: in the step (a), the buffer solution is acetic acid-sodium acetate buffer solution; the adding amount is 0.1-0.2 time of the weight of ceftizoxime acid; preparing an acetic acid-sodium acetate buffer solution: 54.6g of sodium acetate is dissolved in 20mL of 1mol/L acetic acid solution, and then the solution is diluted to 500mL by adding water.
The technical scheme of the invention is further improved as follows: in the step (b), the salt forming agent is sodium acetate solution, and the molar ratio of the sodium acetate to the ceftizoxime acid is 1.05-1.15: 1; the water consumption for dissolving the sodium acetate is 4 to 5 times of the weight of the ceftizoxime acid; the addition time is 60-120 min.
The technical scheme of the invention is further improved as follows: in the step (c), the amount of the added sodium chloride is 0.1-0.2 time of the mass of the ceftizoxime acid.
The technical scheme of the invention is further improved as follows: the dosage of the active carbon used in the step (d) is 10 to 15 percent of the weight of the ceftizoxime acid, and the decoloring time is 30 to 60 min.
The technical scheme of the invention is further improved as follows: in the step (e), ethanol is added for the first time, the volume usage amount of the ethanol is 7-8 times of the weight of the ceftizoxime acid, and the amount of the added crystal seeds is 5% -7% of the weight of the ceftizoxime acid.
The technical scheme of the invention is further improved as follows: in the step (e), ethanol is added again, and the volume dosage of the ethanol is 55-60 times of the weight of the ceftizoxime acid.
The technical scheme of the invention is further improved as follows: in the step (e), the temperature is reduced, the crystal growing temperature is 0-2 ℃ in the crystal growing process, and the crystal growing time is 60-90 min.
Due to the adoption of the technical scheme, the invention has the following technical effects:
1. according to the ceftizoxime sodium for injection, the organic solvent used for crystallization is a single solvent and can be recycled, so that the product quality and the stability can be effectively improved; the addition of the buffer solution and the sodium chloride in the crystallization system can effectively improve the fluidity of the product and is easier for subpackaging the powder injection.
2. The preparation method is simple in technological process operation, and the prepared ceftizoxime sodium product for injection has the advantages of good stability, low color grade index, low impurity content and high product content.
3. The invention provides a novel method for preparing ceftizoxime sodium for injection; and industrialization is easy to realize.
4. The ceftizoxime sodium powder injection preparation for injection prepared by the invention has smaller angle of repose and better powder flowability, and can meet the requirement of flowability in the production process.
5. The invention is more suitable for preparing powder injection.
Detailed Description
The present invention will be described in further detail with reference to specific examples below:
a method for preparing ceftizoxime sodium for injection, which is easy to subpackage powder injection preparations.
The preparation method comprises the following steps:
(a) reducing the temperature of the purified water to 0-5 ℃; adding ceftizoxime acid into purified water, and adding a buffer solution; wherein the amount of the purified water is 2.0-2.5 times of the weight of the ceftizoxime acid. Preferably, the buffer used is an acetic acid-sodium acetate buffer; the adding amount is 0.1-0.2 times of the weight of ceftizoxime acid. The preparation method of the acetic acid-sodium acetate buffer solution comprises the following steps: 54.6g of sodium acetate is dissolved in 20mL of 1mol/L acetic acid solution, and then the solution is diluted to 500mL by adding water.
(b) Adding a salt forming agent into the solution obtained in the step (a), controlling the temperature to be 0-5 ℃, and stirring until the solution is clear. Preferably, the salt forming agent is sodium acetate solution, and the molar ratio of the sodium acetate to the ceftizoxime acid is 1.05-1.15: 1; the water consumption for dissolving the sodium acetate is 4 to 5 times of the weight of the ceftizoxime acid; the addition time is 60-120 min.
(c) Adding sodium chloride into the solution obtained in the step (b), and stirring until the solution is clear; preferably, the amount of the added sodium chloride is 0.1 to 0.2 times of the mass of the ceftizoxime acid.
(d) Adding activated carbon into the solution obtained in the step (c) for decoloring, and filtering after decoloring; preferably, the dosage of the active carbon is 10-15% of the weight of ceftizoxime acid, and the decoloring time is 30-60 min.
(e) And (d) controlling the temperature of the filtrate obtained in the step (d) to be 13-15 ℃, adding ethanol for the first time, then adding ceftizoxime sodium seed crystal, growing crystals, adding ethanol again after a large amount of crystals are obtained, cooling, continuing to grow crystals, filtering, washing and drying to obtain ceftizoxime sodium powder. Preferably, the volume usage of the ethanol added for the first time is 7-8 times of the weight of the ceftizoxime acid, and the amount of the added crystal seeds is 5% -7% of the weight of the ceftizoxime acid; and adding ethanol again, wherein the volume dosage of the ethanol is 55-60 times of the weight of the ceftizoxime acid. Cooling, and growing crystal at 0-2 deg.C for 60-90 min.
(f) And (e) aseptically packaging the ceftizoxime sodium powder obtained in the step (e) to obtain the ceftizoxime sodium powder injection for injection.
The following are specific examples:
example 1
Ceftizoxime sodium for injection is prepared by the method. The specific operation content is as follows:
adding 60mL of purified water into a reaction tank, cooling to 0-5 ℃, adding 30.0g of ceftizoxime acid under stirring, adding 3g of acetic acid-sodium acetate buffer solution under stirring, controlling the temperature of the system to be 0-2 ℃, slowly adding sodium acetate solution (6.75g of sodium acetate is dissolved in 120mL of purified water) for 60min, and uniformly stirring until the solution is clear. After the solution is clear, 3.0g of sodium chloride is added into the feed liquid, and the mixture is stirred again until the solution is clear.
Adding 3.0g of activated carbon into the solution, stirring for 60min, filtering, performing sterile filtration, feeding into a crystallization tank, washing with 10mL of purified water, and combining into the crystallization tank.
Controlling the crystallization temperature to be 15 ℃, adding 210mL of ethanol, adding 1.5g of sterile ceftizoxime sodium seed crystal, growing the crystals for 30min, after a large amount of crystals are produced, adding 1650mL of ethanol, and controlling the adding time to be 120 min. After the addition, the temperature is reduced to 0-2 ℃, the crystals are grown for 60min, and then the filter cake is filtered and washed by 200mL of ethanol. Vacuum drying at 40 deg.C until water content is less than or equal to 8.5%. Discharging to obtain 29.5g of ceftizoxime sodium sterile powder; the yield after seed crystal removal is 93.3%; and (3) carrying out sterile subpackaging on the ceftizoxime sodium powder to obtain the ceftizoxime sodium powder injection for injection.
Example 2
Adding 70mL of purified water into a reaction tank, cooling to 0-5 ℃, adding 30.0g of ceftizoxime acid under stirring, adding 6g of acetic acid-sodium acetate buffer solution under stirring, controlling the temperature of the system to be 0-5 ℃, slowly adding a sodium acetate solution (7.38g of sodium acetate is dissolved in 150mL of purified water) within 120min, and uniformly stirring until the solution is clear. After the solution is clear, 6.0g of sodium chloride is added into the feed liquid, and the mixture is stirred again until the solution is clear.
Adding 4.5g of activated carbon into the solution, stirring for 30min, filtering, performing sterile filtration, feeding into a crystallization tank, washing with 10mL of purified water, and combining into the crystallization tank.
Controlling the crystallization temperature at 13 ℃, adding 240mL of ethanol, adding 2.1g of sterile ceftizoxime sodium seed crystal, growing the crystals for 60min, after a large amount of crystals are produced, adding 1800mL of ethanol, and controlling the adding time for 120 min. After the addition, the temperature is reduced to 0-2 ℃, the crystals are grown for 120min, and then the filter cake is filtered and washed by 200mL of ethanol. Vacuum drying at 40 deg.C until water content is less than or equal to 8.5%. Discharging to obtain 30.2g of ceftizoxime sodium sterile powder. The yield after seed crystal removal is 93.7%; and (3) carrying out sterile subpackaging on the ceftizoxime sodium powder to obtain the ceftizoxime sodium powder injection for injection.
Example 3
Adding 50L of purified water into a reaction tank, cooling to 0-5 ℃, adding 20.0kg of ceftizoxime acid under stirring, adding 2kg of acetic acid-sodium acetate buffer solution under stirring, controlling the temperature of the system to be 0-5 ℃, slowly adding sodium acetate solution (4.68kg of sodium acetate is dissolved in 80L of purified water) within 120min, and uniformly stirring until the solution is clear. After the solution is clear, 3kg of sodium chloride is added into the feed liquid, and the mixture is stirred again until the solution is clear.
Adding 2kg of activated carbon into the solution, stirring for 30min, filtering, performing sterile filtration, feeding into a crystallization tank, washing with 6L of purified water, and combining to the crystallization tank.
Controlling the crystallization temperature at 13 ℃, adding 160L of ethanol, adding 1kg of sterile ceftizoxime sodium seed crystal, growing the crystals for 60min, after a large amount of crystals are produced, adding 1200L of ethanol, and controlling the adding time for 120 min. After the addition, the temperature is reduced to 0-2 ℃, the crystals are grown for 120min, and then the filter cake is filtered and washed by 120L of ethanol. Vacuum drying at 40 deg.C until water content is less than or equal to 8.5%. Discharging to obtain 19.8kg of ceftizoxime sodium sterile powder. The yield after seed crystal removal is 94.0%; and (3) carrying out sterile subpackaging on the ceftizoxime sodium powder to obtain the ceftizoxime sodium powder injection for injection.
The following are comparative examples of examples, for a total of 5 comparative examples.
Comparative examples 1 to 4
Comparative examples 1-4 were prepared similarly to example 1, except that: no buffer was added to the procedure of comparative example 1; comparative example 2 crystalline system no sodium chloride was added; in comparative example 3, the added buffer solution is 0.3 times of the weight of ceftizoxime acid; in comparative example 4, 0.3 times the weight of ceftizoxime acid was added.
Comparative example 5 was conducted in accordance with the method for producing ceftizoxime sodium in example 1 described in patent document CN 109553626A.
The quality tests were carried out on the examples and comparative examples, and the data are given in the following table:
TABLE 1
According to the data in the table 1, the process is determined to be within the scope of the claims, the product quality is stable, the LOD, the content, the color grade and the impurity level are equivalent, and the process reproducibility is good; especially, the product has high content and good purity. And (3) analyzing that the content of the product and the color grade quality index are influenced by introducing too much buffer solution and inorganic salt into the crystallization system through a comparative example 3 and a comparative example 4.
The example 3 samples were subjected to a 6 month accelerated stability study and the data are given in the following table:
according to the experimental data in table 2, it can be seen that the product has stable moisture, content, color grade and impurity quality after accelerated experiment, and all indexes meet the quality requirements of 2015 edition of Chinese pharmacopoeia.
In order to better verify that the ceftizoxime sodium product prepared by the invention has certain advantages in fluidity, 3 samples of ceftizoxime sodium for injection obtained in examples 1-3, ceftizoxime sodium for injection sold in markets and ceftizoxime sodium for injection obtained in comparative examples 1-5 are taken for sample repose angle detection and comparison, and the results are shown in table 3.
TABLE 3
According to the detection results in the table 3, compared with the market available 1-2 and the comparative examples 1-5, the ceftizoxime sodium powder injection preparation for injection prepared by the invention has smaller angle of repose, and according to the powder property, the better the powder flowability is, the smaller the angle of repose is; the powder particles have rough surfaces, and the larger the adhesiveness, the larger the angle of repose. The product prepared by the method has good fluidity, and can meet the requirement of fluidity in the production process; the comparative sample was relatively poor in flowability.
The upper and lower limit values and interval values of the process parameters (such as temperature, time, molar ratio and the like) of the invention can realize the invention, and the examples are not listed.
In conclusion, the invention designs reasonable process routes and process parameters, and the product prepared by the method is more suitable for subpackaging powder injection preparations, so that the ceftizoxime sodium for injection is prepared.
Claims (9)
1. A preparation method of ceftizoxime sodium for injection is characterized by comprising the following steps: the method comprises the following steps:
(a) reducing the temperature of the purified water to 0-5 ℃; adding ceftizoxime acid into purified water, and adding a buffer solution;
(b) adding a salt forming agent into the solution obtained in the step (a), controlling the temperature to be 0-5 ℃, and stirring until the solution is clear;
(c) adding sodium chloride into the solution obtained in the step (b), and stirring until the solution is clear;
(d) adding activated carbon into the solution obtained in the step (c) for decoloring, and filtering after decoloring;
(e) controlling the temperature of the filtrate obtained in the step (d) to be 13-15 ℃, adding ethanol for the first time, then adding ceftizoxime sodium seed crystal, and growing the crystals; after a large amount of crystals are discharged, adding ethanol again, cooling, continuing to grow crystals, filtering, washing and drying to obtain ceftizoxime sodium powder;
(f) and (e) aseptically packaging the ceftizoxime sodium powder obtained in the step (e) to obtain the ceftizoxime sodium powder injection for injection.
2. The preparation method of ceftizoxime sodium for injection according to claim 1, wherein the preparation method comprises the following steps: in the step (a), the amount of the purified water is 2.0-2.5 times of the weight of the ceftizoxime acid.
3. The preparation method of ceftizoxime sodium for injection according to claim 1, wherein the ceftizoxime sodium is prepared by mixing a solution of ceftizoxime sodium and a solution of ceftizoxime sodium; in the step (a), the buffer solution is acetic acid-sodium acetate buffer solution; the adding amount is 0.1-0.2 time of the weight of ceftizoxime acid; preparing an acetic acid-sodium acetate buffer solution: 54.6g of sodium acetate is dissolved in 20mL of 1mol/L acetic acid solution, and then the solution is diluted to 500mL by adding water.
4. The preparation method of ceftizoxime sodium for injection according to claim 1, wherein the preparation method comprises the following steps: in the step (b), the salt forming agent is sodium acetate solution, and the molar ratio of the sodium acetate to the ceftizoxime acid is 1.05-1.15: 1; the water consumption for dissolving the sodium acetate is 4 to 5 times of the weight of the ceftizoxime acid; the addition time is 60-120 min.
5. The preparation method of ceftizoxime sodium for injection according to claim 1, wherein the preparation method comprises the following steps: in the step (c), the amount of the added sodium chloride is 0.1-0.2 time of the mass of the ceftizoxime acid.
6. The preparation method of ceftizoxime sodium for injection according to claim 1, wherein the preparation method comprises the following steps: the dosage of the active carbon used in the step (d) is 10 to 15 percent of the weight of the ceftizoxime acid, and the decoloring time is 30 to 60 min.
7. The preparation method of ceftizoxime sodium for injection according to claim 1, wherein the preparation method comprises the following steps: in the step (e), ethanol is added for the first time, the volume usage amount of the ethanol is 7-8 times of the weight of the ceftizoxime acid, and the amount of the added crystal seeds is 5% -7% of the weight of the ceftizoxime acid.
8. The preparation method of ceftizoxime sodium for injection according to claim 1, wherein the preparation method comprises the following steps: in the step (e), ethanol is added again, and the volume dosage of the ethanol is 55-60 times of the weight of the ceftizoxime acid.
9. The preparation method of ceftizoxime sodium for injection according to claim 1, wherein the preparation method comprises the following steps: in the step (e), the temperature is reduced, the crystal growing temperature is 0-2 ℃ in the crystal growing process, and the crystal growing time is 60-90 min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010506830.7A CN111777625B (en) | 2020-06-05 | 2020-06-05 | Preparation method of ceftizoxime sodium for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010506830.7A CN111777625B (en) | 2020-06-05 | 2020-06-05 | Preparation method of ceftizoxime sodium for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111777625A true CN111777625A (en) | 2020-10-16 |
| CN111777625B CN111777625B (en) | 2021-06-29 |
Family
ID=72753998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010506830.7A Active CN111777625B (en) | 2020-06-05 | 2020-06-05 | Preparation method of ceftizoxime sodium for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111777625B (en) |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010426A (en) * | 2010-12-02 | 2011-04-13 | 哈药集团制药总厂 | Method for preparing ceftizoxime sodium |
| WO2011113361A1 (en) * | 2010-03-17 | 2011-09-22 | Liu Li | Ceftizoxime sodium crystalline hydrate, preparation methods and uses thereof |
| WO2013010297A1 (en) * | 2011-07-15 | 2013-01-24 | 海南灵康制药有限公司 | Method for purifying ceftizoxime sodium |
| CN102911186A (en) * | 2012-11-13 | 2013-02-06 | 天津青松华药医药有限公司 | Ceftizoxime sodium preparation and refining method |
| CN107602588A (en) * | 2017-08-17 | 2018-01-19 | 华北制药河北华民药业有限责任公司 | A kind of method for crystallising of cephalosporin analog antibiotic |
| CN108440569A (en) * | 2018-03-16 | 2018-08-24 | 深圳华润九新药业有限公司 | The preparation method of Ceftriaxone Sodium sphaerocrystal |
| CN108948048A (en) * | 2018-07-26 | 2018-12-07 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefathiamidine |
| CN109160923A (en) * | 2017-07-26 | 2019-01-08 | 刘兆娟 | A kind of 1/4 water Cefobutazine sodium compound |
| CN109232610A (en) * | 2018-09-04 | 2019-01-18 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefonicid dibenzylethylenediamsalt salt |
| CN109553626A (en) * | 2018-12-29 | 2019-04-02 | 山东罗欣药业集团股份有限公司 | A kind of refining methd of ceftizoxime sodium |
| CN109748926A (en) * | 2019-01-23 | 2019-05-14 | 华北制药河北华民药业有限责任公司 | A kind of purification process of cefazolin |
| CN110128449A (en) * | 2019-05-22 | 2019-08-16 | 方长明 | 7- phenylacetyl amido -3- desacetoxycephalosporanic acid salt and its preparation method and application |
-
2020
- 2020-06-05 CN CN202010506830.7A patent/CN111777625B/en active Active
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011113361A1 (en) * | 2010-03-17 | 2011-09-22 | Liu Li | Ceftizoxime sodium crystalline hydrate, preparation methods and uses thereof |
| CN102010426A (en) * | 2010-12-02 | 2011-04-13 | 哈药集团制药总厂 | Method for preparing ceftizoxime sodium |
| WO2013010297A1 (en) * | 2011-07-15 | 2013-01-24 | 海南灵康制药有限公司 | Method for purifying ceftizoxime sodium |
| CN102911186A (en) * | 2012-11-13 | 2013-02-06 | 天津青松华药医药有限公司 | Ceftizoxime sodium preparation and refining method |
| CN109160923A (en) * | 2017-07-26 | 2019-01-08 | 刘兆娟 | A kind of 1/4 water Cefobutazine sodium compound |
| CN107602588A (en) * | 2017-08-17 | 2018-01-19 | 华北制药河北华民药业有限责任公司 | A kind of method for crystallising of cephalosporin analog antibiotic |
| CN108440569A (en) * | 2018-03-16 | 2018-08-24 | 深圳华润九新药业有限公司 | The preparation method of Ceftriaxone Sodium sphaerocrystal |
| CN108948048A (en) * | 2018-07-26 | 2018-12-07 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefathiamidine |
| CN109232610A (en) * | 2018-09-04 | 2019-01-18 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefonicid dibenzylethylenediamsalt salt |
| CN109553626A (en) * | 2018-12-29 | 2019-04-02 | 山东罗欣药业集团股份有限公司 | A kind of refining methd of ceftizoxime sodium |
| CN109748926A (en) * | 2019-01-23 | 2019-05-14 | 华北制药河北华民药业有限责任公司 | A kind of purification process of cefazolin |
| CN110128449A (en) * | 2019-05-22 | 2019-08-16 | 方长明 | 7- phenylacetyl amido -3- desacetoxycephalosporanic acid salt and its preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| 温玉麟: "头抱菌素类抗生素的稳定性 (上)", 《国外医药杭生素分册》 * |
| 章波等: "粉体流动性的研究及其在中药制剂中的应用", 《中成药》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111777625B (en) | 2021-06-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101584671B (en) | Cefazedone sodium medicament powder injection and method for synthesizing raw medicine of Cefazedone sodium | |
| CN102268019B (en) | Cefadroxil compound and preparation method thereof | |
| JP2001500521A (en) | Cefditoren pivoxil crystalline material and method for producing the same | |
| CN104788472B (en) | Spherical particles of cefazolin sodium monohydrate and preparation method for crystallization thereof | |
| CN109628541B (en) | Method for synthesizing penicillin V salt by enzyme method | |
| CN105566352A (en) | New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation | |
| CN101906109B (en) | Method for preparing cefuroxime sodium | |
| CN111777625B (en) | Preparation method of ceftizoxime sodium for injection | |
| CN112535666B (en) | Preparation method of high-stability cefuroxime sodium powder injection preparation for injection | |
| CN115304517B (en) | Separation and purification method of probenecid sodium process impurities | |
| CN105315300B (en) | A kind of cefoxitin sodium, preparation method and the usage | |
| CN109232610B (en) | Refining method of cefonicid dibenzylethylenediamine salt | |
| CN108440569B (en) | Preparation method of ceftriaxone sodium spherical crystal | |
| CN102746324B (en) | Purification method of cefotiam hydrochloride and aseptic powder injection of cefotiam hydrochloride | |
| CN110974832B (en) | Preparation method of cefamandole nafate for injection | |
| CN106565749B (en) | The method for promoting Cefamandole Nafate quality using three-dimensional column plate purification solvent | |
| CN112679524B (en) | Preparation method of ceftriaxone sodium | |
| CN102010432B (en) | Cefodizime sodium compound and novel method thereof | |
| CN111793076B (en) | Preparation method of cefpirome sulfate for injection | |
| CN101863906B (en) | Crystallization method of cefcapene ester hydrochloride monohydrate | |
| CN111233894B (en) | Cefditoren pivoxil delta3Process for the preparation of isomers | |
| CN112279867B (en) | Preparation method of cefoperazone sodium | |
| CN112094281B (en) | Preparation method of cefepime hydrochloride for injection | |
| CN117088896A (en) | Refining method of ceftiofur hydrochloride | |
| CN110563748B (en) | Cefazolin sodium injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |