CN109824699A - A kind of purification process of cefepime Hydrochloride - Google Patents
A kind of purification process of cefepime Hydrochloride Download PDFInfo
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- CN109824699A CN109824699A CN201910063721.XA CN201910063721A CN109824699A CN 109824699 A CN109824699 A CN 109824699A CN 201910063721 A CN201910063721 A CN 201910063721A CN 109824699 A CN109824699 A CN 109824699A
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- cefepime hydrochloride
- crude product
- purification process
- cefepime
- dispersing agent
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Abstract
The invention discloses a kind of purification process of cefepime Hydrochloride, belong to chemical pharmacy field, using cefepime Hydrochloride crude product as raw material, adjust the pH of cefepime Hydrochloride crude product lysate, add dispersing agent, obtain cefepime Hydrochloride after isoelectric point crystallizing；The present invention can be improved the purity of cefepime Hydrochloride, and the cefepime Hydrochloride being prepared has the advantages that low color grade, epigranular, good fluidity.
Description
Technical field
The present invention relates to a kind of purification process of compound, especially a kind of purification process of beta-lactam antibiotic,
Belong to chemical pharmacy field.
Background technique
Entitled 1- [[(6R, 7R) -7- [(2Z)-(thiazolamine -4- base) -2- (the methoxy imido of cefepime Hydrochloride chemistry
Base) acetylamino] -2- carboxyl -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -3- base] methyl] -1- methyl
One hydrochloride monohydrate of pyrrolidines is white to micro-yellow powder or crystalline powder, readily soluble in water or in methanol,
Slightly soluble in ethyl alcohol, insoluble in ether, structural formula is as follows:
Cefepime Hydrochloride has effect to gram-positive bacteria and negative bacterium, currently, being clinically mainly used for sensitive bacteria
Caused various infection.The purification process of cefepime Hydrochloride is mainly activated carbon adsorption, chromatography post separation, crystallization etc., specially
Sharp document CN201610314754.3 describes a kind of preparation method of cefepime Hydrochloride suitable for industrialized production, wherein salt
The purifying of sour Cefepime uses method for crystallising: cefepime Hydrochloride crude product being dissolved into organic solvent, through active carbon filter core
After system filtering, recrystallisation solvent crystallization is added, obtains the cefepime Hydrochloride product of high-purity.This method is needed using active carbon
Cartridge systems, equipment investment is big, complicated for operation, and equipment operation and maintenance cost are high.
Summary of the invention
The technical problem to be solved by the invention is to provide a kind of purification process of cefepime Hydrochloride, can be improved hydrochloric acid
The purity of Cefepime, the cefepime Hydrochloride being prepared have the advantages that low color grade, epigranular, good fluidity.
In order to solve the above technical problems, the technical scheme adopted by the invention is that:
A kind of purification process of cefepime Hydrochloride adjusts cefepime Hydrochloride using cefepime Hydrochloride crude product as raw material
The pH of crude product lysate adds dispersing agent, obtains cefepime Hydrochloride after isoelectric point crystallizing.
Above-mentioned technical proposal of the invention further improvement lies in that including the following steps:
A. cefepime Hydrochloride crude product is dissolved in the mixed liquor of water and organic solvent, stirring and dissolving obtains hydrochloric acid cephalo pyrrole
Oxime crude product lysate；
B. the pH of cefepime Hydrochloride crude product lysate is adjusted；
C. dispersing agent is added, adjusts pH, growing the grain；
D. crystallization agent is added, cool down growing the grain；
E. crystal obtains cefepime Hydrochloride after filtration, washing and drying.
Above-mentioned technical proposal of the invention further improvement lies in that: the body of the mixed liquor of water and organic solvent in step A
Product ml is 2.5~4.5:1 with cefepime Hydrochloride crude product quality grams ratio, and solution temperature is 20~30 DEG C.
Technical solution of the present invention further improvement lies in that: the body of water and organic solvent in the mixed liquor of water and organic solvent
For product than being 1:1.5~2.5, organic solvent is the combination of any one or more of acetone, acetonitrile or n,N-Dimethylformamide.
Technical solution of the present invention further improvement lies in that: in step B adjust pH to 4.0~5.0, adjust PH used in solution
For any one of di-n-propylamine, diethylamine or triethylamine.
Technical solution of the present invention further improvement lies in that: in step C adjust pH used in acid solution be hydrochloric acid, adjust pH to
0.8~1.0, temperature is 20~25 DEG C when adjusting pH.
Technical solution of the present invention further improvement lies in that: step C dispersing agent be ethyl acetate and acetone mixed solvent,
The volume ratio of ethyl acetate and acetone is 1:1.5~2.0, dispersing agent volume ml and cefepime Hydrochloride crude product quality grams
Than for 5~6:1, growing the grain temperature is 20~25 DEG C, rearing crystal time is 0.5~1h.
Technical solution of the present invention further improvement lies in that: crystallization agent is acetone or alcohol, crystallization agent volume milli in step D
It rises number and cefepime Hydrochloride crude product quality grams ratio is 10~15:1, cooling growing the grain temperature is 10~15 DEG C, and rearing crystal time is
0.5~1h.
Technical solution of the present invention further improvement lies in that: temperature is 40~50 DEG C when dry in step E, pressure is-
0.10~-0.08MPa.
By adopting the above-described technical solution, the technological progress achieved by the present invention is:
A kind of purification process of cefepime Hydrochloride provided by the invention can be improved the purity of cefepime Hydrochloride, system
Standby obtained cefepime Hydrochloride has the advantages that low color grade, epigranular, good fluidity.
The present invention is when dissolving cefepime Hydrochloride crude product, using the mixed liquor of water and organic solvent, when organic solvent is
The volume ratio of the combination of any one or more of acetone, acetonitrile or N,N-dimethylformamide, water and organic solvent is 1:1.5
When~2.5, cefepime Hydrochloride crude product can be made to dissolve well, it can also be ensured that cefepime Hydrochloride is steady in lysate
It is qualitative, while the dissolution, decoloration, crystallization effect of product can be effectively improved.The volume of the mixed liquor of dissolution water and organic solvent
Ml with cefepime Hydrochloride crude product quality grams ratio be 2.5~4.5:1 when, it is ensured that be completely dissolved, while subtracting as far as possible
The dosage of few subsequent decolorising agent and dispersing agent, improves efficiency, save the cost.
The step of present invention is not decolourized, but the pH by adjusting cefepime Hydrochloride crude product lysate, hydrochloric acid cephalo
The pH value of pyrrole oxime crude product lysate is about 1.6~2.1, when adjusting pH to 4.0~5.0, adds dispersing agent, adjust pH value to
Isoelectric point recrystallization, it is ensured that the cefepime Hydrochloride color grade being prepared meets the requirements, and simplifies operating procedure, section
Decoloring equipment investment has been saved, production cost is reduced, has improved production efficiency.
The present invention uses isoelectric point crystallizing, when adjusting pH to 0.8~1.0, the isoelectric point of closer cefepime Hydrochloride,
The solubility of cefepime Hydrochloride is minimum at this time, and the granularity that crystal is easy the crystal for being precipitated, and being precipitated is relatively uniform, with smart ammonia
The granularity of acid is close.The present invention is precipitated crystal step by step, the crystal purity guaranteed is higher simultaneously using crystallizing twice simultaneously
Completely, product yield is high for crystallization.It joined dispersing agent when crystallizing for the first time, when dispersing agent is molten for the mixing of ethyl acetate and acetone
When agent, it is ensured that crystallizing system is more stable, and feed liquid is not sticky, and the crystal of formation is more dispersed, after crystal is largely precipitated,
It carries out second to crystallize, what second of crystallization was added crystallization agent will can tie for the first time when crystallization agent is acetone or alcohol
Uncrystallized cefepime Hydrochloride crystallizes out in system when brilliant, and guarantees that crystal has certain growth course, improves salt
The yield of sour Cefepime crystal.
Specific embodiment
Here is certain specific embodiments of the invention, to be described in further detail.
A kind of purification process of cefepime Hydrochloride adjusts cefepime Hydrochloride using cefepime Hydrochloride crude product as raw material
The pH of crude product lysate adds dispersing agent, obtains cefepime Hydrochloride after isoelectric point crystallizing.
Preparation method includes the following steps:
A. cefepime Hydrochloride crude product is dissolved in the mixed liquor of water and organic solvent, 20~30 DEG C of stirring and dissolvings obtain salt
Sour Cefepime crude product lysate；
The volume ml of the mixed liquor of water and organic solvent and cefepime Hydrochloride crude product quality grams ratio be 2.5~
4.5:1；In the mixed liquor of water and organic solvent the volume ratio of water and organic solvent be 1:1.5~2.5, organic solvent be acetone,
The combination of any one or more of acetonitrile or N,N-dimethylformamide；
B. the pH to 4.0~5.0 of cefepime Hydrochloride crude product lysate is adjusted；
Adjusting solution used in pH is any one of di-n-propylamine, diethylamine or triethylamine；
C. dispersing agent is added, temperature be 20~25 DEG C under the conditions of, with hydrochloric acid solution adjust pH to 0.8~1.0,20~25
DEG C 0.5~1h of growing the grain；
Dispersing agent is the mixed solvent of ethyl acetate and acetone, and the volume ratio of ethyl acetate and acetone is 1:1.5~2.0,
Dispersing agent volume ml and cefepime Hydrochloride crude product quality grams ratio are 5~6:1；
D. crystallization agent is added, cool down 10~15 DEG C of 0.5~1h of growing the grain；
Crystallization agent is acetone or alcohol, and crystallization agent volume ml and cefepime Hydrochloride crude product quality grams ratio are 10
~15:1；
E. crystal obtains after temperature is 40~50 DEG C, pressure is dry under the conditions of being -0.10~-0.08MPa through being filtered, washed
To cefepime Hydrochloride.
Embodiment 1
A kind of purification process of cefepime Hydrochloride adjusts cefepime Hydrochloride using cefepime Hydrochloride crude product as raw material
The pH of crude product lysate adds dispersing agent, obtains cefepime Hydrochloride after isoelectric point crystallizing.
Preparation method includes the following steps:
A. 20g cefepime Hydrochloride crude product is taken, is added in the mixed liquor of 20mL purified water and 30mL acetonitrile, 30 DEG C of temperature control,
Stirring obtains cefepime Hydrochloride crude product lysate to dissolved clarification；
B. the pH to 5.0 that diethylamine adjusts cefepime Hydrochloride crude product lysate is added；
C. volume ratio is added as the ethyl acetate of 1:1.5 and the mixed liquor 100mL of acetone, under the conditions of 25 DEG C of temperature control, is added dropwise
Hydrochloric acid solution adjusts pH to 0.8,20 DEG C of growing the grain 0.5h；
D. acetone 200mL is added dropwise, cool down 10 DEG C of growing the grain 1h；
E. crystal obtains after temperature is 40 DEG C, pressure is dry under the conditions of being -0.098MPa through filtering, 100mL acetone washing
Cefepime Hydrochloride.
Embodiment 2~3
Embodiment 2~3 is identical as the production craft step in embodiment 1, except that the selection of technological parameter, as follows
Shown in face table 1.
Comparative example 1~4
The preparation method of comparative example 1~4 is similar to Example 1, and difference is only that: the uncomfortable pH of step B in comparative example 1, and
It is plus decolorising agent decolourizes, dispersing agent is not added in step C；Decolorising agent is also not added without step B, i.e., uncomfortable pH in comparative example 2；
Dispersing agent is not added in step C in comparative example 3, that is, dispersing agent is not added, decolorising agent is also not added；Without step B in comparative example 4, in step C
Without dispersing agent, i.e., dispersing agent uncomfortable pH, is not added, decolorising agent is also not added.
Comparative example 5 is brilliant according to cefepime Hydrochloride in the embodiment 4 recorded in patent document CN201610314754.3
The preparation method of body carries out.
Table 1
In order to preferably verify the superiority of cefepime Hydrochloride prepared by the present invention, inventor is to Examples 1 to 3, right
The cefepime Hydrochloride and commercially available cefepime Hydrochloride that ratio 1~5 obtains are detected, testing result such as following table 2
It is shown.
Table 2
It can be seen that compared with comparative example 1~5 according to the testing result in table 2, the hydrochloric acid cephalo pyrrole that the present invention prepares
Color grade, impurity summation etc. are significantly lower than comparative example in oxime, and content reaches 90.8~91.2%, hence it is evident that be higher than comparative example 88.2~
90.2% level, yield reach 97.6~98.1%, about 5~8 percentage points higher than comparative example 90.2~92.1%.The present invention
Preparation cefepime Hydrochloride purity is high, color grade it is low, the moisture, content, color grade and impurity level in each embodiment are suitable, work
Skill reproducibility is good.
In order to preferably verify the effect that cefepime Hydrochloride prepared by the present invention is mixed with arginine, Example 1~
3, comparative example 1~5 obtains cefepime Hydrochloride and commercially available cefepime Hydrochloride each 10g, it is arginine mixed with 5.5g respectively
It is dispensed after conjunction, pH detection is carried out to the sample after packing, the results are shown in Table 3.
Table 3
It can be seen that compared with comparative example 1~5 and commercial product according to the testing result in table 3, what the present invention prepared
Cefepime dihydrochloride for injection powder injection formulation pH stablize, after packing between each sample pH difference it is smaller, illustrate cefepime Hydrochloride and
Arginine mixes relatively uniform, and sample homogeneity and stability are preferable.And pH difference is larger in comparative example, illustrates hydrochloric acid cephalo
Exist when pyrrole oxime is mixed with arginine and mix non-uniform problem, is had differences between each sample after packing, to the stability of product
It has a certain impact with safety.
Claims (9)
1. a kind of purification process of cefepime Hydrochloride, it is characterised in that: using cefepime Hydrochloride crude product as raw material, adjust hydrochloric acid
The pH of Cefepime crude product lysate adds dispersing agent, obtains cefepime Hydrochloride after isoelectric point crystallizing.
2. a kind of purification process of cefepime Hydrochloride according to claim 1, it is characterised in that include the following steps:
A. cefepime Hydrochloride crude product is dissolved in the mixed liquor of water and organic solvent, it is thick that stirring and dissolving obtains cefepime Hydrochloride
Product lysate；
B. the pH of cefepime Hydrochloride crude product lysate is adjusted；
C. dispersing agent is added, adjusts pH, growing the grain；
D. crystallization agent is added, cool down growing the grain；
E. crystal obtains cefepime Hydrochloride after filtration, washing and drying.
3. a kind of purification process of cefepime Hydrochloride according to claim 2, it is characterised in that: water and have in step A
The volume ml and cefepime Hydrochloride crude product quality grams ratio of the mixed liquor of solvent are 2.5 ~ 4.5:1, and solution temperature is
20~30℃。
4. a kind of purification process of cefepime Hydrochloride according to claim 3, it is characterised in that: water and organic solvent
The volume ratio of water and organic solvent is 1:1.5 ~ 2.5 in mixed liquor, and organic solvent is acetone, acetonitrile or n,N-Dimethylformamide
Any one or more of combination.
5. a kind of purification process of cefepime Hydrochloride according to claim 2, it is characterised in that: adjust pH in step B
To 4.0 ~ 5.0, adjusting solution used in PH is any one of di-n-propylamine, diethylamine or triethylamine.
6. a kind of purification process of cefepime Hydrochloride according to claim 2, it is characterised in that: adjust pH institute in step C
It is hydrochloric acid with acid solution, adjusts pH to 0.8 ~ 1.0, temperature is 20 ~ 25 DEG C when adjusting pH.
7. a kind of purification process of cefepime Hydrochloride according to claim 2, it is characterised in that: step C dispersing agent is
The volume ratio of the mixed solvent of ethyl acetate and acetone, ethyl acetate and acetone be 1:1.5 ~ 2.0, dispersing agent volume ml with
Cefepime Hydrochloride crude product quality grams ratio is 5 ~ 6:1, and growing the grain temperature is 20 ~ 25 DEG C, and rearing crystal time is 0.5 ~ 1h.
8. a kind of purification process of cefepime Hydrochloride according to claim 2, it is characterised in that: crystallization agent in step D
For acetone or alcohol, crystallization agent volume ml and cefepime Hydrochloride crude product quality grams ratio are 10 ~ 15:1, and cool down growing the grain temperature
Degree is 10 ~ 15 DEG C, and rearing crystal time is 0.5 ~ 1h.
9. a kind of purification process of cefepime Hydrochloride according to claim 2, it is characterised in that: when dry in step E
Temperature is 40 ~ 50 DEG C, and pressure is -0.10~-0.08MPa.
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| CN201910063721.XA CN109824699B (en) | 2019-01-23 | 2019-01-23 | Method for purifying cefepime hydrochloride |
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| CN201910063721.XA CN109824699B (en) | 2019-01-23 | 2019-01-23 | Method for purifying cefepime hydrochloride |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101200473A (en) * | 2007-06-07 | 2008-06-18 | 深圳信立泰药业股份有限公司 | Method for preparing cefepime dihydrochloride monohydrate crystal |
| CN102408440A (en) * | 2011-12-27 | 2012-04-11 | 山东鑫泉医药有限公司 | Synthesis method of cefepime hydrochloride |
| CN103554136A (en) * | 2013-10-31 | 2014-02-05 | 哈药集团制药总厂 | Preparation method of cefmenoxine hydrochloride dry powder |
| CN104817573A (en) * | 2015-04-11 | 2015-08-05 | 长春工业大学 | Method for preparing cefepime dihydrochloride |
| CN107201391A (en) * | 2017-07-04 | 2017-09-26 | 吉林省爱诺德生物工程有限公司 | A kind of synthetic method of cefepime Hydrochloride |
-
2019
- 2019-01-23 CN CN201910063721.XA patent/CN109824699B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101200473A (en) * | 2007-06-07 | 2008-06-18 | 深圳信立泰药业股份有限公司 | Method for preparing cefepime dihydrochloride monohydrate crystal |
| CN102408440A (en) * | 2011-12-27 | 2012-04-11 | 山东鑫泉医药有限公司 | Synthesis method of cefepime hydrochloride |
| CN103554136A (en) * | 2013-10-31 | 2014-02-05 | 哈药集团制药总厂 | Preparation method of cefmenoxine hydrochloride dry powder |
| CN104817573A (en) * | 2015-04-11 | 2015-08-05 | 长春工业大学 | Method for preparing cefepime dihydrochloride |
| CN107201391A (en) * | 2017-07-04 | 2017-09-26 | 吉林省爱诺德生物工程有限公司 | A kind of synthetic method of cefepime Hydrochloride |
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