CN110437260A - A kind of cefuroxime sodium raw materials and injection and preparation method thereof - Google Patents
A kind of cefuroxime sodium raw materials and injection and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
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- 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
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- 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
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- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
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Abstract
The present invention relates to a kind of cefuroxime sodium raw materials and injections and preparation method thereof, belong to pharmaceutical technology field.Cefuroxime sodium raw materials of the present invention are by with special drop rate, while being added dropwise and being prepared according to 95% ethanol solution of specific blend solvent burden ratio, the cefuroxime acid solution that certain concentration is prepared and Sodium acetate trihydrate in specific solvent environment.It is significantly improved by the raw material by the cefuroxime sodium for injection product quality and stability of special process control preparation, especially reduces the generation in relation to object 2, strict control product quality, to ensure that the safety and validity of medication.
Description
Technical field
The present invention relates to a kind of cefuroxime sodium raw materials and injections and preparation method thereof, belong to pharmaceutical technology field.
Background technique
Cefuroxime Sodium is developed by the GlaxoSmithKline company of Britain, and 1978 most early in Germany, Ireland, English
State, Italy (trade name Curoxim) listing.It is listed by Shin Nihon Jitsugyo company in Japan within 1980, trade name
" Zinacef ", only peroral dosage form.October nineteen eighty-three obtains U.S. FDA approval, trade name Zinacef by Teligent company.
Injection in 1987 is in Discussion on Chinese Listed, and trade name Xi Lixin, tablet lists at home within 1989.Cefuroxime Sodium is at home
Outer listing for many years, and has been recorded into China, Britain, the U.S., European Pharmacopoeia, and safety and effectiveness is clear.
Cefuroxime Sodium belongs to two generation cephalosporins, by tying with the penicillin binding protein (PBPs) on bacterial cell membrane
It closes, inhibits cell division and growth, finally make bacterolysis and death.With broad-spectrum antibacterial action, wide adaptation range, to golden Portugal
Bacterium, streptococcus, meningococcus, Bacillus influenzae etc. have height antibacterial action, to the effect of gram-negative bacteria compared with first generation cephalo
It is stronger, it can be effective to the S. aureus L-forms of penicillin resistant to anti-beta-lactamase.Clinic is mainly used for respiratory tract sense caused by sensitive bacteria
Dye, ear, nose, the infection of larynx section, urethral infection, Skin and soft tissue infection, bone and the infection of joint, stranguria syndrome including septicemia and
Other infection such as meningitis.Enter in cerebrospinal fluid for treating meninx inflammation Shi Keyou enough drug, to meningococcus institute
The meningitis of cause is significant in efficacy.
Entitled (6R, the 7R) -7- of Cefuroxime Sodium chemistry [2- (furans -2- base) -2- (methoxyimino) acetylamino] -3-
Carbamoyloxymethyl -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid sodium salt.It is to be white to micro-
Yellow powder or crystalline powder, it is odorless, have draw it is moist, it is readily soluble in water, it is slightly molten in methyl alcohol, it is insoluble in ethanol, than rotation
Degree is+55 ° to+65 °.
Chinese patent literature CN101906109B provides a kind of preparation method of Cefuroxime Sodium, and this method includes cephalo furan
The step of octanoic acid generates Cefuroxime Sodium with mixed sodium reactant salt, wherein the mixed sodium salt includes sodium acetate, sodium lactate and different
Two or three in Sodium Caprylate.The product crystal of this method preparation is evenly dispersed, and good fluidity, dissolubility is good, in color grade, contains
There is better performance in the indexs such as amount and impurity.Chinese patent literature CN104771372B discloses a kind of injection cephalo furan
Pungent sodium powder-needle preparation, is prepared by following steps: (1) sodium acetate solution is made in sodium acetate solvent dissolution, spare；(2) it is added
Cefuroxime acid is added to dissolution in solvent and water, stirring；Active carbon, decolorization filtering is added, mixed solvent washs filter residue, filter flask,
Filtrate enters in crystallizing tank；(3) NCPC Hebei Huamin Pharmaceutical Co., Ltd. applies particle process crystal product molecule
Assembling and form optimisation technique, temperature control control mixing speed, and sodium acetate solution is added dropwise；Dissolved agent is added by flow rate；(4)
It filters, washs, be dried in vacuo, weigh, packing；(5) the preparation packing for carrying out different size, obtains cefuroxime sodium for injection.
The Cefuroxime Sodium powder as made from the preparation method reaches excellent hydrodynamic performance, even particle size distribution, color grade, clear
Clear degree, purity are improved.Chinese patent literature CN106565748B discloses the preparation of a kind of Cefuroxime Sodium and its preparation
Method, including 3- deacetylation-preparation of 7-amino-cephalosporanic acid, the preparation of cefuroxime acid and the preparation of Cefuroxime Sodium three
Step, the present invention change charging reaction mode, are added simultaneously into crystallizing tank with 2~4h sterile at sodium agent solution, sterile cephalo
Cefuroxime acid solution and acetone improve reaction mass, change simultaneously crystallizing system and crystallization mode, and finished product color is good, purity is high.
Study seldom to related object 2 in the prior art, national requirements carries out strict control to the impurity, sends out through research
Existing, above-mentioned patented technology product is bad to controlling in relation to object 2, increases during accelerated test very fast.It therefore need to be to product matter
Amount is further promoted, and by optimizing content of the technique strict control in relation to object 2, develops that a kind of quality is more stable, adverse reaction
Lower cefuroxime sodium for injection.
Summary of the invention
Present invention aims in view of the drawbacks of the prior art, it is former to provide a kind of Cefuroxime Sodium that quality is more reliable
Material and injection, the cefuroxime sodium raw materials are by with special drop rate, while being added dropwise according to spy in specific solvent environment
Determine mixed solvent proportion, certain concentration prepare cefuroxime acid solution and Sodium acetate trihydrate 95% ethanol solution preparation and
At.It is significantly mentioned by the raw material by the cefuroxime sodium for injection product quality and stability of special process control preparation
It rises, especially reduces the generation in relation to object 2, strict control product quality, to ensure that the safety and validity of medication.
Purpose to realize the present invention, using following technical scheme:
The present invention provides a kind of preparation methods of cefuroxime sodium raw materials, comprising the following steps:
(1) preparation of cefuroxime acid solution: the mixing that methanol, dehydrated alcohol and water are separately added into material-compound tank A is molten
Agent stirs and simultaneously controls temperature to 10-15 DEG C, is then added cefuroxime acid, 10-15 DEG C of temperature control and is completely dissolved, and obtains cephalo
Cefuroxime acid solution, it is spare；
(2) preparation of salt forming agent solution: being added 95% ethyl alcohol in material-compound tank B, stirs and controls temperature to 10-15
DEG C, it is then added Sodium acetate trihydrate, 10-15 DEG C of temperature control and is completely dissolved, obtain salt forming agent solution, it is spare；
(3) step (1), (2) described methanol, dehydrated alcohol, water and 95% ethyl alcohol salt-forming reaction: are added in material-compound tank C
Methanol, dehydrated alcohol, water and 95% ethyl alcohol of respective volume 20%, stir evenly, are then pressurized to 0.2MPa with nitrogen, lead to
It crosses three-level aseptic filtration (0.45um, 0.22um, 0.22um) mixed solvent is filled into sterile reactor tank, stir and by temperature
10-15 DEG C is controlled, sterile cefuroxime sodium crystal seed is added, then according to the dropwise addition scheme in following table, by material-compound tank A and ingredient
Solution in tank B through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added drop-wise in sterile reactor tank respectively, is added dropwise
After continue stir and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, it is separated by solid-liquid separation, uses dehydrated alcohol
Solid product is washed in three times, and is dried in vacuo 5-10 hours, and sterile Cefuroxime Sodium bulk pharmaceutical chemicals are obtained.
In step (1), the preferred each solvent burden ratio for preparing cefuroxime acid solution is methanol: dehydrated alcohol: water=
5.5:10.8:0.2.In step (1), the compound concentration of preferred cefuroxime acid solution is 7%-11% (kg/L).Step
(1), in step (2), the molar ratio of the cefuroxime acid and Sodium acetate trihydrate is preferably 1:1.1.It is excellent in step (2)
The compound concentration of the salt forming agent solution of choosing is 2.5%-4.0% (kg/L).In step (3), the Seed charge is cephalo furan
The 1 ‰ of octanoic acid.In step (3), the overall accumulated amount (L) for washing dehydrated alcohol used in solid product is that cefuroxime acid puts into weight
(kg) 4 times.In step (3), vacuum drying condition is dry under the vacuum degree of 35-45 DEG C ,≤- 0.095Mpa.Step
(3) in, the dropwise addition scheme be see the table below:
Further, the preparation method of above-mentioned a kind of cefuroxime sodium raw materials, comprising the following steps:
(1) preparation of cefuroxime acid solution: in clean stainless steel material-compound tank A distinguish metered methanol (55L),
Dehydrated alcohol (108L), water (2L) stir and then fluid temperature control in stainless cylinder of steel A are added and are claimed in advance to 10-15 DEG C
Measured cefuroxime acid (15kg), 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare；
(2) metered 95% ethyl alcohol the preparation of salt forming agent solution: is distinguished in clean stainless steel material-compound tank B
(165L) is stirred and is then added to 10-15 DEG C and shifts to an earlier date load weighted acetate trihydrate fluid temperature control in stainless cylinder of steel B
Sodium (5.29kg), 10-15 DEG C of temperature control and after being completely dissolved obtain salt forming agent solution, obtain spare；
(3) metered methanol (11L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(21.6L), water (0.4L), 95% ethyl alcohol (33L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level degerming
Mixed solvent is filled into sterile reactor tank by filter (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid
Temperature is controlled to 10-15 DEG C, is added and is shifted to an earlier date load weighted sterile cefuroxime sodium crystal seed (15g), then according to the drop in following table
Add scheme, the solution in material-compound tank A and material-compound tank B through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is dripped respectively
It is added in sterile reactor tank, continues to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, into
Row is separated by solid-liquid separation, and washs solid product in three times with dehydrated alcohol (60L), and in 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
Lower drying 8 hours obtains sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 200 | 280 |
| 10-30 | 500 | 500 |
| 30- adds material | 1200 | 1200 |
Further, the preparation method of above-mentioned a kind of cefuroxime sodium raw materials, comprising the following steps:
(1) metered methanol the preparation of cefuroxime acid solution: is distinguished in clean stainless steel material-compound tank A
(275L), dehydrated alcohol (540L), water (10L), stir simultaneously by stainless cylinder of steel A fluid temperature control to 10-15 DEG C, then plus
Enter load weighted cefuroxime acid (75kg) in advance, 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare；
(2) metered 95% ethyl alcohol the preparation of salt forming agent solution: is distinguished in clean stainless steel material-compound tank B
(825L) is stirred and is then added to 10-15 DEG C and shifts to an earlier date load weighted acetate trihydrate fluid temperature control in stainless cylinder of steel B
Sodium (26.45kg), 10-15 DEG C of temperature control and after being completely dissolved obtains salt forming agent solution, spare；
(3) metered methanol (55L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(108L), water (2L), 95% ethyl alcohol (165L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level aseptic filtration
Mixed solvent is filled into sterile reactor tank by (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid temperature
Degree control arrives 10-15 DEG C, is added and shifts to an earlier date load weighted sterile cefuroxime sodium crystal seed (75g), then according to the dropwise addition in following table
Solution in material-compound tank A and material-compound tank B through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added dropwise scheme respectively
Into sterile reactor tank, continues to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, it carries out
It is separated by solid-liquid separation, washs solid product in three times with dehydrated alcohol (300L), and under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
It is 8 hours dry, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 1000 | 1400 |
| 10-30 | 2500 | 2500 |
| 30- adds material | 6000 | 6000 |
The present invention additionally provides a kind of preparation method of cefuroxime sodium for injection powder injection formulation simultaneously, and specific steps are such as
Under:
By sterile cefuroxime sodium bulk pharmaceutical chemicals made from the above method, sterile preparation workshop is handed over, spiral shell is used under A grades of laminar flows
Bar packing, and fills high-purity sterile nitrogen, by the obtained cefuroxime sodium for injection of different size direct packaging (0.25g, 0.5g,
0.75g, 1.5g, 2.25g, 2.5g), and control remaining oxygen≤2%.
The present invention develops special process condition to prepare cefuroxime sodium raw materials and its injection, with prior art phase
Than, product of the present invention obtains more preferably Control of Impurities, and stability is more excellent, after accelerating 6 months, retention time 0.82- in related object 2
1.0 related object is only 0.3%-0.4%, and well below standard limits 0.6%, and product index was accelerating in the prior art
Exceed 0.6% in journey already.
The preferred Sodium acetate trihydrate of Cefuroxime Sodium feed preparation process of the present invention is used as salt forming agent, 95% ethyl alcohol into salt
Agent solvent, and guarantee that the concentration range of salt forming agent solution is 2.5%-4.0%；It is preferred that cefuroxime acid feeds intake with Sodium acetate trihydrate
Molar ratio is 1:1.1；It is preferred that the optimum solvent composition and its proportion of cefuroxime acid solution are methanol: dehydrated alcohol: water=
5.5:10.8:0.2.
In addition, also especially carrying out multi-faceted research to the mode of dropwise addition and rate, salt forming agent solution or elder generation is first added in discovery
Addition cefuroxime acid solution is all bad, and obtained product color grade is unstable, moisture is higher, purity is relatively low, related object is higher, together
When be added two kinds of solution mode it is more preferable, further more various drop rates the case where, at the uniform velocity be added dropwise, be segmented accelerate drop
Add, be segmented and first accelerate dropwise addition of slowing down afterwards, eventually finding optimal dropwise addition scheme is 0-10min cefuroxime acid solution and salt forming agent
Solution is slowly added to 20ml/min and 25-30ml/min rate simultaneously respectively, two kinds of solution of 10min-30min simultaneously with
50ml/min rate is added dropwise, and two kinds of solution are added dropwise simultaneously with the dropwise addition of 120ml/min rate in 30min-.Cefuroxime Sodium dissolution
State is most unstable, perishable that impurity is caused to increase.First excessive be added a little of salt forming agent can ensure that reaction sufficiently, is prevented by the present invention
The only generation of other side reactions avoids generating impurity, and under the conditions of the specific flow velocity and dropwise addition mode, so that entire reaction
System reaches a homeostasis, realize cefuroxime acid can fast reaction generate Cefuroxime Sodium and at once be precipitated crystallize,
It is greatly lowered the generation of impurity in this way.
Under above-mentioned all these process optimization condition collective effects, it is finally obtained that moisture of the present invention is low, color grade is good, pure
Degree is high, in relation to the splendid product of indices such as object is low.
The preparation process of cefuroxime sodium for injection of the present invention, by controlling powder-injection remaining oxygen≤2%, further to protect
The stability for demonstrate,proving formulation products is more preferable.
Specific embodiment
Below by specific embodiment, invention is further described in detail, but is merely used to help understand this hair
It is bright, it enables those skilled in the art to implement or use the present invention, does not form any restrictions to the present invention.
Comparative example 1 prepares the cefuroxime sodium for injection in patent CN200910203295.1
Comparative example 1 of the present invention is the cephalo furan according to the method preparation of " embodiment 1 " in patent CN200910203295.1
Pungent sodium raw materials sample, then cefuroxime sodium for injection sample is prepared by the powder-injection preparation method of " embodiment 1-1 " in the present invention
Product.
Comparative example 2 prepares the cefuroxime sodium for injection in patent CN201510104252.3
Comparative example 2 of the present invention is the injection according to the method preparation of " embodiment 3 " in patent CN201510104252.3
Cefuroxime sodium sample.
Comparative example 3 prepares the cefuroxime sodium for injection in patent CN201610871443.7
Comparative example 3 of the present invention is the injection according to the method preparation of " embodiment 1 " in patent CN201610871443.7
Cefuroxime sodium sample.
Embodiment 1 prepares cefuroxime sodium raw materials of the present invention
(1) preparation of cefuroxime acid solution: in clean stainless steel material-compound tank A distinguish metered methanol (50L),
Dehydrated alcohol (98L), water (2L) stir and then fluid temperature control in stainless cylinder of steel A are added and are claimed in advance to 10-15 DEG C
Measured cefuroxime acid (15kg), 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare；
(2) metered 95% ethyl alcohol the preparation of salt forming agent solution: is distinguished in clean stainless steel material-compound tank B
(150L) is stirred and is then added to 10-15 DEG C and shifts to an earlier date load weighted acetate trihydrate fluid temperature control in stainless cylinder of steel B
Sodium (5.29kg), 10-15 DEG C of temperature control and after being completely dissolved obtains salt forming agent solution, spare；
(3) metered methanol (10L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(19.6L), water (0.4L), 95% ethyl alcohol (30L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level degerming
Mixed solvent is filled into sterile reactor tank by filter (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid
Temperature is controlled to 10-15 DEG C, is added and is shifted to an earlier date load weighted sterile cefuroxime sodium crystal seed (15g), then according to the drop in following table
Add scheme, the prepared feed liquid of both the above through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added drop-wise to sterile
In reactor tank, continues to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, solid-liquid point is carried out
From washing solid product in three times with dehydrated alcohol (60L), and dry 7 small under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
When, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 200 | 250 |
| 10-30 | 500 | 500 |
| 30- adds material | 1200 | 1200 |
Embodiment 2 prepares cefuroxime sodium raw materials of the present invention
(1) preparation of cefuroxime acid solution: in clean stainless steel material-compound tank distinguish metered methanol (55L),
Dehydrated alcohol (108L), water (2L) stir and then fluid temperature control in stainless cylinder of steel are added and are claimed in advance to 10-15 DEG C
Measured cefuroxime acid (15kg), 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare；
(2) preparation of salt forming agent solution: distinguishing metered 95% ethyl alcohol (165L) in clean stainless steel material-compound tank,
It stirs and then fluid temperature control in stainless cylinder of steel is added to 10-15 DEG C and shifts to an earlier date load weighted Sodium acetate trihydrate
(5.29kg), 10-15 DEG C of temperature control and after being completely dissolved obtains salt forming agent solution, spare；
(3) metered methanol (11L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(21.6L), water (0.4L), 95% ethyl alcohol (33L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level degerming
Mixed solvent is filled into sterile reactor tank by filter (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid
Temperature is controlled to 10-15 DEG C, is added and is shifted to an earlier date load weighted sterile cefuroxime sodium crystal seed (15g), then according to the drop in following table
Add scheme, the prepared feed liquid of both the above through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added drop-wise to sterile
In reactor tank, continues to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, solid-liquid point is carried out
From washing solid product in three times with dehydrated alcohol (60L), and dry 8 small under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
When, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 200 | 280 |
| 10-30 | 500 | 500 |
| 30- adds material | 1200 | 1200 |
Embodiment 3 prepares cefuroxime sodium raw materials of the present invention
(1) preparation of cefuroxime acid solution: in clean stainless steel material-compound tank A distinguish metered methanol (60L),
Dehydrated alcohol (118L), water (2L) stir and then fluid temperature control in stainless cylinder of steel A are added and are claimed in advance to 10-15 DEG C
Measured cefuroxime acid (15kg), 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare；
(2) metered 95% ethyl alcohol the preparation of salt forming agent solution: is distinguished in clean stainless steel material-compound tank B
(180L) is stirred and is then added to 10-15 DEG C and shifts to an earlier date load weighted acetate trihydrate fluid temperature control in stainless cylinder of steel B
Sodium (5.29kg), 10-15 DEG C of temperature control and after being completely dissolved obtains salt forming agent solution, spare；
(3), metered methanol (12L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(23.6L), water (0.4L), 95% ethyl alcohol (36L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level degerming
Mixed solvent is filled into sterile reactor tank by filter (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid
Temperature is controlled to 10-15 DEG C, is added and is shifted to an earlier date load weighted sterile cefuroxime sodium crystal seed (15g), then according to the drop in following table
Add scheme, the prepared feed liquid of both the above through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added drop-wise to sterile
In reactor tank, continues to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, solid-liquid point is carried out
From washing solid product in three times with dehydrated alcohol (60L), and dry 9 small under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
When, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 200 | 300 |
| 10-30 | 500 | 500 |
| 30- adds material | 1200 | 1200 |
Embodiment 1 ' prepares cefuroxime sodium raw materials of the present invention
(1) metered methanol the preparation of cefuroxime acid solution: is distinguished in clean stainless steel material-compound tank A
(250L), dehydrated alcohol (490L), water (10L), stir simultaneously by stainless cylinder of steel A fluid temperature control to 10-15 DEG C, then plus
Enter load weighted cefuroxime acid (75kg) in advance, 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare.
(2) metered 95% ethyl alcohol the preparation of salt forming agent solution: is distinguished in clean stainless steel material-compound tank B
(750L) is stirred and is then added to 10-15 DEG C and shifts to an earlier date load weighted acetate trihydrate fluid temperature control in stainless cylinder of steel B
Sodium (26.45kg), 10-15 DEG C of temperature control and after being completely dissolved, salt forming agent solution is spare.
(3) metered methanol (50L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(98L), water (2L), 95% ethyl alcohol (150L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level aseptic filtration
Mixed solvent is filled into sterile reactor tank by (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid temperature
Degree control arrives 10-15 DEG C, is added and shifts to an earlier date load weighted sterile cefuroxime sodium crystal seed (75g), then according to the dropwise addition in following table
The prepared feed liquid of both the above through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added drop-wise to sterile anti-by scheme
It answers in tank, continue to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, solid-liquid point is carried out
From washing solid product in three times with dehydrated alcohol (300L), and dry 7 under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
Hour, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 1000 | 1250 |
| 10-30 | 2500 | 2500 |
| 30- adds material | 6000 | 6000 |
Embodiment 2 ' prepares cefuroxime sodium raw materials of the present invention
(1) metered methanol the preparation of cefuroxime acid solution: is distinguished in clean stainless steel material-compound tank A
(275L), dehydrated alcohol (540L), water (10L), stir simultaneously by stainless cylinder of steel A fluid temperature control to 10-15 DEG C, then plus
Enter load weighted cefuroxime acid (75kg) in advance, 10-15 DEG C of temperature control and after being completely dissolved is spare.
(2) metered 95% ethyl alcohol the preparation of salt forming agent solution: is distinguished in clean stainless steel material-compound tank B
(825L) is stirred and is then added to 10-15 DEG C and shifts to an earlier date load weighted acetate trihydrate fluid temperature control in stainless cylinder of steel B
Sodium (26.45kg), 10-15 DEG C of temperature control and after being completely dissolved are spare.
(3) metered methanol (55L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(108L), water (2L), 95% ethyl alcohol (165L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level aseptic filtration
Mixed solvent is filled into sterile reactor tank by (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid temperature
Degree control arrives 10-15 DEG C, is added and shifts to an earlier date load weighted sterile cefuroxime sodium crystal seed (75g), then according to the dropwise addition in following table
The prepared feed liquid of both the above through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added drop-wise to sterile anti-by scheme
It answers in tank, continue to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, solid-liquid point is carried out
From washing solid product in three times with dehydrated alcohol (300L), and dry 8 under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
Hour, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 1000 | 1400 |
| 10-30 | 2500 | 2500 |
| 30- adds material | 6000 | 6000 |
Embodiment 3 ' prepares cefuroxime sodium raw materials of the present invention
(1) metered methanol the preparation of cefuroxime acid solution: is distinguished in clean stainless steel material-compound tank A
(300L), dehydrated alcohol (590L), water (10L), stir simultaneously by stainless cylinder of steel A fluid temperature control to 10-15 DEG C, then plus
Enter load weighted cefuroxime acid (75kg) in advance, 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare；
(2) metered 95% ethyl alcohol the preparation of salt forming agent solution: is distinguished in clean stainless steel material-compound tank B
(900L) is stirred and is then added to 10-15 DEG C and shifts to an earlier date load weighted acetate trihydrate fluid temperature control in stainless cylinder of steel B
Sodium (26.45kg), 10-15 DEG C of temperature control and after being completely dissolved obtains salt forming agent solution, spare；
(3) metered methanol (60L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(118L), water (2L), 95% ethyl alcohol (180L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level aseptic filtration
Mixed solvent is filled into sterile reactor tank by (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid temperature
Degree control arrives 10-15 DEG C, is added and shifts to an earlier date load weighted sterile cefuroxime sodium crystal seed (75g), then according to the dropwise addition in following table
The prepared feed liquid of both the above through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added drop-wise to sterile anti-by scheme
It answers in tank, continue to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, solid-liquid point is carried out
From washing solid product in three times with dehydrated alcohol (300L), and dry 9 under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
Hour, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 1000 | 1500 |
| 10-30 | 2500 | 2500 |
| 30- adds material | 6000 | 6000 |
Embodiment 4 ' prepares cefuroxime sodium raw materials of the present invention
(1) preparation of cefuroxime acid solution: in clean stainless steel material-compound tank distinguish metered methanol (225L),
Dehydrated alcohol (440L), water (10L) stir and then fluid temperature control in stainless cylinder of steel are added and are claimed in advance to 10-15 DEG C
Measured cefuroxime acid (75kg), 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare；
(2) preparation of salt forming agent solution: distinguishing metered 95% ethyl alcohol (675L) in clean stainless steel material-compound tank,
It stirs and then fluid temperature control in stainless cylinder of steel is added to 10-15 DEG C and shifts to an earlier date load weighted Sodium acetate trihydrate
(26.45kg), 10-15 DEG C of temperature control and after being completely dissolved obtains salt forming agent solution, spare；
(3) metered methanol (45L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(88L), water (2L), 95% ethyl alcohol (135L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level aseptic filtration
Mixed solvent is filled into sterile reactor tank by (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid temperature
Degree control arrives 10-15 DEG C, is added and shifts to an earlier date load weighted sterile cefuroxime sodium crystal seed (75g), then according to the dropwise addition in following table
The prepared feed liquid of both the above through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added drop-wise to sterile anti-by scheme
It answers in tank, continue to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, solid-liquid point is carried out
From washing solid product in three times with dehydrated alcohol (300L), and dry 5 under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
Hour, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 1000 | 1150 |
| 10-30 | 2500 | 2500 |
| 30- adds material | 6000 | 6000 |
Embodiment 5 ' prepares cefuroxime sodium raw materials of the present invention
(1) metered methanol the preparation of cefuroxime acid solution: is distinguished in clean stainless steel material-compound tank A
(360L), dehydrated alcohol (705L), water (10L), stir simultaneously by stainless cylinder of steel A fluid temperature control to 10-15 DEG C, then plus
Enter load weighted cefuroxime acid (75kg) in advance, 10-15 DEG C of temperature control and after being completely dissolved is spare；
(2) metered 95% ethyl alcohol the preparation of salt forming agent solution: is distinguished in clean stainless steel material-compound tank B
(1075L) is stirred and is then added to 10-15 DEG C and shifts to an earlier date load weighted acetate trihydrate fluid temperature control in stainless cylinder of steel B
Sodium (26.45kg), 10-15 DEG C of temperature control and after being completely dissolved are spare；
(3) metered methanol (72L), dehydrated alcohol salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
(141L), water (2L), 95% ethyl alcohol (215L), stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through three-level aseptic filtration
Mixed solvent is filled into sterile reactor tank by (0.45um, 0.22um, 0.22um), is stirred and by sterile reaction pot liquid temperature
Degree control arrives 10-15 DEG C, is added and shifts to an earlier date load weighted sterile cefuroxime sodium crystal seed (75g), then according to the dropwise addition in following table
The prepared feed liquid of both the above through three-level aseptic filtration (0.45um, 0.22um, 0.22um) and is added drop-wise to sterile anti-by scheme
It answers in tank, continue to stir after being added dropwise and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, solid-liquid point is carried out
From washing solid product in three times with dehydrated alcohol (300L), and dry 10 under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa
Hour, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
| Time (min) | Speed (ml/min) is added in cefuroxime acid solution | Speed (ml/min) is added in salt forming agent solution |
| 0-10 | 1000 | 1500 |
| 10-30 | 2500 | 2500 |
| 30- adds material | 6000 | 6000 |
The preparation of embodiment 1-1 cefuroxime sodium for injection
By sterile cefuroxime sodium bulk pharmaceutical chemicals obtained by embodiment 1, sterile preparation workshop is handed over, is used under A grades of laminar flows
Screw rod packing, and fills high-purity sterile nitrogen, by the obtained cefuroxime sodium for injection of different size direct packaging (0.25g,
0.5g,0.75g,1.5g,2.25g,2.5g).Remaining oxygen is 1.2%-1.6%.
The preparation of embodiment 2-1 cefuroxime sodium for injection
By sterile cefuroxime sodium bulk pharmaceutical chemicals obtained by embodiment 2, sterile preparation workshop is handed over, is used under A grades of laminar flows
Screw rod packing, and fills high-purity sterile nitrogen, by the obtained cefuroxime sodium for injection of different size direct packaging (0.25g,
0.5g,0.75g,1.5g,2.25g,2.5g).Remaining oxygen is 1.3%-1.7%.
The preparation of embodiment 3-1 cefuroxime sodium for injection
By sterile cefuroxime sodium bulk pharmaceutical chemicals obtained by embodiment 3, sterile preparation workshop is handed over, is used under A grades of laminar flows
Screw rod packing, and fills high-purity sterile nitrogen, by the obtained cefuroxime sodium for injection of different size direct packaging (0.25g,
0.5g,0.75g,1.5g,2.25g,2.5g).Remaining oxygen is 1.1%-1.4%.
The preparation of 1 ' -1 cefuroxime sodium for injection of embodiment
By sterile cefuroxime sodium bulk pharmaceutical chemicals obtained by embodiment 1 ', sterile preparation workshop is handed over, is used under A grades of laminar flows
Screw rod packing, and fills high-purity sterile nitrogen, by the obtained cefuroxime sodium for injection of different size direct packaging (0.25g,
0.5g,0.75g,1.5g,2.25g,2.5g).Remaining oxygen is 1.3%-1.6%.
The preparation of 2 ' -1 cefuroxime sodium for injection of embodiment
By sterile cefuroxime sodium bulk pharmaceutical chemicals obtained by embodiment 2 ', sterile preparation workshop is handed over, is used under A grades of laminar flows
Screw rod packing, and fills high-purity sterile nitrogen, by the obtained cefuroxime sodium for injection of different size direct packaging (0.25g,
0.5g,0.75g,1.5g,2.25g,2.5g).Remaining oxygen is 1.2%-1.5%.
The preparation of 3 ' -1 cefuroxime sodium for injection of embodiment
By sterile cefuroxime sodium bulk pharmaceutical chemicals obtained by embodiment 3 ', sterile preparation workshop is handed over, is used under A grades of laminar flows
Screw rod packing, and fills high-purity sterile nitrogen, by the obtained cefuroxime sodium for injection of different size direct packaging (0.25g,
0.5g,0.75g,1.5g,2.25g,2.5g).Remaining oxygen is 1.2%-1.7%.
The preparation of 4 ' -1 cefuroxime sodium for injection of embodiment
By sterile cefuroxime sodium bulk pharmaceutical chemicals obtained by embodiment 4 ', sterile preparation workshop is handed over, is used under A grades of laminar flows
Screw rod packing, and fills high-purity sterile nitrogen, by the obtained cefuroxime sodium for injection of different size direct packaging (0.25g,
0.5g,0.75g,1.5g,2.25g,2.5g).Remaining oxygen is 1.2%-1.4%.
The preparation of 5 ' -1 cefuroxime sodium for injection of embodiment
By sterile cefuroxime sodium bulk pharmaceutical chemicals obtained by embodiment 5 ', sterile preparation workshop is handed over, is used under A grades of laminar flows
Screw rod packing, and fills high-purity sterile nitrogen, by the obtained cefuroxime sodium for injection of different size direct packaging (0.25g,
0.5g,0.75g,1.5g,2.25g,2.5g).Remaining oxygen is 1.3%-1.6%.
The type and dosage screening test of 1 salt forming agent of test example and solvent for use
To investigate the influence of the type and dosage of different salt forming agents and its dosage and solvent for use to Cefuroxime Sodium, design
Prescription under 21 different conditions, as shown in table 1.Same salt forming agent 3 prescriptions corresponding with same solvent are in table 1
One control group, such as: prescription 1-3.Adjustment while having chosen salt forming agent amount and quantity of solvent in a control group, main purpose
It is to ensure that the molar concentration of solution after this kind of salt forming agent dissolves in this kind of solvent is identical, by the comparison of different prescriptions, preferably
(i.e. salt forming agent dosage is rubbed with the optimal of 1.5kg cefuroxime acid for optimal salt forming agent type and optimal salt forming agent dosage out
That ratio).
Cefuroxime Sodium preparation method:
1, the preparation of cefuroxime acid solution: by cefuroxime acid (1.5kg) be dissolved at 10-15 DEG C methanol (5.5L),
The in the mixed solvent of acetone (10.8L), water (0.2L)；
2, it the preparation of salt forming agent solution: according to prescription in table 1, is prepared under conditions of 10-15 DEG C；
3, salt-forming reaction: the amount of above-mentioned cefuroxime acid solution and salt forming agent solution used various solvents when preparing is taken
20%, be configured to the solvent bottom material of crystallization, stirring, temperature is maintained at 10-15 DEG C, is added Cefuroxime Sodium (1.5g), so
Be added dropwise cefuroxime acid solution and salt forming agent solution simultaneously afterwards, cefuroxime acid solution with flow velocity 100mL/min dropwise addition, then according to
According to prescription salt forming agent amount of solution different in table 1, it is adjusted to salt agent solution drop rate, makes two kinds of solution as far as possible at the uniform velocity while dripping
It adds complete, then proceedes to stirring and gained mixture is cooled to 5 DEG C, filtering, with dehydrated alcohol (6L) washed product in three times,
And it is 8 hours dry under 40 DEG C, the vacuum degree of≤- 0.095Mpa.
The prescription of the different salt forming agents of table 1 and its dosage
To the salt forming agent that prescription 1- prescription 21 configures, the above method is taken to prepare Cefuroxime Sodium.Then sample is carried out
Quality testing analysis, the results are shown in Table 2.Moisture, pH, color grade and polymer detection method according to Chinese Pharmacopoeia version two in 2015
Cefuroxime Sodium purity detects using high-efficient liquid phase technique in portion, and the detection method in relation to substance 1 and in relation to substance 2 is seen below.
Detection method of the Cefuroxime Sodium in relation to substance 1:
Face and uses brand-new.It takes this product appropriate, be dissolved in water and dilute the solution being made in every 1ml containing 0.5mg, as test sample
Solution, precision measure test solution 1ml, set in 100ml measuring bottle, be diluted with water to scale, shake up, and as contrast solution, shine
High performance liquid chromatography (general rule 0512) measurement, using octyl silane group silica gel as filler: molten with 50mmol/L ammonium formate
Liquid is mobile phase A, and using acetonitrile as Mobile phase B, flow velocity is 1.5ml per minute, and according to the form below carries out linear gradient elution；Detection wavelength
For 273nm, taking cefuroxime reference substance is about 10mg, is set in 20ml measuring bottle, adds 0.1mol/L sodium hydroxide solution 1ml to make molten
Solution after placing 15 minutes, adds 0.1mol/L hydrochloric acid solution to neutralize, is diluted with water to scale, as system suitability solution, takes 20
μ l injects liquid chromatograph, records chromatogram, point between cefuroxime and rear other impurities peak (relative retention time is about 1.1)
It should be greater than 3.0 from degree.
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 60 | 80 | 20 |
| 100 | 60 | 40 |
| 110 | 60 | 40 |
| 110.1 | 95 | 5 |
| 120 | 95 | 5 |
Precision measures each 20 μ l of test solution and control solution, is injected separately into liquid chromatograph, records chromatogram.For
If any impurity peaks in the chromatogram of test sample solution, impurity content is calculated by multiplied by the principal component Self-control method of correction factor,
Corresponding limit regulation in following table should be met.
Detection method of the Cefuroxime Sodium in relation to substance 2:
Face and uses brand-new.It takes this product appropriate, be dissolved in water and dilute the solution being made in every 1ml containing 0.5mg, as test sample
Solution separately takes cefuroxime reference substance appropriate, accurately weighed, is dissolved in water and quantifies dilution that every 1ml is made is molten containing about 1 μ g
Liquid, as contrast solution, precision measures contrast solution 1ml, sets in 10ml measuring bottle, be diluted with water to scale, shake up, as sensitive
Solution is spent, is measured according to molecular exclusion chromatography (general rule 0514).It is filler (TSK-GEL with spherical hydrophilic modifying silica gel
G2000swxl, 7.8mm × 30cm, 5 μm or the comparable chromatographic column of efficiency)；It is with 5mmol/L ammonium acetate solution-acetonitrile (95:5)
Mobile phase, flow velocity are 0.6ml per minute, Detection wavelength 273nm.Cefuroxime reference substance about 10mg is taken, is set in 20ml measuring bottle,
Add 0.1mol/L sodium hydroxide solution 1ml to make to dissolve, after placing 15 minutes, adds 0.1mol/L hydrochloric acid solution to neutralize, be diluted with water
It takes 20 μ l to inject liquid chromatograph as system suitability solution to scale, records chromatogram, cefuroxime peak retention time
About 14.5 minutes, cefuroxime peak and the separating degree of adjacent degradation impurity peak time before it should meet the requirements.Take sensitivity molten
20 μ l of liquid injects liquid chromatograph, records chromatogram, and the signal-to-noise ratio of principal component peak height should be greater than 10.Precision measures test solution
With each 20 μ l of contrast solution, it is injected separately into liquid chromatograph, records chromatogram, if any impurity peaks in test solution chromatogram,
Impurity peak area moral of the relative retention time less than 0.82 and the main peak area (0.2%) for being not greater than reference substance solution, relatively
Impurity peak area of the retention time between 0.82~1.0 is not greater than 3 times (0.6%) of the main facet product of contrast solution.
2 prescription 1- prescription of table, 21 sample quality testing result
The reason of selecting above-mentioned three kinds of salt forming agents is that these three salt forming agents have preferable dissolubility in organic solvent.Wherein
The dissolubility of sodium iso-octoate is best, but the by-product isooctyl acid after salt-forming reaction might have and remain in product on a small quantity, because
It may cause sterile product for isooctyl acid is not soluble in water there are the increased risks of insoluble little particulate；Sodium lactate is usually with water-soluble
The form of liquid exists, and can only in the 95% higher solvent of ethyl alcohol or water content stabilizing dissolved, in low molten of water content
There is the possibility that oily sodium lactate is precipitated in agent, the content that will lead to finished product reduces；Sodium acetate trihydrate, the pair after itself and reaction
Acetic acid product has preferable dissolubility in solvent and water, it can be ensured that after Sodium acetate trihydrate and the reaction of not participating in reaction
Acetic acid can be dissolved in solvent, and remaining acetate in minute or sodium acetate will not to the dissolubility and visible foreign matters of product
Constituting influences.
Prescription 1-6 is used as salt forming agent using sodium lactate (60%), and products obtained therefrom moisture is higher, yield is low, color is differential, purity
It is relatively low, higher in relation to object 1 and related object 2, polymer is higher, product quality is bad；Prescription 7-15 using sodium iso-octoate be used as at
Salt agent, products obtained therefrom moisture is lower, high income, color grade are good but higher in relation to object 1 and related object 2, product quality or not enough reason
Think；For prescription 16-21 using Sodium acetate trihydrate as salt forming agent, products obtained therefrom moisture is low, with high purity, and wherein prescription 19-21 is used
95% ethyl alcohol is as salt forming agent solvent, and products obtained therefrom moisture is lower, yield is higher, color grade is more preferable, purity is higher, in relation to 1 and of object
Related object 2 is lower, and the related object more particularly to retention time in object 2 less than 0.82 is not detected, retention time 0.82-1.0
Related object be only 0.14%-0.16%.Final preferred salt forming agent is Sodium acetate trihydrate, and salt forming agent solvent is 95% ethyl alcohol,
Salt forming agent dosage is 529g, i.e., cefuroxime acid and Sodium acetate trihydrate molar ratio are 1:1.1.
The screening test of 2 salt forming agent solution concentration of test example
On the basis of test example 1, influence of the salt forming agent solution concentration to Cefuroxime Sodium is prepared further is investigated.By table
Prescription 1-7 configures 95% ethanol solution of 529g Sodium acetate trihydrate various concentration in 3, and the method described below is taken to prepare cephalo furan
Pungent sodium.And to sample carry out quality testing analysis, moisture, pH, color grade, polymer, purity, in relation to object 1, the detection in relation to object 2
Method is same as above, and the results are shown in Table 4.
Cefuroxime Sodium preparation method:
1, the preparation of cefuroxime acid solution: by cefuroxime acid (1.5kg) be dissolved at 10-15 DEG C methanol (5.5L),
The in the mixed solvent of acetone (10.8L), water (0.2L)；
2, it the preparation of salt forming agent solution: according to prescription in table 3, is prepared under conditions of 10-15 DEG C；
3, salt-forming reaction: the amount of above-mentioned cefuroxime acid solution and salt forming agent solution used various solvents when preparing is taken
20%, be configured to the solvent bottom material of crystallization, stirring, temperature is maintained at 10-15 DEG C, is added Cefuroxime Sodium (1.5g), so
Be added dropwise cefuroxime acid solution and salt forming agent solution simultaneously afterwards, cefuroxime acid solution with flow velocity 100mL/min dropwise addition, then according to
According to prescription salt forming agent amount of solution different in table 3, it is adjusted to salt agent solution drop rate, makes two kinds of solution as far as possible at the uniform velocity while dripping
It adds complete, then proceedes to stirring and gained mixture is cooled to 5 DEG C, filtering, with dehydrated alcohol (6L) washed product in three times,
And it is 8 hours dry under 40 DEG C, the vacuum degree of≤- 0.095Mpa.
The prescription of 3 salt forming agent solution various concentration of table
4 prescription 1-7 sample quality testing result of table
By table 4 as it can be seen that the yield and pH of Cefuroxime Sodium are gradually increased, to cephalo furan as salt forming agent concentration increases
The influence of pungent sodium moisture, color grade and purity is less obvious, and the influence to Cefuroxime Sodium in relation to object 1 and in relation to object 2 is more obvious,
Related object more particularly to retention time in object 2 less than 0.82, prescription 3-5 are to be not detected, prescription 1, prescription 2,6 and of prescription
Prescription 7 is 0.02%, and the related object in relation to retention time 0.82-1.0 in object 2, and prescription 3-5 is below 0.2%, prescription 1,
Prescription 2, prescription 6 and prescription 7 are respectively 0.36%, 0.31%, 0.30% and 0.32%, therefore final preferred salt forming agent concentration out
Range is 2.5%-4.0%.
The screening test of 3 cefuroxime acid solution solvent for use formula of test example
To investigate the influence of different solvents and its dosage to Cefuroxime Sodium used in cefuroxime acid solution, 9 are devised
Prescription under different condition, as shown in table 5.Every 3 prescriptions that identical several solvents are used in table 5 are a control group, such as:
Prescription 1- prescription 3.It is remained unchanged in total dosage 1650L of a control group internal solvent, by adjusting the proportion shape of various solvents
At different prescriptions.Main purpose is to ensure that cefuroxime acid is dissolved in the molar concentration of the solvent solution formed in different prescriptions
It is identical, by the comparison of different prescriptions, preferred optimal solvent burden ratio prescription out.
Cefuroxime Sodium preparation method:
1, the preparation of cefuroxime acid solution: according to prescription in table 5, cefuroxime acid (1.5kg) is molten at 10-15 DEG C
In different in the mixed solvents；
2, Sodium acetate trihydrate (529g) preparation of salt forming agent solution: is dissolved in 95% ethyl alcohol (16.5L) at 10-15 DEG C
In；
3, salt-forming reaction: the amount of above-mentioned cefuroxime acid solution and salt forming agent solution used various solvents when preparing is taken
20%, be configured to the solvent bottom material of crystallization, stirring, temperature is maintained at 10-15 DEG C, be added Cefuroxime Sodium (1.5g), with
Cefuroxime acid solution and salt forming agent solution is at the uniform velocity added dropwise in flow velocity 100mL/min simultaneously, continues stirring after being added dropwise and by institute
Mixture is cooled to 5 DEG C, filtering, with dehydrated alcohol (6L) washed product in three times, and 40 DEG C ,≤- 0.095Mpa it is true
It is 8 hours dry under reciprocal of duty cycle.
The prescription of 5 different solvents of table and its dosage
Different mixed solvents are configured by prescription 1-9 in table 5, the above method is taken to prepare Cefuroxime Sodium.And to sample into
Row quality testing analysis, moisture, color grade, polymer, purity, are same as above in relation to object 1, the detection method in relation to object 2 pH, are as a result seen
Table 6.
6 prescription 1- prescription of table, 9 sample quality testing result
As seen from the data in Table 6,5 products obtained therefrom moisture of prescription is low, color grade is good, it is with high purity, in relation to object 1 and related object 2 more
Low, product quality is more preferable, therefore the final optimum solvent composition for preferably going out cefuroxime acid solution and its proportion are methanol: anhydrous
Ethyl alcohol: water=5.5:10.8:0.2.
4 cefuroxime acid solution of test example, salt forming agent solution adding manner and addition rate screening test
To investigate cefuroxime acid solution and salt forming agent solution adding manner and influence of the rate to Cefuroxime Sodium being added,
The prescription under the conditions of different additions is devised, as shown in table 7.
Cefuroxime Sodium preparation method:
1, the preparation of cefuroxime acid solution: by cefuroxime acid (1.5kg) be dissolved at 10-15 DEG C methanol (5.5L),
The in the mixed solvent of dehydrated alcohol (10.8L), water (0.2L)；
2, the preparation of salt forming agent solution: Sodium acetate trihydrate (529g) is dissolved in 95% ethyl alcohol (16.5L) at 15 DEG C；
3, salt-forming reaction: the amount of above-mentioned cefuroxime acid solution and salt forming agent solution used various solvents when preparing is taken
20%, be configured to the solvent bottom material of crystallization, stirring, temperature is maintained at 10-15 DEG C, is added Cefuroxime Sodium (1.5g), so
It is added dropwise afterwards according to scheme in table 9, continues stirring after being added dropwise and gained mixture is cooled to 5 DEG C, filtered, use is anhydrous
Ethyl alcohol (6L) washed product in three times, and it is 8 hours dry under 40 DEG C, the vacuum degree of≤- 0.095Mpa.
The different cefuroxime acid solutions of table 7 and salt forming agent solution adding manner and the screening test one that rate is added
Cefuroxime acid solution and salt forming agent solution is added by the scheme of prescription 1-22 in table 7, and takes above method system
Standby Cefuroxime Sodium, then quality testing analysis, moisture, pH, color grade, polymer, purity, related object 1, related object are carried out to sample
2 detection method is same as above, and the results are shown in Table 8.
Table 8: 22 sample quality testing result of prescription 1- prescription
By testing result it is found that the quality index of prescription 18 is better than other all prescriptions, by a part of to being first added
A part of 7 prescription 12 of cefuroxime acid solution contrast groups prescription and simultaneously is first added in salt forming agent solution contrast groups prescription 1- prescription 6
Contrast groups prescription 13- prescription 22 is added and is compared analysis, discovery is first added thereto product obtained by the mode of a certain solution
Color grade is unstable, moisture is higher, purity is relatively low, related object is higher, while the mode being added is much better, while being added again into one
Step compares the situation under different rates.
Prescription 13-15 is two kinds of solution while being at the uniform velocity added dropwise that wherein the drop rate of prescription 14 is 100ml/min, made
The related object of product is lower, quality is preferable；Prescription 16-19 is two kinds of solution while being added dropwise, and accelerates to be added dropwise simultaneously after 30min
Rate is to being added dropwise, and wherein product purity obtained by prescription 18 is higher, moisture is lower, related object is lower, and product quality is better than
Product obtained by prescription 14；Prescription 20-22 is two kinds of solution while being added dropwise, and accelerates drop rate simultaneously after 30min, in turn
Further accelerate drop rate simultaneously after 90min again to being added dropwise, obtained product quality is produced not as good as obtained by prescription 18
Product.It is excellent to have selected preferable dropwise addition mode and the case where rate behavior is prescription 18: 0- by the comparative study of prescription 1-22
For two kinds of solution of 30min simultaneously with the dropwise addition of 50ml/min rate, two kinds of solution are added dropwise simultaneously with 120ml/min rate in 30min-
It is added dropwise.
Experimental program is advanced optimized on the basis of prescription 18, has carried out prescription 23-28 screening test in table 9.By in table 9
Cefuroxime acid solution and salt forming agent solution is added in the scheme of prescription 23-28, and the above method is taken to prepare Cefuroxime Sodium, then
Quality testing analysis carried out to sample, it is moisture, pH, color grade, polymer, purity, same in relation to object 1, the detection method in relation to object 2
On, it the results are shown in Table 10.
The different cefuroxime acid solutions of table 9 and salt forming agent solution adding manner and the screening test two that rate is added
Table 10: 28 sample quality testing result of prescription 23- prescription
By testing result it is found that the quality index of prescription 26, prescription 27 is better than other all prescriptions.
On the basis of the dropwise addition scheme of prescription 18, by the way that two kinds of solution are first slowly added dropwise in 0-10min, product matter is found
Amount is slightly promoted, and the product quality as obtained by prescription 23, prescription 26-28 is better than product obtained by prescription 18, it is seen that first 10 minutes
The necessity being first slowly added dropwise is more conducive to react abundant progress.
But if changing the addition rate after 90min, no matter accelerates or slow down, such as prescription 24, prescription 25, obtained production
Quality be not it is too ideal, no more than product obtained by prescription 18.
Then it is further compared between prescription 23, prescription 26-28, finds the obtained production of prescription 26, prescription 27
Quality is promoted more significant, it is seen that the flow velocity that cefuroxime acid solution and salt forming agent solution are slowly added dropwise in first 10 minutes matches
Also most important, thus determine that the best scheme that is added dropwise is 0-10min cefuroxime acid solution and salt forming agent solution respectively with 20ml/
Min and 25-30ml/min rate is slowly added to simultaneously, and two kinds of solution of 10min-30min are added dropwise simultaneously with 50ml/min rate,
Two kinds of solution are added dropwise simultaneously with the dropwise addition of 120ml/min rate in 30min-.
5 study on the stability of test example
By above-described embodiment 1-1,2-1,3-1,1 ' -1,2 ' -1,3 ' -1,4 ' -1,5 ' -1 and comparative example 1, comparative example 2, right
0.75g gauge hypodermic prepared by ratio 3 is simulated listing with Cefuroxime Sodium and is packed, at 40 DEG C of temperature, relative humidity 75%
It is placed 6 months under part, investigates the projects such as moisture, pH, color grade, content, related object 1, related object 2, polymer, the results are shown in Table 11.
In addition to content, the detection method of all detection projects is same as above.
The detection method of content: it is measured according to high performance liquid chromatography (general rule 0512).
Chromatographic condition and system suitability are using octyl silane group silica gel as filler；With acetate buffer
It (takes sodium acetate 0.68g, glacial acetic acid 5.8g to be diluted with water into 1000ml, adjusts pH value to 3.4)-acetonitrile (85:15) with glacial acetic acid
For mobile phase.Detection wavelength is 273nm.It takes this product appropriate, be dissolved in water and dilute the solution being made in every 1ml containing 0.5mg, set
60 DEG C of water-baths are placed 30 minutes, let cool, cefuroxime portions turn is made to remove carbamyl cefuroxime, molten as system suitability
Liquid takes 20 μ l to inject liquid chromatograph, records chromatogram, and cefuroxime peak and the separating degree for going to carbamyl cefuroxime peak are answered big
In 3.0.Cefuroxime peak is about that the separating degree that impurity is peak-to-peak at 1.1 should meet the requirements with relative retention time.
Measuring method takes this product appropriate, accurately weighed, and being dissolved in water and quantifying dilution is made solution in every 1ml containing 0.1mg,
As test solution (face with newly formed or deposit under the conditions of 2~8 DEG C), precision measures 20 μ l and injects liquid chromatograph, note
Record chromatogram；It separately takes cefuroxime reference substance appropriate, is measured in the same method, be marked with C in calculated by peak area test sample by outer16H16N4O8S
Content.
Table 11 0.75g gauge hypodermic Cefuroxime Sodium stability test result
By above-described embodiment 1-1,2-1,3-1,1 ' -1,2 ' -1,3 ' -1,4 ' -1,5 ' -1 and comparative example 1, comparative example 2, right
1.5g gauge hypodermic prepared by ratio 3 is simulated listing with Cefuroxime Sodium and is packed, at 40 DEG C of temperature, 75% condition of relative humidity
It is lower to place 6 months, the projects such as moisture, pH, color grade, content, related object 1, related object 2, polymer are investigated, the results are shown in Table 12.Institute
There is the detection method of detection project to be same as above.
Table 12 1.5g gauge hypodermic Cefuroxime Sodium stability test result
It is seen by the result of table 11, table 12, compared with comparative example 1-3, product quality prepared by various embodiments of the present invention is more preferable,
And stability is more preferably, after accelerating 6 months, related object of the retention time less than 0.82 is 0.07- in the related object 2 of comparative example 1-3
0.09%, and each embodiment is 0.01%-0.04%；The related object of retention time 0.82-1.0 in the related object 2 of comparative example 1-3
More than 0.6%, and each embodiment is 0.30%-0.39%.The present invention passes through production of the special process strict control in relation to object 2
It is raw, while to miscellaneous in relation to impurity H, list in object 1, total miscellaneous control is also more preferable, product quality is further improved, is clinical application
Provide better choice.
The above is only the preferred embodiment of the present invention, are not intended to limit the invention, and those skilled in the art are come
It says, without departing from the principle of the present invention, several improvement, the retouching, equivalent replacement that can also be made should be included in this
Within the protection scope of invention.
Claims (7)
1. a kind of preparation method of cefuroxime sodium raw materials, which is characterized in that comprise the steps of:
(1) preparation of cefuroxime acid solution: it is separately added into the mixed solvent of methanol, dehydrated alcohol and water in material-compound tank A, stirs
It mixes and controls temperature to 10-15 DEG C, be then added cefuroxime acid, 10-15 DEG C of temperature control and be completely dissolved, obtain cefuroxime acid
Solution, it is spare；
(2) preparation of salt forming agent solution: being added 95% ethyl alcohol in material-compound tank B, stirs and controls temperature to 10-15 DEG C, so
After be added Sodium acetate trihydrate, 10-15 DEG C of temperature control and be completely dissolved, obtain salt forming agent solution, it is spare；
(3) step (1), (2) described methanol, dehydrated alcohol, water and 95% ethyl alcohol salt-forming reaction: is added respectively in material-compound tank C
Methanol, dehydrated alcohol, water and 95% ethyl alcohol of volume 20%, stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through
Mixed solvent is filled into sterile reactor tank by the aseptic filtration of 0.45um, 0.22um, 0.22um three-level, is stirred and is controlled temperature
To 10-15 DEG C, sterile cefuroxime sodium crystal seed is added, then according to the scheme of dropwise addition, by the solution in material-compound tank A and material-compound tank B
It through the aseptic filtration of 0.45um, 0.22um, 0.22um three-level and is added drop-wise in sterile reactor tank respectively, continues to stir after being added dropwise
And gained mixture is cooled to 5-10 DEG C；In an aseptic environment, it is separated by solid-liquid separation, washs solid-state in three times with dehydrated alcohol
Product, and be dried in vacuo 5-10 hours, obtain sterile Cefuroxime Sodium bulk pharmaceutical chemicals.
2. the preparation method of cefuroxime sodium raw materials according to claim 1, which is characterized in that in step (1), the head
Each solvent burden ratio of spore cefuroxime acid solution is methanol: dehydrated alcohol: water=5.5:10.8:0.2；The cefuroxime acid solution,
Its compound concentration kg/L is 7%-11%.
3. the preparation method of cefuroxime sodium raw materials according to claim 2, which is characterized in that in step (2), it is described at
Salt agent solution, compound concentration kg/L are 2.5%-4.0%；The molar ratio of the cefuroxime acid and Sodium acetate trihydrate is excellent
It is selected as 1:1.1.
4. the preparation method of cefuroxime sodium raw materials according to claim 3, which is characterized in that in step (3), the crystalline substance
Kind additional amount is the 1 ‰ of cefuroxime acid；The overall accumulated amount L of dehydrated alcohol used in solid product is washed as cefuroxime acid investment
4 times of weight kg；Vacuum drying condition is dry under the vacuum degree of 35-45 DEG C ,≤- 0.095Mpa；The dropwise addition scheme
It is as follows:
5. the preparation method of cefuroxime sodium raw materials according to claim 1, which is characterized in that specifically include following step
It is rapid:
(1) metered methanol 55L, anhydrous second the preparation of cefuroxime acid solution: are distinguished in clean stainless steel material-compound tank A
Alcohol 108L, water 2L are stirred and are then added to 10-15 DEG C and shift to an earlier date load weighted cephalo fluid temperature control in stainless cylinder of steel A
Cefuroxime acid 15kg, 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare；
(2) metered 95% ethyl alcohol 165L, stirring the preparation of salt forming agent solution: are distinguished in clean stainless steel material-compound tank B
And then fluid temperature control in stainless cylinder of steel B is added to 10-15 DEG C and shifts to an earlier date load weighted Sodium acetate trihydrate 5.29kg, control
Warm 10-15 DEG C and after being completely dissolved, salt forming agent solution is obtained, is obtained spare；
(3) metered methanol 11L, dehydrated alcohol 21.6L, water salt-forming reaction: are distinguished in clean stainless steel material-compound tank C
0.4L, 95% ethyl alcohol 33L, stir evenly, are then pressurized to 0.2MPa with nitrogen, pass through 0.45um, 0.22um, 0.22um three-level
Mixed solvent is filled into sterile reactor tank by aseptic filtration, is stirred and is controlled fluid temperature in sterile reactor tank to 10-15
DEG C, it is added and shifts to an earlier date load weighted sterile cefuroxime sodium crystal seed 15g, then according to the scheme of dropwise addition, by material-compound tank A and material-compound tank B
Interior solution through the aseptic filtration of 0.45um, 0.22um, 0.22um three-level and is added drop-wise in sterile reactor tank respectively, after being added dropwise
Continue to stir and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, it is separated by solid-liquid separation, with dehydrated alcohol 60L points
It washs solid product three times, and 8 hours dry under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa, obtains sterile cephalo furan
Pungent sodium raw materials medicine；
Wherein, scheme is added dropwise are as follows:
6. the preparation method of cefuroxime sodium raw materials according to claim 1, which is characterized in that specifically include following step
It is rapid:
(1) metered methanol 275L, anhydrous the preparation of cefuroxime acid solution: is distinguished in clean stainless steel material-compound tank A
Ethyl alcohol 540L, water 10L are stirred and then fluid temperature control in stainless cylinder of steel A are added load weighted in advance to 10-15 DEG C
Cefuroxime acid (75kg), 10-15 DEG C of temperature control and after being completely dissolved obtains cefuroxime acid solution, spare；
(2) preparation of salt forming agent solution: metered 95% ethyl alcohol (825L) is distinguished in clean stainless steel material-compound tank B, is stirred
It mixes and then fluid temperature control in stainless cylinder of steel B is added to 10-15 DEG C and shifts to an earlier date load weighted Sodium acetate trihydrate
(26.45kg), 10-15 DEG C of temperature control and after being completely dissolved obtains salt forming agent solution, spare；
(3) salt-forming reaction: in clean stainless steel material-compound tank C distinguish metered methanol 55L, dehydrated alcohol 108L, water 2L,
95% ethyl alcohol 165L, stirs evenly, is then pressurized to 0.2MPa with nitrogen, passes through 0.45um, 0.22um, 0.22um three-level degerming
Mixed solvent is filled into sterile reactor tank by filtering, is stirred and is added fluid temperature control in sterile reactor tank to 10-15 DEG C
Enter load weighted sterile cefuroxime sodium crystal seed 75g in advance, it, will be molten in material-compound tank A and material-compound tank B then according to the scheme of dropwise addition
Liquid through the aseptic filtration of 0.45um, 0.22um, 0.22um three-level and is added drop-wise in sterile reactor tank respectively, continues to stir after being added dropwise
It mixes and gained mixture is cooled to 5-10 DEG C；In an aseptic environment, it is separated by solid-liquid separation, is washed in three times with dehydrated alcohol 300L
It washs solid product, and 8 hours dry under 35-45 DEG C, the vacuum degree of≤- 0.095Mpa, it is former to obtain sterile Cefuroxime Sodium
Expect medicine；
Wherein, scheme is added dropwise are as follows:
7. a kind of preparation method of cefuroxime sodium for injection powder injection formulation, which is characterized in that specific step is as follows:
By sterile cefuroxime sodium bulk pharmaceutical chemicals made from claim 1 the method, sterile preparation workshop is handed over, under A grades of laminar flows
Dispensed using screw rod, and fill high-purity sterile nitrogen, by different size direct packaging be made specification be respectively 0.25g, 0.5g,
The cefuroxime sodium for injection of 0.75g, 1.5g, 2.25g, 2.5g, and control remaining oxygen≤2%.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103102357A (en) * | 2013-02-21 | 2013-05-15 | 广东立国制药有限公司 | Synthesis method of cefuroxime sodium |
| CN103374019A (en) * | 2012-04-12 | 2013-10-30 | 珠海保税区丽珠合成制药有限公司 | Preparation method of cefuroxlme sodium |
| CN104771372A (en) * | 2015-03-10 | 2015-07-15 | 华北制药河北华民药业有限责任公司 | Cefuroxime sodium powder preparation for injection |
| CN106361706A (en) * | 2016-09-30 | 2017-02-01 | 华北制药河北华民药业有限责任公司 | Cefuroxime sodium powder preparation for injection |
| CN106565748A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Preparation method for cefuroxime sodium and preparation thereof |
-
2019
- 2019-08-27 CN CN201910793868.4A patent/CN110437260B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103374019A (en) * | 2012-04-12 | 2013-10-30 | 珠海保税区丽珠合成制药有限公司 | Preparation method of cefuroxlme sodium |
| CN103102357A (en) * | 2013-02-21 | 2013-05-15 | 广东立国制药有限公司 | Synthesis method of cefuroxime sodium |
| CN104771372A (en) * | 2015-03-10 | 2015-07-15 | 华北制药河北华民药业有限责任公司 | Cefuroxime sodium powder preparation for injection |
| CN106361706A (en) * | 2016-09-30 | 2017-02-01 | 华北制药河北华民药业有限责任公司 | Cefuroxime sodium powder preparation for injection |
| CN106565748A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Preparation method for cefuroxime sodium and preparation thereof |
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