CN104873466A - Ceftriaxone sodium powder-injection for injection - Google Patents
Ceftriaxone sodium powder-injection for injection Download PDFInfo
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- CN104873466A CN104873466A CN201510104263.1A CN201510104263A CN104873466A CN 104873466 A CN104873466 A CN 104873466A CN 201510104263 A CN201510104263 A CN 201510104263A CN 104873466 A CN104873466 A CN 104873466A
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- ceftriaxone
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- acetone
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Abstract
The invention discloses a ceftriaxone sodium powder-injection for injection. the powder-injection is prepared by the following steps: (1) weighing a ceftriaxone sodium crude raw material at 20 DEG C, adding water, stirring and dissolving, adding active carbon, decolouring, filtering, and washing with mixed solvents; (2) by a particle process crystal product molecular assembly and shape-state optimization technology of North China Pharmaceutical Hebei Huamin Pharmaceutical Co., Ltd., adding a solventing-out agent acetone according to a stream acceleration table at 15 DEG C at the stirring speed of 300 r/min; (3) carrying out suction filtration, washing a filter cake with acetone, putting the filter cake into a vacuum drying oven and carrying out vacuum drying at 30-40 DEG C; and (4) sub-packaging preparations of different specifications, and controlling environmental temperature and humidity until temperature is 20-24 DEG C and humidity is less than 40% so as to obtain the ceftriaxone sodium for injection. In comparison with a traditional technology, ceftriaxone sodium prepared by the above preparation method has advantages of less impurity, high stability and the like.
Description
Technical field
The present invention relates to a kind of ceftriaxone for inj injectable powder, belong to medical art.
Background technology
Ceftriaxone sodium, also known as rocephin, is the semi-synthetic cephalosporin of the third generation that is novel, long-acting, wide spectrum, belongs to beta-lactam antibiotic, play bactericidal action by the synthesis of anti-bacteria cell wall.Have powerful antibacterial activity to most of gram positive bacteria and negative bacterium, antimicrobial spectrum comprises bacillus pyocyaneus, escherichia coli, pneumobacillus, hemophilus influenza, aerogenesis enterobacteria, Proteus, Diplococcus and S. aureus L-forms etc.Clinical be mainly used in sensitive organism infect meningitis, pneumonia, skin soft-tissue infection, peritonitis, urinary system infection, gonorrhea, liver and gall infect, surgical wound, septicemia and genital infection etc.
Ceftriaxone sodium molecular formula C
18h
16n
8na
2o
7s
33.5H
2o, molecular weight is 661.59, and structural formula is as follows:
Its chemical name is [6R [6 α; 7 β (Z)]]-3-[[(1; 2; 5; 6-tetrahydrochysene-2-methyl-5; 6-dioxo-1,2,4-triazine-3-base) sulfo-] methyl]-7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl group] is amino]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt three times of semihydrates.
1969, Roche company of Switzerland takes to cephalosporin structure and bioactive research, and synthesized ceftriaxone sodium at Late Cambrian in 1978, code name is Ro-13-9904.Japan also to start the basic research of ceftriaxone sodium in 1978, and in November, 1980 and in June, 1981 successively carried out the Ith, II clinical trial phase.Early 1980s, Sichuan Industrial Institute of Antibiotics and Dongbei Pharmaceutical General Factory take the lead in launching at home basic research and the trial-production of ceftriaxone sodium, go through several years tackling key problem, successfully achieve suitability for industrialized production in the early 1990s.
It is little that the industrial crystallization process of ceftriaxone sodium faces product particle mean size, the uneven first-class phenomenon of particle size distribution, and cause because granularity is less than normal coalescent be cause one of ceftriaxone sodium crystalline product key factor off quality.As can be seen here, in industrial crystallization process, the control of Granularity Distribution has very important practical significance.
NCPC Hebei Huamin Pharmaceutical Co., Ltd.'s systematic study ceftriaxone sodium product form feature, establishes crystal habit optimization method, uses coupling crystallization new technique to achieve molecular assembly assembling with regularly arranged.And the equipment that exploitation is advanced, the configuration of optimization device and inside dimension, to reach excellent hydrodynamic performance, ensure that product crystal form is perfect, even particle size distribution.Due to influencing each other of Coupling Crystallization Alternative parameter, and the maximization of coupling crystallizer, control giving the computer of flow process to bring obvious large time delay to affect, for above controlling difficulties, utilize BACH system, and develop Adaptive Fuzzy Control algorithm software, solve the impact that large time delay effect associates with multivariate, ensure the operational stability of coupling crystallization flow process; Fully realize automatization and operation accuracy, reduce personal error.Consider that the general character of cephalo-type process of producing product is for realizing resource-sharing, the equipment that fully realizes maximizes economization and produces, and reduces product cost, and the Flexible Production Technology of exploitation advanced person is also the key of this project.From raw material to final products, each link of whole process is all optimized, and uses advanced technology, equipment and control and management system, ensures that whole production process is reached advanced world standards.
The less stable of ceftriaxone sodium, all unstable to heat, meta-acid environment, meta-alkali environment, show that outward appearance is easy to change, content reduces, occurs the problems such as catabolite, the reason of appearance may be to be mingled with in partial impurities, crystal formation the reasons such as residual solvent in crystallization.
Address this problem and must research and develop the crucial production technology of novel coupling crystallization, to optimize the process parameters such as solvent burden ratio, temperature, time, pressure, pH value, crystallization is carried out under the suitable conditions, thus ensure the quality of product.
Summary of the invention
The object of the invention is to provide a kind of preparation method of ceftriaxone for inj injectable powder, adopt the crucial production technology of novel coupling crystallization, the ceftriaxone for inj powder body obtained is made to reach excellent hydrodynamic performance, crystal form is perfect, even particle size distribution, the larger raising of color level, clarity, purity and stability.
For achieving the above object, the invention provides a kind of ceftriaxone for inj injectable powder, prepared by following steps:
(1) at 20 DEG C, take crude product of ceftriaxone sodium raw material, add distilled water, stirring and dissolving, add active carbon, filter after decolouring, wash filtering residue, filter flask with the mixed solvent of acetone and water, filtrate enters in crystallization bottle.
(2) at 15 DEG C, mixing speed is under 300 turns/min, presses surface low rate of acceleration and adds dissolved agent acetone:
| Time (min) | Rate of addition (ml/min) |
| 0-10 | 0.2-0.3 |
| 10-30 | 0 |
| 30-60 | 0.6-0.8 |
| 60-90 | 0.9-1.1 |
| 90-130 | 1.1-1.3 |
| 130-210 | 3.0-3.2 |
| 210-250 | 3.6-3.8 |
| 250-270 | 0 |
(3) sucking filtration, uses washing with acetone filter cake, filter cake is put into vacuum drying oven, at 30-40 DEG C vacuum drying, weigh, aseptic subpackaged.
Preferably, in step (1), the compound concentration of crude product of ceftriaxone sodium is not more than 0.4g/ml.
Preferably, in step (1), the volume ratio of mixed solvent acetone and water is 1 ~ 5:1.
Preferably, in step (1), the volume ratio of mixed solvent acetone and water is 1 ~ 3:1.
Preferably, in step (2), press surface low rate of acceleration and add dissolved agent acetone:
| Time (min) | Rate of addition (ml/min) |
| 0-10 | 0.2-0.3 |
| 10-30 | 0 |
| 30-60 | 0.7-0.8 |
| 60-90 | 1-1.1 |
| 90-130 | 1.2-1.3 |
| 130-210 | 3.1-3.2 |
| 210-250 | 3.7-3.8 |
| 250-270 | 0 |
Preferably, in step (2), press surface low rate of acceleration and add dissolved agent acetone:
| Time (min) | Rate of addition (ml/min) |
| 0-10 | 0.25 |
| 10-30 | 0 |
| 30-60 | 0.8 |
| 60-90 | 1 |
| 90-130 | 1.25 |
| 130-210 | 3.15 |
| 210-250 | 3.75 |
| 250-270 | 0 |
Preferably, in step (3), vacuum drying oven temperature is 35 ~ 40 DEG C.
Compared with the ceftriaxone sodium that traditional handicraft is obtained, the ceftriaxone sodium impurity that the present invention obtains is few, the few thus stability advantages of higher of residual solvent in raw material.
Accompanying drawing explanation
Fig. 1 is the microscope figure of ceftriaxone sodium prepared by the embodiment of the present invention 1;
Detailed description of the invention
Embodiment 1
(1) at 20 DEG C, the crude product of ceftriaxone sodium raw material of precise 30g, add the distilled water of 50mL, open stirring, about 10-15 minute dissolves completely, then adds 3g active carbon, decolour 30 minutes, filter, wash filtering residue, filter flask 2 times with the mixed solvent that 60ml volume ratio is (acetone: water=3:1), filtrate enters in crystallization bottle.
(2) at 15 DEG C, mixing speed is under 300 turns/min, presses surface low rate of acceleration and adds dissolved agent acetone:
| Time (min) | Acetone speed (ml/min) |
| 0-10 | 0.21 |
| 10-30 | 0 |
| 30-60 | 0.8 |
| 60-90 | 1 |
| 90-130 | 1.1 |
| 130-210 | 3.1 |
| 210-250 | 3.6 |
| 250-270 | 0 |
(3) carry out sucking filtration after crystallization, with 20ml*3 washing with acetone filter cake, filter cake is put into vacuum drying oven, vacuum drying oven temperature, at 40 DEG C, vacuum drying, to be weighed, subpackage.
Embodiment 2
(1) at 20 DEG C, the crude product of ceftriaxone sodium raw material of precise 30g, add the distilled water of 50mL, open stirring, about 10-15 minute dissolves completely, then adds 3g active carbon, decolour 30 minutes, filter, wash carbon, filter flask 2 times with the mixed solvent that 60ml volume ratio is (acetone: water=2:1), filtrate enters in crystallization bottle.
(2) at 15 DEG C, mixing speed is under 300 turns/min, presses surface low rate of acceleration and adds dissolved agent acetone:
| Time (min) | Acetone speed (ml/min) |
| 0-10 | 0.25 |
| 10-30 | 0 |
| 30-60 | 0.8 |
| 60-90 | 1 |
| 90-130 | 1.25 |
| 130-210 | 3.15 |
| 210-250 | 3.75 |
| 250-270 | 0 |
(3) filtration washing is dry, carries out sucking filtration, with 20ml*3 washing with acetone filter cake, filter cake is put into vacuum drying oven after crystallization, and vacuum drying oven temperature, at 35 DEG C, vacuum drying, to be weighed, subpackage.
Embodiment 3
(1) at 20 DEG C, the crude product of ceftriaxone sodium raw material of precise 30g, add the distilled water of 50mL, open stirring, about 10-15 minute dissolves completely, then adds 3g active carbon, decolour 30 minutes, filter, wash filtering residue, filter flask 2 times with the mixed solvent that 60ml volume ratio is (acetone: water=2:1), filtrate enters in crystallization bottle.
(2) at 15 DEG C, mixing speed is under 300 turns/min, presses surface low rate of acceleration and adds dissolved agent acetone:
| Time (min) | Acetone speed (ml/min) |
| 0-10 | 0.3 |
| 10-30 | 0 |
| 30-60 | 0.7 |
| 60-90 | 1.1 |
| 90-130 | 1.25 |
| 130-210 | 3.1 |
| 210-250 | 3.8 |
| 250-270 | 0 |
(3) carry out sucking filtration after crystallization, with 20ml*3 washing with acetone filter cake, filter cake is put into vacuum drying oven, vacuum drying oven temperature, at 35 DEG C, vacuum drying, to be weighed, subpackage.
Embodiment 4:
According to the aseptic ceftriaxone sodium of above-mentioned example suitability for industrialized production, getting 0.05kg respectively cleans between the rear subpackage sending into B level of de-bag, under A level laminar flow, adopt screw filling machine to be divided in sterile vial by former medicine according to different packing specifications (0.25g/ bottle, 0.5g/ bottle, 1.0g/ bottle, 2.0g/ bottle), the humiture that controls environment is 20 ~ 24 DEG C, humidity is less than 40%, obtains ceftriaxone for inj powder injection formulation.
Compared with conventional art, the ceftriaxone sodium crystal kenel that this technology is produced is homogeneous, and have obvious granule under microscope, crystal form is thick, as shown in Figure 1.
Ceftriaxone sodium belongs to the higher product of anaphylaxis, and the ceftriaxone sodium that this technology is produced is greatly improved on sensitization source, wherein 2-mercaptobenzothiazole can control even not detect in very substandard, and domestic similar manufacturer can detect substantially;
Ceftriaxone sodium color level all can control at below 3#, and content can reach more than 93%, and be in a leading position level; Single contaminant can control below 0.2%, and in product, impurity number is few, generally only has 1 to 2.
The ceftriaxone sodium injection that above-described embodiment and traditional handicraft are produced is simulated to go on the market and packs, temperature 40 DEG C, place 6 months under relative humidity 75% condition, respectively at the 1st, 2,3, sampling in June, investigate the project such as appearance character, color level, content, related substance, and with 0 day results contrast.
Shown in result of the test sees the following form:
As can be seen from above-mentioned accelerated test result, adopt ceftriaxone for inj injectable powder of the present invention within 6 months, to investigate through accelerated test, there is not significant change in indices, traditional handicraft then there occurs significant change.Therefore the stability of ceftriaxone sodium that prepared by the present invention is higher than conventional art.
More than describe preferred embodiment of the present invention in detail.Should be appreciated that those of ordinary skill in the art just design according to the present invention can make many modifications and variations without the need to creative work.Therefore, all technical staff in the art, all should by the determined protection domain of claims under this invention's idea on the basis of existing technology by the available technical scheme of logical analysis, reasoning, or a limited experiment.
Claims (7)
1. a ceftriaxone for inj injectable powder, is characterized in that, described ceftriaxone for inj injectable powder is prepared by following steps:
(1) at 20 DEG C, take crude product of ceftriaxone sodium raw material, add distilled water, stirring and dissolving, add active carbon, filter after decolouring, wash filtering residue, filter flask with the mixed solvent of acetone and water, filtrate enters in crystallization bottle;
(2) at 15 DEG C, mixing speed is under 300 turns/min, presses surface low rate of acceleration and adds dissolved agent acetone:
(3) sucking filtration, uses washing with acetone filter cake, filter cake is put into vacuum drying oven, at 30-40 DEG C vacuum drying, weigh, aseptic subpackaged;
(4) carry out the preparation subpackage of different size, the humiture that controls environment is 20 ~ 24 DEG C, and humidity is less than 40%, obtains ceftriaxone for inj powder injection formulation.
2. ceftriaxone for inj injectable powder according to claim 1, is characterized in that, in described step (1), the compound concentration of described crude product of ceftriaxone sodium is not more than 0.4g/ml.
3. ceftriaxone for inj injectable powder according to claim 1, is characterized in that, in described step (1), the volume ratio of described mixed solvent acetone and water is 1 ~ 5:1.
4. ceftriaxone for inj injectable powder according to claim 1, is characterized in that, in described step (1), the volume ratio of described mixed solvent acetone and water is 1 ~ 3:1.
5. ceftriaxone for inj injectable powder according to claim 1, is characterized in that, in described step (2), presses surface low rate of acceleration and adds dissolved agent acetone:
6. ceftriaxone for inj injectable powder according to claim 1, is characterized in that, in described step (2), presses surface low rate of acceleration and adds dissolved agent acetone:
7. ceftriaxone for inj injectable powder according to claim 1, is characterized in that, in described step (3), described vacuum drying oven temperature is 35 ~ 40 DEG C.
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|---|---|---|---|
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Cited By (8)
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| CN104926834A (en) * | 2015-05-28 | 2015-09-23 | 浙江长典医药有限公司 | Ceftriaxone sodium compound entity for children and preparation for ceftriaxone sodium compound entity for children |
| CN105418641A (en) * | 2015-12-30 | 2016-03-23 | 中山市金城道勃法制药有限公司 | Original-quality ceftriaxone sodium and pharmaceutical preparation thereof |
| CN106432275A (en) * | 2016-09-21 | 2017-02-22 | 临沂草之美医药科技有限公司 | Method for preparing crystalline ceftriaxone sodium compound as drug for treating surgical infection |
| CN106432278A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Crystalline compound of drug ceftriaxone sodium for treating surgical operation infections |
| CN106432279A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Method for preparing medicine ceftriaxone sodium crystal compound for treating surgical infection |
| CN106432274A (en) * | 2016-09-21 | 2017-02-22 | 临沂草之美医药科技有限公司 | Crystalline compound of drug ceftriaxone sodium for treating surgical operation infections |
| CN106562971A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Ceftriaxone sodium powder-needle preparation production method |
| CN109010280A (en) * | 2018-07-23 | 2018-12-18 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of ceftriaxone sodium for injection powder injection formulation |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926834A (en) * | 2015-05-28 | 2015-09-23 | 浙江长典医药有限公司 | Ceftriaxone sodium compound entity for children and preparation for ceftriaxone sodium compound entity for children |
| CN105418641A (en) * | 2015-12-30 | 2016-03-23 | 中山市金城道勃法制药有限公司 | Original-quality ceftriaxone sodium and pharmaceutical preparation thereof |
| CN105418641B (en) * | 2015-12-30 | 2018-08-10 | 广东金城金素制药有限公司 | It is a kind of former to develop quality Ceftriaxone Sodium and its pharmaceutical preparation |
| CN106432275A (en) * | 2016-09-21 | 2017-02-22 | 临沂草之美医药科技有限公司 | Method for preparing crystalline ceftriaxone sodium compound as drug for treating surgical infection |
| CN106432274A (en) * | 2016-09-21 | 2017-02-22 | 临沂草之美医药科技有限公司 | Crystalline compound of drug ceftriaxone sodium for treating surgical operation infections |
| CN106432278A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Crystalline compound of drug ceftriaxone sodium for treating surgical operation infections |
| CN106432279A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Method for preparing medicine ceftriaxone sodium crystal compound for treating surgical infection |
| CN106562971A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Ceftriaxone sodium powder-needle preparation production method |
| CN106562971B (en) * | 2016-09-30 | 2019-03-22 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of ceftriaxone sodium powder-needle preparation |
| CN109010280A (en) * | 2018-07-23 | 2018-12-18 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of ceftriaxone sodium for injection powder injection formulation |
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