CN104873466B - A kind of ceftriaxone sodium for injection powder-injection - Google Patents
A kind of ceftriaxone sodium for injection powder-injection Download PDFInfo
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- CN104873466B CN104873466B CN201510104263.1A CN201510104263A CN104873466B CN 104873466 B CN104873466 B CN 104873466B CN 201510104263 A CN201510104263 A CN 201510104263A CN 104873466 B CN104873466 B CN 104873466B
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Abstract
The invention discloses a kind of ceftriaxone sodium for injection powder-injection, are prepared by following steps：(1) at 20 DEG C, crude product of ceftriaxone sodium raw material is weighed, adds water, stirring and dissolving adds in activated carbon, filtered after decoloration, mixed solvent washing；(2) NCPC Hebei Huamin Pharmaceutical Co., Ltd. is using the assembling of particle process crystal product molecule and form optimisation technique, and at 15 DEG C, mixing speed is under 300 turns/min, and dissolved agent acetone is added in by stream rate of acceleration table；(3) filter, wash filter cake with acetone, filter cake is put into vacuum drying chamber, be dried in vacuo at 30 40 DEG C；(4) the preparation packing of different size is carried out, controlling ambient temperature and humidity, humidity is less than 40%, obtains ceftriaxone sodium for injection for 20~24 DEG C.By Ceftriaxone Sodium made from the preparation method compared with traditional handicraft, have many advantages, such as that impurity is few, stability is high.
Description
Technical field
The present invention relates to a kind of ceftriaxone sodium for injection powder-injection, belong to pharmaceutical technology field.
Background technology
Ceftriaxone Sodium is also known as ceftriaxone, is new, long-acting, wide spectrum the semi-synthetic cynnematin of the third generation, belong to β-
Lactam antibiotics plays bactericidal effect by inhibiting bacteria the synthesis of cell membrane.To most of gram positive bacterias and the moon
Property bacterium have a powerful antibacterial activity, antimicrobial spectrum includes Pseudomonas aeruginosa, Escherichia coli, pneumobacillus, haemophilus influenzae, aerogenesis intestines
Bacterium, Proteus, Diplococcus and S. aureus L-forms etc..The meningitis, pneumonia, skin that clinic is mainly used for sensitive bacteria infection are soft
Tissue infection, peritonitis, urinary system infection contamination, gonorrhoea, liver and gall infection, surgery wound, septicemia and genital infection etc..
Ceftriaxone Sodium molecular formula C18H16N8Na2O7S3·3.5H2O, molecular weight 661.59, 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- dioxos -1,2,4-
Triazine -3- bases) thio] methyl] -7- [[(2- amino -4- thiazolyls) (methoxyimino) acetyl group] amino] -8- oxos -5-
Thia -1- azabicyclos [4.2.0] oct-2-ene -2- carboxylic acid disodium salt three times semihydrates.
1969, Roche companies of Switzerland took to the research of cynnematin structure and bioactivity, in 1978 for the first time
It was found that and Ceftriaxone Sodium, code name Ro-13-9904 are synthesized.The basis that Japan also began to Ceftriaxone Sodium in 1978
Research, and successively carried out the I, the II clinical trial phase in November, 1980 and in June, 1981.In the early 1980s, Sichuan
Dongbei Pharmaceutical General Factory takes the lead in being unfolded at home the basic research and trial-production of Ceftriaxone Sodium antibiotic industrial research in one's power, after number
Year tackling key problem, industrialized production is successfully realized in the early 1990s.
The industrial crystallization process of Ceftriaxone Sodium faces phenomena such as product particle mean size is small, and size distribution is inhomogenous, and by
It is one of an important factor for initiation Ceftriaxone Sodium crystalline product is off quality in being coalesced caused by granularity is less than normal.Thus may be used
See, the control of Granularity Distribution is with very important practical significance during industrial crystallization.
NCPC Hebei Huamin Pharmaceutical Co., Ltd.'s system research Ceftriaxone Sodium product form feature, builds
Found crystal habit optimization method, using coupling crystallization new technology realize molecular assembly assembling with it is regularly arranged.And it develops
Advanced equipment optimizes the configuration and inside dimension of device, to reach excellent hydrodynamic performance, ensures that product crystalline form is complete
U.S., even particle size distribution.Due to influencing each other for Coupling Crystallization Alternative parameter, and the enlargement of crystallizer is coupled,
To the control of the computer of flow apparent large time delay will be brought to influence, for more than controlling difficulties, using BACH systems, and developed certainly
Adaptive fuzzy control algorithm software solves large time delay effect and the associated influence of multivariable, ensures the operation of coupling crystallization flow
Stability；It fully realizes automation and operation accuracy, reduces human error.In view of the general character of cephalo-type process of producing product
To realize resource-sharing, fully realize that equipment maximizes economization production, reduce product cost, develop advanced flexible production skill
Art is also this item purpose key.Each link from raw material to final products whole process is optimized, and use is advanced
Technology, equipment and control and management system, ensure that entire production process is reached advanced world standards.
The stability of Ceftriaxone Sodium is poor, unstable to heat, meta-acid environment, meta-alkali environment, shows appearance mutability
The reason for color, content reduce, the problems such as catabolite occur, occur may be to be mingled in partial impurities, crystal form to remain in crystallization
The reasons such as solvent.
Solve the problems, such as that this must research and develop the crucial production technology of new coupling crystallization, with optimize solvent burden ratio, temperature, when
Between, the processes parameter such as pressure, pH value, crystallization is made to carry out under the suitable conditions, so as to ensure the quality of product.
The content of the invention
It is an object of the present invention to provide a kind of preparation methods of ceftriaxone sodium for injection powder-injection, are crystallized using new coupling
Crucial production technology makes ceftriaxone sodium for injection powder obtained reach excellent hydrodynamic performance, and crystalline form is perfect, granularity
It is evenly distributed, color grade, clarity, purity and the larger raising of stability.
To achieve the above object, the present invention provides a kind of ceftriaxone sodium for injection powder-injection, by following steps system
It is standby：
(1) at 20 DEG C, crude product of ceftriaxone sodium raw material is weighed, adds in distilled water, stirring and dissolving adds in activated carbon, takes off
It is filtered after color, washs filter 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 in 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) filter, wash filter cake with acetone, filter cake is put into vacuum drying chamber, be dried in vacuo, claim at 30-40 DEG C
Weight, it is 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 in 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 in 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 chamber temperature is 35~40 DEG C.
Compared with Ceftriaxone Sodium made from traditional handicraft, ceftriaxone sodium impurity produced by the present invention is few, residual in raw material
Stay solvent few thus the advantages that stability is high.
Description of the drawings
Fig. 1 is the microscope figure of Ceftriaxone Sodium prepared by the embodiment of the present invention 1；
Specific embodiment
Embodiment 1
(1) at 20 DEG C, the crude product of ceftriaxone sodium raw material of precise 30g adds in the distilled water of 50mL, opens stirring,
It is completely dissolved within about 10-15 minutes, then adds in 3g activated carbons, decolourize 30 minutes, filtering is (acetone with 60ml volume ratios：Water=
3:1) mixed solvent washing filter residue, filter flask 2 times, 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 in 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) filtered after crystallizing, wash filter cake with 20ml*3 acetone, filter cake is put into vacuum drying chamber,
Vacuum drying chamber temperature is dried in vacuo, weighs at 40 DEG C, packing.
Embodiment 2
(1) at 20 DEG C, the crude product of ceftriaxone sodium raw material of precise 30g adds in the distilled water of 50mL, opens stirring,
It is completely dissolved within about 10-15 minutes, then adds in 3g activated carbons, decolourize 30 minutes, filtering is (acetone with 60ml volume ratios：Water=
2:1) mixed solvent washing carbon, filter flask 2 times, 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 in 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 dried, and is filtered after crystallization, washs filter cake with 20ml*3 acetone, filter cake is put into
In vacuum drying chamber, vacuum drying chamber temperature is dried in vacuo, weighs at 35 DEG C, packing.
Embodiment 3
(1) at 20 DEG C, the crude product of ceftriaxone sodium raw material of precise 30g adds in the distilled water of 50mL, opens stirring,
It is completely dissolved within about 10-15 minutes, then adds in 3g activated carbons, decolourize 30 minutes, filtering is (acetone with 60ml volume ratios：Water=
2:1) mixed solvent washing filter residue, filter flask 2 times, 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 in 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) filtered after crystallizing, wash filter cake with 20ml*3 acetone, filter cake is put into vacuum drying chamber,
Vacuum drying chamber temperature is dried in vacuo, weighs at 35 DEG C, packing.
Embodiment 4：
According to the sterile Ceftriaxone Sodium of examples detailed above industrialized production, B grades are sent into after taking the de- bag of 0.05kg cleanings respectively
Packing between, under A grades of laminar flows using screw filling machine by active compound according to different packing specification (0.25g/ bottles, 0.5g/ bottles,
1.0g/ bottles, 2.0g/ bottles) it is divided in sterile vial, controlling ambient temperature and humidity, humidity is less than 40%, is noted for 20~24 DEG C
It penetrates with ceftriaxone sodium powder-needle preparation.
Compared with traditional technology, the Ceftriaxone Sodium crystal kenel of this technology production is homogeneous, there is apparent under microscope
Grain, crystalline form is coarse, as shown in Figure 1.
Ceftriaxone Sodium belongs to the higher product of allergic reaction, and the Ceftriaxone Sodium of this technology production has in sensitization source
Very big improvement, wherein 2-mercaptobenzothiazole can be controlled even to be not detected in very substandard, and domestic similar manufacturer's base
It can be detected on this；
Ceftriaxone Sodium color grade can be controlled in below 3#, and content can reach more than 93%, and be in a leading position level；It is single miscellaneous
Mass-energy is controlled below 0.2%, and impurity number is few in product, general only 1 to 2.
By above-described embodiment and conventionally produced ceftriaxone sodium injection simulation listing packaging, in 40 DEG C of temperature,
Placed 6 months under the conditions of relative humidity 75%, respectively at the 1st, 2,3, sampling in June, investigate appearance character, color grade, content, related
The projects such as substance, and with 0 day results contrast.
Result of the test see the table below shown：
The accelerated examination of ceftriaxone sodium for injection powder-injection using the present invention is can be seen that from above-mentioned accelerated test result
It tests 6 months and investigates, significant change does not occur for indices, and significant change then has occurred in traditional handicraft.Therefore present invention system
The stability of standby Ceftriaxone Sodium is higher than traditional technology.
The preferred embodiment of the present invention described in detail above.It should be appreciated that those of ordinary skill in the art without
Creative work is needed according to the present invention can to conceive and makes many modifications and variations.Therefore, all technologies in the art
Personnel are available by logical analysis, reasoning, or a limited experiment on the basis of existing technology under this invention's idea
Technical solution, all should be in the protection domain being defined in the patent claims.
Claims (5)
1. a kind of ceftriaxone sodium for injection powder-injection, which is characterized in that the ceftriaxone sodium for injection powder-injection by with
It is prepared by lower step：
(1) at 20 DEG C, crude product of ceftriaxone sodium raw material is weighed, adds in distilled water, stirring and dissolving adds in activated carbon, after decoloration
Filtering washs filter residue, filter flask with the mixed solvent of acetone and water, and 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 in dissolved agent acetone：
(3) filter, wash filter cake with acetone, filter cake is put into vacuum drying chamber, be dried in vacuo, weigh at 30-40 DEG C, nothing
Bacterium dispenses；
(4) the preparation packing of different size is carried out, controlling ambient temperature and humidity, humidity is less than 40%, is injected for 20~24 DEG C
With ceftriaxone sodium powder-needle preparation；
In the step (1), the compound concentration of the crude product of ceftriaxone sodium is not more than 0.4g/ml；
In the step (1), the volume ratio of the mixed solvent acetone and water is 1~5:1.
2. ceftriaxone sodium for injection powder-injection according to claim 1, which is characterized in that described in the step (1)
The volume ratio of mixed solvent acetone and water is 1~3:1.
3. ceftriaxone sodium for injection powder-injection according to claim 1, which is characterized in that in the step (2), press
Surface low rate of acceleration adds in dissolved agent acetone：
4. ceftriaxone sodium for injection powder-injection according to claim 1, which is characterized in that in the step (2), press
Surface low rate of acceleration adds in dissolved agent acetone：
5. ceftriaxone sodium for injection powder-injection according to claim 1, which is characterized in that described in the step (3)
Vacuum drying chamber temperature is 35~40 DEG C.
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Families Citing this family (8)
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| CN109010280B (en) * | 2018-07-23 | 2021-04-06 | 华北制药河北华民药业有限责任公司 | Preparation method of ceftriaxone sodium powder injection preparation for injection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104370941A (en) * | 2014-12-15 | 2015-02-25 | 四川制药制剂有限公司 | Injection ceftriaxone sodium preparation method |
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| US20050059821A1 (en) * | 2003-09-17 | 2005-03-17 | Debashish Datta | Method for manufacture of ceftriaxone sodium |
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|---|---|---|---|---|
| CN104370941A (en) * | 2014-12-15 | 2015-02-25 | 四川制药制剂有限公司 | Injection ceftriaxone sodium preparation method |
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| 丙酮在头孢曲松钠精制中的应用与研究;曹观贞，等;《临床合理用药》;20150131;第8卷(第1A期);第118-120页 * |
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