CN106220647A - A kind of cefathiamidine compound and preparation thereof and preparation method - Google Patents
A kind of cefathiamidine compound and preparation thereof and preparation method Download PDFInfo
- Publication number
- CN106220647A CN106220647A CN201610588576.3A CN201610588576A CN106220647A CN 106220647 A CN106220647 A CN 106220647A CN 201610588576 A CN201610588576 A CN 201610588576A CN 106220647 A CN106220647 A CN 106220647A
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- Prior art keywords
- cefathiamidine
- impurity
- preparation
- control limit
- compound
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- 0 C*CC(*[C@@](*)([C@@]1(*2C(C(*(C)*)=O)=C(COC(*3CC3)=O)C*1)*=I)C2=O)=O Chemical compound C*CC(*[C@@](*)([C@@]1(*2C(C(*(C)*)=O)=C(COC(*3CC3)=O)C*1)*=I)C2=O)=O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/28—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by an aliphatic carboxylic acid, which is substituted by hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
Abstract
The present invention provides a kind of cefathiamidine compound and preparation i.e. Cefathiamidine for injection thereof; described cefathiamidine compound or preparation vacuum packaging or be filled with noble gas, nitrogen, carbon dioxide are protected; make cefathiamidine isolation and the contacting of oxygen in air; quality stability can be greatly enhanced; efficiently control impurity level; its Control of Impurities is: impurity A≤1.0%; impurity B≤0.5%; impurity C≤0.1%, impurity D≤0.5%, other single the most miscellaneous≤0.2%; total impurities≤2.0%; solve purity difference, shade deviation, the problem of poor stability.
Description
Technical field
The present invention relates to a kind of cefathiamidine compound and preparation thereof and preparation method, belong to pharmaceutical technology field.
Background technology
Prior art is recorded, and cefathiamidine (Cefathiamidine) has another name called C-18, entitled (6R, the 7R)-3 of chemistry
[(acetoxyl group) methyl]-7-[α-(N, N'-diisopropylamidinateand sulfenyl)-acetylamino] 8-oxo-5-thia-1-azabicyclo
[4,2,0] oct-2-ene-2-formic acid betaine, molecular formula is C19H28N4O6S2, molecular weight is 472.59, and its chemical structural formula is:
At present, cefathiamidine compound is by Shanghai Institute of Pharmaceutical Industry and Baiyunshan Pharmaceutics Stock-sharing Co., Ltd., Guangzhou City
The beta-lactam antibiotic of common independent research, has stronger antibacterial action, particularly has enterococcus gram positive bacteria
Unique curative effect, uses extensively clinically.
Cefathiamidine compound has a unique molecular structure of amphion inner salt, heat, meets light, meets moist lability, easily
Decompose variable color.Currently, the cefathiamidine compound raw material that domestic market is sold, its purity is poor, and color and luster is bad, stability
Difference, thus have impact on its quality of the pharmaceutical preparations.
Summary of the invention
The problem above existed for cefathiamidine compound, at feed change building-up process or the crystal knot of prior art
In the case of structure all cannot improve its product quality, the present inventor finds through research, creatively finds cefathiamidine
Compound or preparation carry out being vacuum-packed or are filled with in it is packed noble gas, nitrogen, carbon dioxide are protected, can be greatly
Ground improves the quality stability of cefathiamidine compound, efficiently controls its impurity level, and more one step solves purity difference, color and luster
Difference, the problem of poor stability.
An object of the present invention is to provide a kind of cefathiamidine compound, and its structural formula is:
Wherein,
Concrete structure is:
Present invention also offers a kind of cefathiamidine preparation for injection, will divide by cefathiamidine compound of the present invention
Dress is made, and specification is 0.25～5.0g.
It is another object of the present invention to, use specific method and technological means in cefathiamidine compound and preparation thereof
Each impurity level controlled, substantially increase its quality criteria requirements, it is ensured that excellent in same kind of product quality
More property and stability.
Cefathiamidine compound of the present invention and preparation thereof, wherein major impurity includes A, B, C, D, to each impurity and
Its control limit is specified respectively.
As in the present invention, the impurity A in cefathiamidine compound and preparation thereof shows as R3=CH2OH, control limit is
1.0%, structural formula is:
As in the present invention, the impurity B in cefathiamidine compound and preparation thereof shows as cefathiamidine Δ2Isomer,
Control limit is 0.5%, and structural formula is:
As in the present invention, the impurity C in cefathiamidine compound and preparation thereof shows as R1=Br, R2For COOH, control
Limit is 0.1%, and structural formula is:
As in the present invention, the impurity D in cefathiamidine compound and preparation thereof shows as R2And R3It is combined into lactone, for-
COOCH2-, control limit is 0.5%, and structural formula is:
As one of preferred embodiment of the invention, the invention provides a kind of cefathiamidine compound and preparation thereof,
Wherein,
Impurity A shows as R3=CH2OH, control limit is 1.0%；
Impurity B shows as cefathiamidine Δ2Isomer, control limit is 0.5%；
Impurity C shows as R1=Br, R2For COOH, control limit is 0.1%；
Impurity D shows as R2And R3It is combined into lactone, for-COOCH2-, control limit is 0.5%；
Other single miscellaneous control limits are 0.2%, and the control limit of total impurities is 2.0%.
One of preferred embodiment as the present invention, above-mentioned is present in the control of each impurity in cefathiamidine or preparation
Limit is filled with noble gas when being by vacuum packaging or packaging, nitrogen, carbon dioxide realize.Thus it is greatly enhanced quality
Stability, efficiently controls impurity level, solves purity difference, shade deviation, the problem of poor stability.
As the present invention one preferred embodiment, wherein noble gas is selected from helium, neon, argon, krypton, xenon, radon etc..
Owing to the impurity level of cefathiamidine compound of the present invention and preparation thereof is superior to commercially available prod, applicant
Through 20 batches of products long-time stability investigate, optimize its storage requirement further, by existing Industry code requirements airtight,
Preserve at the cold secretly place of being dried, be optimized for airtight, in cool dark dry place preservation.Storage requirement is easier to control, workable, and
And Cold Chain Logistics mode can be changed, cost is greatly reduced, there is unforeseeable technique effect.
| Title | Control limit of the present invention | Industry code requirements |
| Cefathiamidine | Airtight, preserve at the cool dark place of being dried | Airtight, preserve at the cold dark place of being dried |
| Cefathiamidine for injection | Airtight, preserve at the cool dark place of being dried | Airtight, preserve at the cold dark place of being dried |
Detailed description of the invention
Following example are to further illustrate the present invention, but definitely not limitation of the scope of the invention.Referring to
Embodiment is further elaborated on the present invention, implements it should be appreciated to those skilled in the art that the present invention is not limited to these
Example and the preparation method of use.And, the present invention can be equal to by those skilled in the art according to description of the invention
Replace, combine, improve or modify, but these are intended to be included in the scope of the present invention.
The preparation of embodiment 1a cefathiamidine raw material
Preparation method according to the cefathiamidine in patent CN102491986A prepares cefathiamidine raw material, by the head of preparation
Spore sulfur amidine raw material inflated with nitrogen is packed, every bag of 50g.
The preparation of embodiment 1b cefathiamidine raw material
Preparation method according to the cefathiamidine in patent CN102491986A prepares cefathiamidine raw material, by the head of preparation
Spore sulfur amidine raw material filling CO 2 is packed, every bag of 50g.
The preparation of embodiment 1c cefathiamidine raw material
Preparation method according to the cefathiamidine in patent CN102491986A prepares cefathiamidine raw material, by the head of preparation
Spore sulfur amidine material vacuum is packed, every bag of 50g.
The preparation of embodiment 2a Cefathiamidine for injection
After cillin bottle wash clean, inflated with nitrogen, cefathiamidine raw material prepared by subpackage embodiment 1a, 0.5g/ bottle, tamponade,
Roll lid.
The preparation of embodiment 2b Cefathiamidine for injection
After cillin bottle wash clean, filling CO 2, cefathiamidine raw material prepared by subpackage embodiment 1b, 0.5g/ bottle, pressure
Plug, rolls lid.
The preparation of embodiment 2c Cefathiamidine for injection
After cillin bottle wash clean, inflated with nitrogen, cefathiamidine raw material prepared by subpackage embodiment 1c, 0.5g/ bottle, tamponade,
Roll lid.
Comparative example:
Marketable material: cefathiamidine, lot number 20131201, producer: Jiangsu Hi-stone Pharmaceutical Co., Ltd., for normal packet
Dress.
Commercial preparation: Cefathiamidine for injection, lot number 1311322, producer: SHANDONG LUOXIN PHARMACY STOCK Co., LTD., for
Ordinary packing.
Embodiment 3 study on the stability: accelerated test
Injection cephalo sulfur prepared by cefathiamidine raw material embodiment 1a, 1b, 1c prepared and embodiment 2a, 2b, 2c
Amidine is accelerated experiment investigation with commercially available cefathiamidine raw material and Cefathiamidine for injection, and investigation condition is temperature 40 DEG C ± 2
DEG C, relative humidity 75% ± 5%, place 6 months, respectively at 0,1,2,3,6 the end of month sample.
Inspection target is character, the color of solution, moisture, acidity, content and has related substance.
Table 1 accelerated test investigates result-1
Table 2 accelerated test investigates result-2
Result: by above-mentioned test data, investigate through 6 months accelerated tests, embodiment of the present invention 1a, 1b, 1c
The every Testing index of Cefathiamidine for injection prepared by the cefathiamidine raw material of preparation and embodiment 2a, 2b, 2c varies less, bright
Aobvious less than commercially available product, absolutely prove the superiority of the present invention, quality stability can be greatly enhanced, efficiently control impurity
Level, solves purity difference, shade deviation, the problem of poor stability.
Embodiment 4 study on the stability long term test
Injection cephalo sulfur prepared by cefathiamidine raw material embodiment 1a, 1b, 1c prepared and embodiment 2a, 2b, 2c
Amidine carries out long term test investigation with commercially available cefathiamidine raw material and Cefathiamidine for injection, and investigation condition is temperature 25 DEG C ± 2
DEG C, relative humidity 60% ± 10%, place 6 months, respectively at 0,3,6,9,12,24 the end of month sample.
Inspection target is character, the color of solution, moisture, acidity, content and has related substance.
Table 3 long term test investigates result-1
Table 4 long term test investigates result-2
Result: by above-mentioned test data, investigate through 24 months long term tests, embodiment of the present invention 1a, 1b, 1c
The every Testing index of Cefathiamidine for injection prepared by the cefathiamidine raw material of preparation and embodiment 2a, 2b, 2c varies less, bright
Aobvious less than commercially available product, absolutely prove the superiority of the present invention, quality stability can be greatly enhanced, efficiently control impurity
Level, solves purity difference, shade deviation, the problem of poor stability.
Claims (7)
1. a cefathiamidine compound, structural formula is:
Wherein,
R2=COO-,
2. a cefathiamidine preparation for injection, it is characterised in that for the cefathiamidine compound subpackage system described in claim 1
Becoming, specification is 0.25～5.0g.
Cefathiamidine compound the most according to claim 1 and 2 or preparation, it is characterised in that major impurity include A, B, C,
D, wherein,
Impurity A shows as R3=CH2OH, control limit is 1.0%；
Impurity B shows as cefathiamidine Δ2Isomer, control limit is 0.5%；
Impurity C shows as R1=Br, R2For COOH, control limit is 0.1%；
Impurity D shows as R2And R3It is combined into lactone, for-COOCH2-, control limit is 0.5%；
Other single miscellaneous control limits are 0.2%, and the control limit of total impurities is 2.0%.
Cefathiamidine compound the most according to claim 1 and 2 or preparation, wherein the control limit of impurity A is 1.0%,
Structural formula is:
The control limit of impurity B is 0.5%, and structural formula is:
The control limit of impurity C is 0.1%, and structural formula is:
The control limit of impurity D is 0.5%, and structural formula is:
5. the cefathiamidine compound prepared described in any one of Claims 1 to 4 or the method for preparation, it is characterised in that logical
It is filled with noble gas, nitrogen, carbon dioxide to control the limit of each impurity when crossing vacuum packaging or packaging.
Method the most according to claim 5, wherein noble gas is selected from helium, neon, argon, krypton, xenon, radon etc..
7., according to the cefathiamidine compound described in any one of claim 1～6 or preparation Cefathiamidine for injection, its feature exists
It is airtight in holding conditions, preserves at the cool dark place of being dried.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610588576.3A CN106220647A (en) | 2016-07-25 | 2016-07-25 | A kind of cefathiamidine compound and preparation thereof and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610588576.3A CN106220647A (en) | 2016-07-25 | 2016-07-25 | A kind of cefathiamidine compound and preparation thereof and preparation method |
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| CN106220647A true CN106220647A (en) | 2016-12-14 |
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ID=57532237
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| CN201610588576.3A Pending CN106220647A (en) | 2016-07-25 | 2016-07-25 | A kind of cefathiamidine compound and preparation thereof and preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113350511A (en) * | 2021-03-01 | 2021-09-07 | 郎俊娜 | Novel sterile powder filling mixed protective gas for injection |
| CN115124552A (en) * | 2022-06-16 | 2022-09-30 | 国药集团威奇达药业有限公司 | Preparation method of deacetyl cefathiamidine |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113350511A (en) * | 2021-03-01 | 2021-09-07 | 郎俊娜 | Novel sterile powder filling mixed protective gas for injection |
| CN113350511B (en) * | 2021-03-01 | 2024-01-02 | 郎俊娜 | Novel sterile powder filling mixed shielding gas for injection |
| CN115124552A (en) * | 2022-06-16 | 2022-09-30 | 国药集团威奇达药业有限公司 | Preparation method of deacetyl cefathiamidine |
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