CN101584665A - Cefotiam hydrochloride medicament composition sterile powder injection and preparation method thereof - Google Patents
Cefotiam hydrochloride medicament composition sterile powder injection and preparation method thereof Download PDFInfo
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- CN101584665A CN101584665A CNA200910304459XA CN200910304459A CN101584665A CN 101584665 A CN101584665 A CN 101584665A CN A200910304459X A CNA200910304459X A CN A200910304459XA CN 200910304459 A CN200910304459 A CN 200910304459A CN 101584665 A CN101584665 A CN 101584665A
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Abstract
The present invention discloses a cefotiam hydrochloride medicament composition sterile powder injection, including 500 to 600 weight shares of cefotiam hydrochloride and 110 to 150 weight shares of anhydrous sodium carbonate. The cefotiam hydrochloride medicament composition sterile powder injection has advantages of a good stability and a high purity. The invention also discloses a method for preparing the cefotiam hydrochloride medicament composition sterile powder injection, including steps of weighing the cefotiam hydrochloride and the anhydrous sodium carbonate according to the formula amount separately and mixing them in a sterile container uniformly. The method is simple, and the cefotiam hydrochloride prepared by the above method has a good stability.
Description
Technical field
The invention belongs to the synthetic and formulation art of medicine, in particular, what the present invention relates to is a kind of cefotiam hydrochloride medicament composition sterile powder injection and preparation method thereof.
Background technology
Cefotiam is by the research and development of Japanese Wu Tian company, and 1981 first at the semi-synthetic cephalosporin of the second filial generation of Japan's listing.This product is approaching to the effect and the cefazolin (cefazolin) of gram positive bacteria, to gram-negative bacteria, more excellent as effects such as haemophilus, escherichia coli, klebsiella spp, proteus mirabilises, enterobacteria, citrobacter, the positive Bacillus proteus of indole etc. also there are antibacterial action.The quiet notes administration of dihydrochloride that clinical use is stable is used for the treatment of the infection due to the sensitive organism, as the infection due to pneumonia, bronchitis, biliary tract infection, peritonitis, urinary tract infection and operation and the wound and septicemia etc.
The English name of cefotiam hydrochloride is Cefotiam Hydrochloride, its chemical name be (6R, 7R)-7-[2 (thiazolamine-4-yl) acetamido]-3-[1-(the 2-dimethyl aminoethyl]-1H-tetrazolium-5-base-sulfidomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid dihydrochloride.Structural formula is as follows:
(formula I)
Chinese Journal of Pharmaceuticals 2004,35 (8) 507-508 pages or leaves, name is called in the article of " cefotiam hydrochloride graphical Synthetic Routes " and discloses existing cefotiam hydrochloride graphical Synthetic Routes, wherein introduced the method for existing several synthetic hydrochloric acid cefotiams, these method steps are various, and resulting cefotiam hydrochloride product appearance color is not good, and purity is not high.
The patent No. is ZL01808592, and name is called the preparation method that discloses a kind of cefotiam hydrochloride in the patent of " cephalosporin intermediate ".In this invention, the 7-ACA that discloses with the tetraphydro-borate form is a raw material, itself and tri-n-butyl amine are reacted, the 2-formamido group thiazolyl chloroacetic chloride that adds hydrochloride form then reacts, last in the product of above-mentioned reaction, add entry and hydrochloric acid is handled, obtain the cefotiam of dihydrochloride form.Defectives such as raw material was not easy to obtain in the preparation method before this preparation method had remedied, step is various, but this synthetic method yield is low, and resulting product purity is also low.
Application number is CN200610010235.4, name is called the preparation method that discloses a kind of cefotiam dihydrate dihydrochloride in the patent application of " preparation method of cefotiam dihydrate dihydrochloride ", described method is with 7-amino-cephalosporanic acid and [(N, N)-dimethyl-amino-ethyl]-reaction of 5-sulfydryl-tetrazole makes [3-[[[(N, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulfur] methyl]-8 oxos-5-thia-1H-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] hydrochloric acid, product and formamido-thiazolyl-4-excess acetyl chloride then, generate the formyl cefotiam, add mineral acid and make solvent, generate the cefotiam hydrochloride crude product, the further refining then cefotiam hydrochloride that obtains.The synthetic cefotiam content in crude product of this method height, color is fabulous, residual considerably less of impurity.In the production of cefotiam aseptic powder, finished product cephalo appearance color is added the thiosulfuric acid sodium reagent in reaction system, make its appearance color good, but the yield that obtains product is low, and the solvent residual amount height.
In sum, though prior art discloses the multiple synthetic method of cefotiam hydrochloride, it is low that existing synthetic method exists resulting cefotiam hydrochloride purity, and step is various, defectives such as yield is low, so research worker is from prior art, by the synthetic method that chooses, and the process conditions in strict each step of control, thereby reach the purpose that addresses the deficiencies of the prior art, in view of this, special this invention of proposition.
Summary of the invention
First purpose of the present invention is to provide a kind of cefotiam hydrochloride medicament composition sterile powder injection.Described cefotiam hydrochloride medicament composition sterile powder injection, it is during as the cefotiam hydrochloridefor inj compositions, good stability, purity height.
To achieve these goals, the technical solution used in the present invention is:
A kind of cefotiam hydrochloride medicament composition sterile powder injection, described cefotiam hydrochloride medicament composition sterile powder injection comprises cefotiam hydrochloride 500-600 weight portion, natrium carbonicum calcinatum 110-150 weight portion, preferred described compositions comprises: cefotiam hydrochloride 500 weight portions, natrium carbonicum calcinatum 121 weight portions, cefotiam hydrochloride wherein is in cefotiam.
The preparation method of cefotiam hydrochloride medicament composition sterile powder injection of the present invention comprises:
(1) preparation of intermediate 1:
With 7-ACA is raw material, under the condition that anhydrous acetonitrile, boron trifluoride etherate exist, with 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazole reaction, adds hydrochloric acid again, then with obtaining intermediate 1 behind the ammonia adjusting pH value:
(2) preparation of intermediate 2:
In 2-formamido group-thiazolyl-4-acetic acid, the limit edged stirs and adds PCl5 in batches, reacts the after-filtration that finishes and obtains intermediate 2;
(3) preparation of intermediate 3:
Add acetonitrile and triethylamine in intermediate 1, cooling obtains intermediate 1 solution; Add acetonitrile in intermediate 2, cooling obtains intermediate 2 solution, and intermediate 2 solution are added in intermediate 1 solution, obtains intermediate 3 after the reaction;
(4) preparation of cefotiam hydrochloride crude product:
Intermediate 3 is added in the mixed solution of entry and hydrochloric acid in batches, heat up, add entry and acetone again, further add acetone then, obtain the cefotiam hydrochloride crude product;
(5) the cefotiam hydrochloride crude product is refining:
The cefotiam hydrochloride crude product is dissolved in water, add active carbon again and adsorb, coarse filtration is taken off charcoal, and filtrate adds the acetone crystallize with 0.22 micron microporous filter membrane fine straining, fine straining liquid, and washing with acetone is used in the back, obtains cefotiam hydrochloride after the drying.
In the step of the present invention (1), the mol ratio of 7-ACA, 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazole, these three kinds of materials of boron trifluoride is 1: (1-1.5): 3; Preferred described mol ratio is 1: 1: 3.
When regulating pH value with ammonia among the present invention, the concentration of ammonia is the ammonia of 25-28%, and the concentration of preferred described ammonia is 28%, and described percentage ratio is mass percent.
After regulating pH value, also comprise filtration among the present invention with ammonia, exsiccant step, wherein exsiccant temperature is 40-45 ℃.
Step of the present invention (1) specifically comprises: be raw material with 7-ACA, it is added in the anhydrous acetonitrile, in the suspension that forms, add 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazole again and form mixed solution, when being remained on-5～5 ℃, the temperature of mixed solution adds boron trifluoride-ether complex, reacted 2-2.5 hour down at 30-38 ℃ behind the mix homogeneously, cool off the back dripping hydrochloric acid again, with obtaining intermediate 1 behind the ammonia adjusting pH value.
Step of the present invention (2) specifically comprises: 2-formamido group-thiazolyl-4-acetic acid is dissolved in the dichloromethane, be cooled to-20 ℃, add PCl5 in batches, stir when adding, the speed that stirs is 110-130 rev/min, after adding finishes, proceeds to stir 1.5-3 hour again, the speed that stirs is 60-80 rev/min, more after filtration, obtain intermediate 2 after the drying.
Step of the present invention (3) specifically comprises: intermediate 1 is suspended in the acetonitrile, is cooled to-15～-20 ℃, behind the dropping triethylamine, it is stirred, is cooled to-35～-45 ℃, obtain mixed liquor; In addition intermediate 2 is added in 100ml～150ml acetonitrile, adds in the aforementioned mixed liquor after being pre-chilled to-25～-35 ℃, stirred 70～90 minutes, be warming up to-15～-25 ℃, obtain crystal at-40～-45 ℃, more after filtration ,-after the 40-45 ℃ drying intermediate 3.
Step of the present invention (5) specifically comprises: with the cefotiam hydrochloride crude product, the water that adds 12-18 ℃ dissolves, adding active carbon again adsorbs, the addition of active carbon is the 5-8% of cefotiam hydrochloride crude product quality, and adsorption time is 25-40 minute, and coarse filtration is taken off charcoal, gained filtrate is with 0.22 micron microporous filter membrane fine straining, fine straining liquid adds the acetone crystallize, and the reuse washing with acetone is drying to obtain cefotiam hydrochloride.
Step described in the present invention (4) specifically comprises: water and HCl (37%) are mixed the formation mixed liquor, and intermediate 3 slowly is added in the mixed liquor in batches, is warming up to the 30-35 degree and keeps 45 hours, adds entry and acetone again; Further add acetone, will obtain the cefotiam hydrochloride crude product after the crystal drying that obtain.
Second purpose of the present invention is to provide a kind of preparation method of cefotiam hydrochloride medicament composition sterile powder injection.
To achieve these goals, the technical solution used in the present invention is:
A kind of preparation method of cefotiam hydrochloride medicament composition sterile powder injection, described method comprises: take by weighing recipe quantity cefotiam hydrochloride and natrium carbonicum calcinatum respectively, mix homogeneously in sterile chamber.
Describe the present invention below:
A kind of cefotiam hydrochloride medicament composition sterile powder injection, described cefotiam hydrochloride medicament composition sterile powder injection comprises: cefotiam hydrochloride 500-600 weight portion, natrium carbonicum calcinatum 110-150 weight portion, preferred described cefotiam hydrochloride composition sterile injectable powder comprises: cefotiam hydrochloride 500 weight portions, natrium carbonicum calcinatum 121 weight portions, cefotiam hydrochloride wherein is in cefotiam.
Cefotiam hydrochloride medicament composition sterile powder injection of the present invention, its good stability, the purity height, its related substances is low.
The preparation method of cefotiam hydrochloride specifically comprises among the present invention
(1) with 7-ACA is raw material, it is added in the anhydrous acetonitrile, in the suspension that forms, add 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazole again and form mixed solution, when being remained on-5～5 ℃, the temperature of mixed solution adds boron trifluoride-ether complex, reacted 2-2.5 hour down at 30-38 ℃ behind the mix homogeneously, cool off the back dripping hydrochloric acid again, with obtaining intermediate 1 behind the ammonia adjusting pH value.
In the above-mentioned reaction, the mol ratio of 7-ACA, 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazole, these three kinds of materials of boron trifluoride is 1: (1-1.5): 3; Preferred described mol ratio is 1: 1: 3.After regulating pH value, also comprise filtration among the present invention with ammonia, exsiccant step, wherein exsiccant temperature is 40-45 ℃.
When regulating pH value with ammonia among the present invention, the concentration of ammonia is the ammonia of 25-28%, and the concentration of preferred described ammonia is 28%, and described percentage ratio is mass percent.Described pH value is 3.0.The ammonia that why adopts 25-28% is as the PH regulator, be because ammonia is weakly alkaline solution, so prior art adopts highly basic such as sodium hydroxide solution relatively, ammonia can not make the partial pH value of solution rise too fast in the process that adds, thereby avoid target product crystal speed when forming to cause some foreign atoms or unreacted raw molecule are wrapped in the crystal too soon, make that resulting target product does not need can reach high purity through complicated post processing mode (only crystal need be got final product after with washing with acetone) yet.
(2) 2-formamido group-thiazolyl-4-acetic acid is dissolved in the dichloromethane, be cooled to-20 ℃, add PCl5 in batches, stir when adding, the speed that stirs is 110-130 rev/min, after adding finishes, proceeds to stir 1.5-3 hour again, the speed that stirs is 60-80 rev/min, more after filtration, obtain intermediate 2 after the drying.Described drying is a vacuum drying, carries out under 28-32 ℃.
The present invention is in the synthetic process of cefotiam hydrochloride, step is many, in order to make final products obtain high yield and purity, extremely important in each step reaction to the control of side reaction, research worker finds in the process of research, by speed and time that control is stirred can be so that the yield of the resulting target product of this step and purity height.May be that the speed of stirring is 110-130 rev/min, has so just avoided the concentration in a certain zone in adding fashionable reaction system to uprise suddenly, has reduced the generation of following side reaction because when adding PCl5 in batches.And after adding finishes and stirs 1.5-3 hour, reaction solution is abundant mix homogeneously, and the speed that stirs is reduced to 60-80 rev/min, helps the generation of primary response so on the contrary, guarantee to react fully between the primary response reactant, thereby obtain target product.
(3) intermediate 1 is suspended in the acetonitrile, is cooled to-15～-20 ℃, behind the dropping triethylamine, it is stirred, is cooled to-35～-45 ℃, obtain mixed liquor; In addition intermediate 2 is added in 100ml～150ml acetonitrile, adds in the aforementioned mixed liquor after being pre-chilled to-25～-35 ℃, stirred 70～90 minutes, be warming up to-15～-25 ℃, obtain crystal at-40～-45 ℃, more after filtration, after the 40-45 ℃ drying intermediate 3.
In this step, intermediate 1 is that mol ratio is 1: 1 with the addition of intermediate 2, with intermediate 1 with after intermediate 2 mixes, stirred 70～90 minutes at-40～-45 ℃ earlier, be warming up to-15～-25 ℃ then, the programming rate of this section is per minute 1-2 ℃, why will control the speed of intensification, because in the middle of the process that heats up, also be crystal formation process, research worker is found, is controlled such programming rate, can make crystal keep the good surface appearance shape, promptly white to faint yellow crystallization or crystalline powder, and programming rate is too fast, then can make the jaundice of crystal outward appearance, make it when using as injection, the clarity of product is better.And programming rate is slow excessively, then makes intermediate 1 slow with the response speed of intermediate 2, makes side reaction increase, and product yield reduces.
(4) water and HCl (37%) are mixed the formation mixed liquor, intermediate 3 slowly is added in the mixed liquor in batches, is warming up to 30-35 ℃ and keeps 4-5 hour, adds entry and acetone again; Further add acetone, crystallization occurs, will obtain the cefotiam hydrochloride crude product after the crystal drying that obtain.
(5) with the cefotiam hydrochloride crude product, the water that adds 12-18 ℃ dissolves, adding active carbon again adsorbs, the addition of active carbon is the 5-8% of cefotiam hydrochloride crude product quality, and adsorption time is 25-40 minute, and coarse filtration is taken off charcoal, gained filtrate is with 0.22 micron microporous filter membrane fine straining, fine straining liquid adds the acetone crystallize, and the reuse washing with acetone is drying to obtain cefotiam hydrochloride.
Among the present invention the cefotiam hydrochloride crude product is being carried out in the purified process, elder generation dissolves it with 12-18 ℃ water, adsorb toward wherein adding proper amount of active carbon then, the clarity of solution when active carbon can improve the cefotiam hydrochloride use, can adsorb thermal source, pigment again, but active carbon also there is certain adsorption to cefotiam hydrochloride simultaneously.Therefore, the present invention has investigated the influence to cefotiam hydrochloride in the cefotiam hydrochloride compositions of temperature, adsorption time.The result shows, when adsorption time 25-40 minute, adsorption temp 12-18 ℃, and best results.
The invention has the beneficial effects as follows: cefotiam hydrochloride of the present invention, its outward appearance are extremely faint yellow crystallization or crystalline powder of white, its content height, and related substance is lower, is controlled at below 2%.When using as injectable powder with cefotiam hydrochloride compositions of the present invention, its clarity is good, and stability is high, and the content of cefotiam polymer is low, is below 0.2%.
The specific embodiment
Embodiment 1
(1) takes by weighing 27.2 gram 7-ACA, it is added in the 140mL anhydrous acetonitrile, formed suspension; In the suspension that forms, add 17.3 gram 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazoles again, form mixed solution, add boron trifluoride-ether complex 160mL when the temperature of mixed solution is remained on-5～5 ℃ and (contain boron trifluoride 20 grams, 0.3mol, reacted 2.5 hours down at 30 ℃ behind the mix homogeneously, be cooled to the hydrochloric acid that splashes into 30mL37% after 5 ℃ again, ice bath is regulated pH value to 3.0 with 28% ammonia down, growing the grain 1 hour, filter, filter cake 50ml washing with acetone obtains 33.1 gram intermediate 1 after 45 ℃ of dryings.
(2) 18.6 gram 2-formamido group-thiazolyl-4-acetic acid are dissolved in the 250mL dichloromethane, be cooled to-20 ℃, add PCl5 in batches, stir when adding, the speed of stirring is 130 rev/mins, after adding finishes, proceeded again to stir 2 hours, the speed that stirs is 80 rev/mins, obtains precipitation more after filtration, obtains 21.6 gram intermediate 2 after will being deposited in 32 ℃ of vacuum dryings.
(3) 16.8 gram intermediate 1 are suspended in the acetonitrile, are cooled to-15 ℃, behind the dropping 25mL triethylamine, it is stirred, is cooled to-40 ℃, obtain mixed liquor; In addition 10.6 gram intermediate 2 are added in the 100ml acetonitrile, add in the aforementioned mixed liquor after being pre-chilled to-30 ℃, stirred 80 minutes, be warming up to-20 ℃, the suspension crystal occurs at-40 ℃, more after filtration, after 40 ℃ of dryings 22.16 gram intermediate 3.
(4) 12mL water and 8mlHCl (37%) are mixed the formation mixed liquor, 13 gram intermediate 3 slowly are added in the mixed liquor in batches, and mixed liquor is warming up to 30 ℃ and kept 4.5 hours, adds 12mL water and 200mL acetone again; Further add 200mL acetone, crystallization occurs, growing the grain is after 1 hour, the crystal that obtains is filtered and obtains 10.8 gram cefotiam hydrochloride crude products after 3 hours in 50 ℃ of dryings.
(5) with 10.8g cefotiam hydrochloride crude product, the 50mL water that adds 18 ℃ dissolves, adding 0.54 gram active carbon again adsorbs, the addition of active carbon is 5% of a cefotiam hydrochloride crude product quality, and adsorption time is 30 minutes, and coarse filtration is taken off charcoal, gained filtrate is with 0.22 micron microporous filter membrane fine straining, fine straining liquid adds the acetone crystallize, and the reuse washing with acetone is drying to obtain 8.96 gram cefotiam hydrochlorides.
Embodiment 2
(1) takes by weighing 27.2 gram 7-ACA, it is added in the 140mL anhydrous acetonitrile, formed suspension; In the suspension that forms, add 25.95 gram 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazoles again, form mixed solution, when being remained on 0～5 ℃, the temperature of mixed solution adds boron trifluoride-ether complex 170mL (containing boron trifluoride 23 grams, 0.35mol), reacted 2 hours down at 38 ℃ behind the mix homogeneously, be cooled to the hydrochloric acid that splashes into 28mL37% after 5 ℃ again, ice bath is regulated pH value to 3.0 with 25% ammonia down, growing the grain 1.5 hours, filter, filter cake 50ml washing with acetone obtains 32.8 gram intermediate 1 after 40 ℃ of dryings.
(2) 18.6 gram 2-formamido group-thiazolyl-4-acetic acid are dissolved in the 250mL dichloromethane, be cooled to-20 ℃, add PCl5 in batches, stir when adding, the speed of stirring is 120 rev/mins, after adding finishes, proceeded again to stir 1.5 hours, the speed that stirs is 70 rev/mins, obtains precipitation more after filtration, obtains 21.9 gram intermediate 2 after will being deposited in 28 ℃ of vacuum dryings.
(3) 16.8 gram intermediate 1 are suspended in the acetonitrile, are cooled to-20 ℃, behind the dropping 28ml triethylamine, it is stirred, is cooled to-35 ℃, obtain mixed liquor; In addition 11.2 gram intermediate 2 are added in the 100ml acetonitrile, add in the aforementioned mixed liquor after being pre-chilled to-35 ℃, stirred 70 minutes, be warming up to-15 ℃, obtain crystal at-45 ℃, more after filtration, after 40 ℃ of dryings 21.96 gram intermediate 3.
(4) 12mL water and 8mlHCl (37%) are mixed the formation mixed liquor, 14 gram intermediate 3 slowly are added in the mixed liquor in batches, and mixed liquor is warming up to 35 ℃ and kept 4 hours, adds 12mL water and 180mL acetone again; Further add 180mL acetone, crystallization occurs, growing the grain is after 1 hour, the crystal that obtains is filtered and obtains 11.5 gram cefotiam hydrochloride crude products after 3.5 hours in 45 ℃ of dryings.
(5) with 10.8g cefotiam hydrochloride crude product, the 60mL water that adds 12 ℃ dissolves, adding 0.864 gram active carbon again adsorbs, the addition of active carbon is 8% of a cefotiam hydrochloride crude product quality, and adsorption time is 25 minutes, and coarse filtration is taken off charcoal, gained filtrate is with 0.22 micron microporous filter membrane fine straining, fine straining liquid adds the acetone crystallize, and the reuse washing with acetone is drying to obtain 8.89 gram cefotiam hydrochlorides.
Embodiment 3
(1) takes by weighing 27.2 gram 7-ACA, it is added in the 140mL anhydrous acetonitrile, formed suspension; In the suspension that forms, add 13.84 gram 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazoles again, form mixed solution, add boron trifluoride-ether complex 160mL when the temperature of mixed solution is remained on-2～2 ℃ and (contain boron trifluoride 20 grams, 0.3mol, reacted 2-2.5 hour down at 30-38 ℃ behind the mix homogeneously, be cooled to again and splash into 37% hydrochloric acid after 2 ℃, ice bath is regulated pH value to 3.0 with 27% ammonia down, growing the grain 1 hour, filter, filter cake 50ml washing with acetone obtains 33.1 gram intermediate 1 after 45 ℃ of dryings.
(2) 18.6 gram 2-formamido group-thiazolyl-4-acetic acid are dissolved in the 250mL dichloromethane, be cooled to-20 ℃, add PCl5 in batches, stir when adding, the speed of stirring is 110 rev/mins, after adding finishes, proceeded again to stir 3 hours, the speed that stirs is 60 rev/mins, obtains precipitation more after filtration, obtains 21.6 gram intermediate 2 after will being deposited in 28-32 ℃ of vacuum drying.
(3) 16.8 gram intermediate 1 are suspended in the acetonitrile, are cooled to-15 ℃, behind the dropping 30mL triethylamine, it is stirred, is cooled to-45 ℃, obtain mixed liquor; In addition 10.1 gram intermediate 2 are added in the 125mL acetonitrile, add in the aforementioned mixed liquor after being pre-chilled to-30 ℃, stirred 90 minutes, be warming up to-18 ℃, obtain crystal at-42 ℃, more after filtration, after 45 ℃ of dryings 21.51 gram intermediate 3.
(4) 12mL water and 8mLHCl (37%) are mixed the formation mixed liquor, 12 gram intermediate 3 slowly are added in the mixed liquor in batches, and mixed liquor is warming up to 32 ℃ and kept 5 hours, adds 12mL water and 200mL acetone again; Further add 200mL acetone, crystallization occurs, growing the grain is after 1 hour, the crystal that obtains is filtered and obtains 9.9 gram cefotiam hydrochloride crude products after 3 hours in 50 ℃ of dryings.
(5) with 9g cefotiam hydrochloride crude product, the 40mL water that adds 15 ℃ dissolves, adding 0.585 gram active carbon again adsorbs, the addition of active carbon is 6.5% of a cefotiam hydrochloride crude product quality, and adsorption time is 40 minutes, and coarse filtration is taken off charcoal, gained filtrate is with 0.22 micron microporous filter membrane fine straining, fine straining liquid adds the acetone crystallize, and the reuse washing with acetone is drying to obtain 7.41 gram cefotiam hydrochlorides.
Embodiment 4
One, formulation and technology
Specification 1:0.5g (presses cefotiam C
18H
23N
9O
4S
3Meter)
Two, preparation method
1. interior packaging material is handled
Antibiotic glass bottle, plug, aluminium lid technology routinely clean, dry, sterilize, and be standby.
2. concrete steps
1., take by weighing recipe quantity cefotiam hydrochloride, natrium carbonicum calcinatum, mix homogeneously in sterile chamber.
2., middle product check.
3., undertaken aseptic subpackaged by specification.
4., evacuation, tamponade, roll lid.
5., packing, full inspection, warehouse-in.
Embodiment 5
One, formulation and technology
Specification 2:1.0g (presses cefotiam C
18H
23N
9O
4S
3Meter)
| Cefotiam hydrochloride (is pressed C 18H 23N 9O 4S 3Meter) | 1000g |
| Natrium carbonicum calcinatum | 242g |
| Make | 1000 bottles |
Two, preparation method
1. interior packaging material is handled
Antibiotic glass bottle, plug, aluminium lid technology routinely clean, dry, sterilize, and be standby.
2. operating procedure
1., take by weighing recipe quantity cefotiam hydrochloride, natrium carbonicum calcinatum, mix homogeneously in sterile chamber.
2., middle product check.
3., undertaken aseptic subpackaged by specification.
4., evacuation, tamponade, roll lid.
5., packing, full inspection, warehouse-in.
Embodiment 6
One, formulation and technology
Specification 3:2.0g (presses cefotiam C
18H
23N
9O
4S
3Meter)
Two, preparation method
1. interior packaging material is handled
Antibiotic glass bottle, plug, aluminium lid technology routinely clean, dry, sterilize, and be standby.
2. operating procedure
1., take by weighing recipe quantity cefotiam hydrochloride, natrium carbonicum calcinatum, mix homogeneously in sterile chamber.
2., middle product check.
3., undertaken aseptic subpackaged by specification.
4., evacuation, tamponade, roll lid.
5., packing, full inspection, warehouse-in.
Test example 1
This test example 1 relates to the quality testing of the prepared cefotiam hydrochloride of the present invention
One, sample and reference substance source
The product that test sample: embodiment 1, embodiment 2, embodiment 3 obtain respectively
The quality contrast is the refining gained of listing cefotiam hydrochloridefor inj with reference substance.
Two, quality testing
The result that the correlated quality of the prepared cefotiam hydrochloride product of embodiment 1 detects among the present invention is as shown in table 1.
The quality testing result of table 1 cefotiam hydrochloride product
Three, influence factor
Be to inquire into the inherent stability of medicine, understand the factor that influence stability of drug products and may degradation pathway and catabolite,, carry out the influence factor and test for production technology, packing, holding conditions and the analytical method of setting up catabolite provide the foundation of science.Get this product, carry out following test.
1, this product (embodiment 1 product) is got in hot test, opening is put in the clean culture dish, spread out≤thin layer that 5mm is thick, under 40 ℃ and 60 ℃ of temperature, placed 10 days, in the 5th day and sampling in the 10th day, detect by stable high spot reviews project, result of the test and 0 day relatively, result of the test sees Table 2, table 3.
Table 2 cefotiam hydrochloride influence factor hot test result (40 ℃)
| Time (my god) character specific optical rotation absorptance acidity | 0 day little yellow crystalline powder+67.97 ° 269.80 1.39 | 5 days little yellow crystalline powder+67.47 ° 270.06 1.40 | 10 days little yellow crystalline powder+67.77 ° 269.56 1.41 |
| The clarity of solution and color | Be shallower than No. 0.5, be shallower than Y4 | Be shallower than No. 0.5, be shallower than Y4 | Be shallower than No. 0.5, be shallower than Y4 |
| Moisture (%) | 4.37 | 4.08 | 4.01 |
| Visible foreign matters | Up to specification | Up to specification | Up to specification |
| Particulate matter | Up to specification | / | Up to specification |
| Related substance (%) | 0.82 | 0.75 | 1.02 |
| Polymer (%) | 0.134 | / | 0.156 |
| Content (%) | 87.52 | 87.74 | 87.97 |
Table 3 cefotiam hydrochloride influence factor hot test result (60 ℃)
2, high wet test is got this product (lot number: embodiment 1 product), opening is put in the clean culture dish, spread out≤thin layer that 5mm is thick, totally two parts, put into the constant humidity hermetic container respectively, placed 10 days under at 25 ℃ respectively at the condition of relative humidity 92.5% and 75%, in the 5th day and sampling in the 10th day, detect by stable high spot reviews project, result of the test and 0 day relatively, result of the test sees Table 4, table 5.
Table 4 cefotiam hydrochloride influence factor high humidity result of the test (75%)
| Time (my god) character specific optical rotation absorptance acidity | 0 day little yellow crystalline powder+67.97 ° 269.80 1.39 | 5 days light yellow crystalline powder+66.95 ° 268.38 1.42 | 10 days yellow crystalline powder+66.46 ° 267.69 1.44 |
| The clarity of solution and color | Be shallower than No. 0.5, be shallower than Y4 | Be shallower than No. 0.5, be shallower than Y6 | Be shallower than No. 0.5, be shallower than Y7 |
| Moisture (%) | 4.37 | 7.68 | 9.72 |
| Visible foreign matters | Up to specification | Up to specification | Up to specification |
| Particulate matter | Up to specification | / | Up to specification |
| Related substance (%) | 0.82 | 0.84 | 1.29 |
| Polymer (%) | 0.134 | / | 0.693 |
| Content (%) | 87.52 | 87.13 | 86.57 |
Table 5 cefotiam hydrochloride influence factor high humidity result of the test (92.5%)
| Time (my god) character specific optical rotation absorptance acidity | 0 day little yellow crystalline powder+67.97 ° 269.80 1.39 | 5 days yellow crystalline powder+66.50 ° 267.29 1.46 | 10 days yellow crystalline powder+66.09 ° 266.21 1.44 |
| The clarity of solution and color | Be shallower than No. 0.5, be shallower than Y4 | Be shallower than No. 0.5, be shallower than Y6 | Be shallower than No. 0.5, be shallower than Y7 |
| Moisture (%) | 4.37 | 9.24 | 12.57 |
| Visible foreign matters | Up to specification | Up to specification | Up to specification |
| Particulate matter | Up to specification | / | Up to specification |
| Related substance (%) | 0.82 | 1.04 | 2.39 |
| Polymer (%) | 0.134 | / | 0.889 |
| Content (%) | 87.52 | 86.93 | 86.07 |
7.3 exposure experiments to light is got this product (embodiment 1 product), opening is put in the clean culture dish, spreads out≤thin layer that 5mm is thick, put under the condition that intensity of illumination is 4500lx and placed 10 days, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stable high spot reviews project.The results are shown in Table 6.
Table 6 cefotiam hydrochloride influence factor exposure experiments to light result
Test example 2
This test example relates to is the influence of the consumption of active carbon in the process of cefotiam hydrochloride crude product refining to this product.
For effectively removing bacterial endotoxin, select for use active carbon to remove bacterial endotoxin.For guaranteeing the yield of product, this product activated carbon dosage is investigated, selected for use the active carbon of variable concentrations to test respectively, select the active carbon of four kinds of concentration of 0%, 5%, 6.5%, 8% (w/w) for use, insulated and stirred absorption is 30 minutes under 12 ℃～18 ℃ conditions, checks every important indicator.The result is as follows:
The selection of table 7. activated carbon dosage
| Concentration of activated carbon (w/w) | Character | Visible foreign matters | Bacterial endotoxin | Content (%) |
| 0％ | Be shallower than No. 0.5 | Against regulation | Against regulation | 100.5 |
| 5％ | Be shallower than No. 0.5 | Up to specification | Up to specification | 98.8 |
| 6.5％ | Be shallower than No. 0.5 | Up to specification | Up to specification | 95.6 |
| 8％ | Be shallower than No. 0.5 | Up to specification | Up to specification | 86.9 |
As can be seen from the above table, after this product adds activated carbon adsorption, visible foreign matters and bacterial endotoxin are all qualified, but the concentration of activated carbon of 6.5% and 8% (w/w) is bigger to principal agent absorption, effectively eliminating under the bacterial endotoxin prerequisite, and the adaptation working condition, the activated carbon dosage of determining this product is 5% (w/w).
Test example 3
This test example relates to the influence to the yield of preparation intermediate 2 of mixing speed and time.
Table 8 mixing speed and time are to the influence of the yield of intermediate 2
| Sequence number | 1 | 2 | 3 | 4 | 5 |
| Mixing speed when adding PCl5 | 130 rev/mins | 120 rev/mins | 110 rev/mins | 130 rev/mins | 60 rev/mins |
| Add mixing speed behind the PCl5 | 80 rev/mins | 70 rev/mins | 60 rev/mins | 130 rev/mins | 60 rev/mins |
| Add the back mixing time | 2 hours | 1.5 hour | 3 hours | 2 hours | 2 hours |
| Yield (%) | 89.7％ | 90.9％ | 89.68％ | 84.7％ | 83.5％ |
As can be seen from the above table, adopt mixing speed of the present invention, can make the yield of intermediate 2 be greatly improved, thereby make the yield of cefotiam hydrochloride also be improved.
Test example 3
This test example relates to design of cefotiam hydrochloride medicament composition sterile powder injection prescription and screening.
1, the character of crude drug
Cefotiam hydrochloride is that white is to faint yellow crystallization or crystalline powder; Odorless or little have special smelly.Its dissolubility is easily molten in water or methanol, and slightly soluble in ethanol is almost insoluble in ether.
2, the selection of dosage form
This product is the sterilized powder that an amount of sodium carbonate of cefotiam hydrochloride anker is made.
3, the natrium carbonicum calcinatum consumption is investigated
Get the about 1.2g of cefotiam hydrochloride ((C18H23N9O4S3) counts 1.0g by cefotiam) and add an amount of natrium carbonicum calcinatum mixing, add the 10ml water dissolution, investigate the dissolving situation.Result of the test is as follows:
Table 9 natrium carbonicum calcinatum consumption is investigated result of the test
| Cefotiam hydrochloride (g) | Natrium carbonicum calcinatum (g) | The dissolving situation | PH value |
| 1.1948 | - | Easily sticking group, dissolution velocity is slow | 1.43 |
| 1.1952 | 0.2137 | Generate a large amount of bubbles, dissolution velocity is fast | 5.72 |
| 1.1940 | 0.2447 | Generate a large amount of bubbles, dissolution velocity is fast | 6.32 |
| 1.2003 | 0.2932 | Generate a large amount of bubbles, dissolution velocity is fast | 6.99 |
| 1.1957 | 0.3250 | Generate a large amount of bubbles, dissolution velocity is fast | 7.18 |
Conclusion: when the adding natrium carbonicum calcinatum is 0.2137～0.3250g (addition in the 1g cefotiam), the pH value of solution is between 5.72～7.18, and the trial target dissolution velocity is fast.Because of this product contains natrium carbonicum calcinatum, when dissolving, can produce carbon dioxide, so after packing is finished, negative pressure will be made in the bottle.
4, developed product character investigation, acid-base value are investigated.
Prepare sample in above-mentioned prescription ratio, investigate character, the acid-base value of mixing powder.The result is as follows:
Table 10 developed product character is investigated and acid-base value is investigated the result
| Sequence number | Character | Acid-base value |
| 1 | Little yellow crystalline powder | 6.41 |
| 2 | Little yellow crystalline powder | 6.39 |
| 3 | Little yellow crystalline powder | 6.41 |
5, the dissolving situation of developed product is investigated
Get the sample of above-mentioned preparation, use clinical in lysate commonly used carry out the dissolving situation and investigate, the result is as follows:
Table 11 developed product dissolving situation in clinical lysate is investigated the result
| Sequence number | Sample weighting amount (g) | Normal saline (ml) | Glucose injection (ml) | The dissolving situation |
| 1 | 1.4315 | 4.0 | - | Dissolving fully |
| 2 | 1.4360 | 4.0 | - | Dissolving fully |
| 3 | 1.4389 | - | 4.0 | Dissolving fully |
| 4 | 1.4367 | - | 4.0 | Dissolving fully |
The medicine of conclusion: 1.0g (by cefotiam (C18H23N9O4S3)) can dissolve with the lysate that is not more than 5ml, and is clinical easy to use.
6, humidity is investigated
Accurate three parts in the fixed above-mentioned preparation sample that claims places load weighted tool plug weighing botle.Be positioned over 25 ± 1 ℃, relative humidity respectively and be under 43%, 59%, 70% the condition, took out to observe respectively after 7 hours and weigh, the result is as follows:
Table 12 sample hygroscopicity is investigated the result
Conclusion: above result shows, this product is to place under 70% the environment caking phenomenon not occur in 7 hours at relative humidity, but the moisture absorption of sample weightening finish obviously increases.
7, quality testing
The quality analysis result that table 13 cefotiam hydrochloride compositions is used as injection
Above test data shows, cefotiam hydrochloride composition stable of the present invention,
8, the influence factor tests investigation
Be to inquire into the inherent stability of medicine, understand the factor that influence stability of drug products and may degradation pathway and catabolite,, carry out the influence factor and test for production technology, packing, holding conditions and the analytical method of setting up catabolite provide the foundation of science.Get this product, carry out following test.
8.1 hot test
Get this product sample (embodiment 5 products), under 40 ℃, 60 ℃ temperature, placed 10 days,, detect by stable high spot reviews project in the 5th day and sampling in the 10th day, result of the test and comparison in 0 day, result of the test sees Table 12, table 13.For investigating this product and the butyl rubber plug compatibility, sample segment is inverted, under 60 ℃ of temperature, placed 5 days, measure the clarity of its solution, result of the test sees Table 14.
Table 14 cefotiam hydrochloride medicament composition sterile powder injection hot test result (40 ℃)
| Inspection item character acid-base value | 0 day little yellow crystalline powder 6.44 | 5 days little yellow crystalline powders 6.30 | 10 days little yellow crystalline powders 6.36 |
| The clarity of solution and color | Up to specification | Up to specification | Up to specification |
| Visible foreign matters | Up to specification | Up to specification | Up to specification |
| Particulate matter | Up to specification | / | Up to specification |
| Loss on drying (%) | 3.77 | 3.65 | 3.50 |
| Related substance (%) | 0.82 | 0.82 | 0.83 |
| Polymer (%) | 0.152 | / | 0.227 |
| Content (%) | 100.66 | 100.26 | 100.43 |
Table 15 cefotiam hydrochloride medicament composition sterile powder injection hot test result (60 ℃)
8.2 strong illumination test
Get this product sample (embodiment 6 products), placing illumination is to place 10 days under the condition of 4500Lx, in the 5th day and sampling in the 10th day, detect by stable high spot reviews project, and result of the test and comparison in 0 day, result of the test sees Table 16.
Table 16 cefotiam hydrochloride medicament composition sterile powder injection exposure experiments to light result
| Inspection item | 0 day | 5 days | 10 days |
| Character | Little yellow crystalline powder | Little yellow crystalline powder | Little yellow crystalline powder |
| Acid-base value | 6.44 | 6.39 | 6.36 |
| The clarity of solution and color | Up to specification | Up to specification | Up to specification |
| Visible foreign matters | Up to specification | Up to specification | Up to specification |
| Particulate matter | Up to specification | / | Up to specification |
| Loss on drying (%) | 3.77 | 3.72 | 3.76 |
| Related substance (%) | 0.82 | 0.86 | 1.15 |
| Polymer (%) | 0.152 | / | 0.146 |
| Content (%) | 100.66 | 100.15 | 99.82 |
Result of the test shows that this product was placed 10 days under high temperature (40 ℃) and illumination condition, every inspection index has no significant change.This product was placed 10 days under high temperature (60 ℃) condition, and related substance, polymer increase to some extent, and content slightly reduces.
Claims (10)
1. cefotiam hydrochloride medicament composition sterile powder injection, it is characterized in that, described cefotiam hydrochloride medicament composition sterile powder injection comprises cefotiam hydrochloride 500-600 weight portion, natrium carbonicum calcinatum 110-150 weight portion, preferred described medicament composition sterile powder injection comprises: cefotiam hydrochloride 500 weight portions, natrium carbonicum calcinatum 121 weight portions, cefotiam hydrochloride wherein is in cefotiam.
2. cefotiam hydrochloride medicament composition sterile powder injection according to claim 1 is characterized in that, the preparation method of described cefotiam hydrochloride comprises:
(1) preparation of intermediate 1:
With 7-ACA is raw material, under the condition that anhydrous acetonitrile, boron trifluoride etherate exist, with 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazole reaction, adds hydrochloric acid again, then with obtaining intermediate 1 behind the ammonia adjusting pH value;
(2) preparation of intermediate 2:
In 2-formamido group-thiazolyl-4-acetic acid, the limit edged stirs and adds PCl5 in batches, reacts the after-filtration that finishes and obtains intermediate 2;
(3) preparation of intermediate 3:
Add acetonitrile and triethylamine in intermediate 1, cooling obtains intermediate 1 solution; Add acetonitrile in intermediate 2, cooling obtains intermediate 2 solution, and intermediate 2 solution are added in intermediate 1 solution, obtains intermediate 3 after the reaction;
(4) preparation of cefotiam hydrochloride crude product:
Intermediate 3 is added in the mixed solution of entry and hydrochloric acid in batches, heat up, add entry and acetone again, further add acetone then, obtain the cefotiam hydrochloride crude product;
(5) the cefotiam hydrochloride crude product is refining
The cefotiam hydrochloride crude product is dissolved in water, add active carbon again and adsorb, coarse filtration is taken off charcoal, and filtrate adds the acetone crystallize with 0.22 micron microporous filter membrane fine straining, fine straining liquid, and washing with acetone is used in the back, obtains cefotiam hydrochloride after the drying.
3. cefotiam hydrochloride medicament composition sterile powder injection according to claim 2, it is characterized in that, in the described step (1), the mol ratio of 7-ACA, 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazole, these three kinds of materials of flurothyl is 1: (1-1.5): 3; Preferred described mol ratio is 1: 1: 3.
4. cefotiam hydrochloride medicament composition sterile powder injection according to claim 2 is characterized in that, when regulating pH value with ammonia, the concentration of ammonia is the ammonia of 25-28%, and the concentration of preferred described ammonia is 28%, and described percentage ratio is mass percent.
5. cefotiam hydrochloride medicament composition sterile powder injection according to claim 2 is characterized in that, also comprises filtration after regulating pH value with ammonia, exsiccant step, and wherein exsiccant temperature is 40-45 ℃.
6. cefotiam hydrochloride medicament composition sterile powder injection according to claim 2, it is characterized in that, described step (1) specifically comprises: be raw material with 7-ACA, it is added in the anhydrous acetonitrile, in the suspension that forms, add 5-sulfydryl-1-dimethylamino-ethyl-1H-tetrazole again and form mixed solution, when being remained on-5～5 ℃, the temperature of mixed solution adds boron trifluoride-ether complex, reacted 2-2.5 hour down at 30-38 ℃ behind the mix homogeneously, cool off the back dripping hydrochloric acid again, with obtaining intermediate 1 behind the ammonia adjusting pH value.
7. cefotiam hydrochloride medicament composition sterile powder injection according to claim 2, it is characterized in that, described step (2) specifically comprises: 2-formamido group-thiazolyl-4-acetic acid is dissolved in the dichloromethane, is cooled to-20 ℃, add PCl5 in batches, stir when adding, the speed that stirs is 110-130 rev/min, after adding finishes, proceeds to stir 1.5-3 hour again, the speed that stirs is 60-80 rev/min, more after filtration, obtain intermediate 2 after the drying.
8. cefotiam hydrochloride medicament composition sterile powder injection according to claim 2, it is characterized in that, described step (3) specifically comprises: intermediate 1 is suspended in the acetonitrile, be cooled to-15～-20 ℃, after dripping triethylamine, it is stirred, is cooled to-35～-45 ℃, obtain mixed liquor; In addition intermediate 2 is added in 100ml～150ml acetonitrile, adds in the aforementioned mixed liquor after being pre-chilled to-25～-35 ℃, stirred 70～90 minutes, be warming up to-15～-25 ℃, obtain crystal at-40～-45 ℃, more after filtration ,-after the 40-45 ℃ drying intermediate 3.
9. cefotiam hydrochloride medicament composition sterile powder injection according to claim 2, it is characterized in that, described step (5) specifically comprises: with the cefotiam hydrochloride crude product, the water that adds 12-18 ℃ dissolves, adding active carbon again adsorbs, the addition of active carbon is the 5-8% of cefotiam hydrochloride crude product quality, adsorption time is 25-40 minute, coarse filtration is taken off charcoal, gained filtrate is with 0.22 micron microporous filter membrane fine straining, fine straining liquid adds the acetone crystallize, and the reuse washing with acetone is drying to obtain cefotiam hydrochloride.
10. the preparation method of any described cefotiam hydrochloride medicament composition sterile powder injection among the claim 1-9, it is characterized in that, described method comprises: take by weighing recipe quantity cefotiam hydrochloride and natrium carbonicum calcinatum respectively, mix homogeneously in sterile chamber.
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