CN105343067B - Amoxicillin sodium for injection potassium clavulanate preparation and preparation method thereof - Google Patents
Amoxicillin sodium for injection potassium clavulanate preparation and preparation method thereof Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract
The present invention relates to amoxicillin sodium for injection potassium clavulanate preparation and preparation method thereof, preparation includes the crystallised sodium amoxycillin and potassium clavulanate that mass ratio is 5:1~10:1, and the granularity of crystallised sodium amoxycillin is 25~35 μm.Preparation method includes preparing crystallised sodium amoxycillin, crystallised sodium amoxycillin is uniformly mixed with potassium clavulanate according to fixed mass ratio, it is packed using 25ml bottle and amoxicillin sodium for injection potassium clavulanate powder needle is made, when clinical, powder needle uses the scheme of making up a prescription of 20ml injection water dissolution, obtains amoxicillin sodium and clavulanate potassium injection solution.The purity is high of crystallised sodium amoxycillin of the invention, impurity is few, and the stability of amoxicillin sodium for injection potassium clavulanate preparation is good, it is not easy to allergy.
Description
Technical field
The present invention relates to technical field of medicine, especially a kind of amoxicillin sodium for injection potassium clavulanate preparation and
Preparation method.
Background technique
Penicillin be in the world first be applied to clinical anti-infection drug, be the antibiotic that the mankind have found earliest,
Nineteen twenty-eight Sheng Mali medical college, London university (Xian Shu London's Imperial College) bacteriology professor's Fleming is sent out in the lab
Existing Penicillium notatum has a bactericidal effect, 1938 by Oxonian money grace, Florey and Basil Heatley (Norman Heatley,
1911-2004) team led extract.
Penicillin (Penicillin or transliteration penicillin) refers in molecule containing penam, can destroy the thin of bacterium
Cell wall and from the breeding period of bacterial cell bactericidal effect a kind of antibiotic, be the antibiotic by being extracted in Penicillium notatum.It is green
Mycin class antibiotic is the general name for the beta-lactam antibiotic for having the similar mechanism of action with penicillin.Penicillins antibiosis
Plain general formula of the chemical structure is as follows:
R indicates a kind of organic group.
The toxicity very little of penicillin antibiotics is the maximum antibiotic of chemotherapeutic index, but its penicillin antibiotics is normal
The allergic reaction seen ranks first in various drugs, and incidence reaches as high as 5%~10%, and allergy main cause is penicillin
Impurity (including related substances, residual solvent, polymer etc.) caused by class production and storage transportational process.
Amoxicillin sodium for injection potassium clavulanate is compound preparation, and component is that Amoxicillin Sodium and potassium clavulanate are equal
Even mixed aseptic powdery.
Amoxicillin Sodium, entitled (2S, 5R, 6R) -3,3- dimethyl -6- [(R)-(-) -2- amino -2- (the 4- hydroxyl of chemistry
Phenyl) acetylamino] -7- oxo -4 thia -1- azabicyclo (3.2.0) heptane -2- sodium formate.Molecular formula:
C16H18N3NaO5S, molecular weight: 387.40.Chemical structural formula are as follows:
Amoxicillin Sodium is a kind of semi-synthetic penicillins antibiotic, the treatment suitable for following disease: 1. haemolysis hammers
The upper respiratory tracts such as tympanitis caused by bacterium, streptococcus pneumonia, staphylococcus or haemophilus influenzae, nasosinusitis, pharyngitis, tonsillitis
Infection.2. urogenital infections caused by escherichia coli, proteus mirabilis or enterococcus faecalis.3. Streptococcus hemolyticus, Portugal
Skin soft-tissue infection caused by grape coccus or escherichia coli.4. Streptococcus hemolyticus, streptococcus pneumonia, staphylococcus or influenza
The lower respiratory tract infection such as haemophilus induced Acute bronchitis, pneumonia.
Potassium clavulanate, entitled chemistry is (Z)-(2S, 5K) -3- (2- hydroxyl ethylidene) -7- oxo -4- oxa- -1- azepine
Bicyclic [3.2.0] heptane -2- carboxylic acid potassium.Molecular formula: C8H8KNO5, molecular weight: 237.25.Chemical structural formula are as follows:
Potassium clavulanate is by artificial synthesized irreversibility competitive type beta-lactamase inhibitor.
That there are purity is low for current amoxicillin sodium for injection potassium clavulanate, and stability is poor, and impurity is more, is easy allergy etc.
Disadvantage.
Summary of the invention
The technical problem to be solved by the invention is to provide a kind of amoxicillin sodium for injection potassium clavulanate preparation and its
Preparation method, the present invention overcomes existing injection preparation purity bottom, stability is poor, impurity is more, is easy the disadvantages of allergy, improves
The purity and crystal size of crystallised sodium amoxycillin, so that amoxicillin sodium and clavulanate potassium powder needle and injection solution is steady
It is qualitative to be improved.
In order to solve the above technical problems, the technical scheme adopted by the invention is that:
Amoxicillin sodium for injection potassium clavulanate preparation, the preparation include the A Moxi that mass ratio is 5:1~10:1
Woods sodium crystal and potassium clavulanate, the granularity of the crystallised sodium amoxycillin are 25~35 μm.
The technical solution adopted in the present invention further include:
The preparation method of amoxicillin sodium for injection potassium clavulanate preparation, the preparation method include following technique step
Suddenly,
A) the crystallised sodium amoxycillin that prepared sizes are 25~35 μm；
B) crystallised sodium amoxycillin is uniformly mixed with potassium clavulanate according to fixed mass ratio；
C it) is packed using 25ml bottle, the content of active constituent in every bottle packaging amoxicillin sodium and clavulanate potassium preparation
For 0.6~1.2g, amoxicillin sodium for injection potassium clavulanate powder needle is obtained；
D when) clinical, every bottle amoxicillin sodium for injection potassium clavulanate powder needle is made up a prescription using the dissolution of 20ml injection water
Scheme obtains amoxicillin sodium and clavulanate potassium injection solution.
Technical solution of the present invention further improvement lies in that: under the preparation of crystallised sodium amoxycillin includes in the step A)
Column processing step,
1) 6-amino-penicillanic acid salting liquid is transferred to D- (-)-para hydroxybenzene acid anhydride ammonia by condensation reaction within a certain period of time
In the mixed anhydride solution of sour dane potassium salts, condensation reaction is carried out, condensation reaction mixed liquor is obtained；
2) the condensation reaction mixed liquor that step 1) obtains is added to the water dilution by hydrolysis, and hydrochloric acid progress is added
Hydrolysis, stratification after stirring hydrolysis, fetches water mutually stand-by；
3) water phase and ammonium hydroxide that step 2) obtains while being slowly added into is filled the knot of buffer by the crystallization of Amoxicillin
In brilliant kettle, add the crystallization that cools down after ammonium hydroxide, stir, stand, filter, then washed respectively with water and isopropanol, vacuum drying, obtain Ah
Amdinocillin crystal；
4) Amoxicillin crystal obtained in step 3) is added to containing the anhydrous of triethylamine by the preparation of Amoxicillin Sodium
In ethyl alcohol, stirs to being completely dissolved, Amoxicillin solution is obtained after membrane filtration degerming, the methyl acetate solution of sodium iso-octoate is added
Enter into Amoxicillin solution, reaction obtains Amoxicillin sodium solution；
5) the Amoxicillin sodium solution in step 4) is transferred to crystallization, washing, dry three conjunction by the crystallization of Amoxicillin Sodium
In one equipment, first cools to crystallization temperature and Amoxicillin Sodium crystal seed is added, keep the temperature and stir, carbon is added dropwise when having crystal precipitation
Acid sodium aqueous solution continues to stir, and completely rear suction filtration to be crystallized, filter cake is washed with methyl acetate, and last close drying obtains A Moxi
Woods sodium crystal.
Technical solution of the present invention further improvement lies in that: in the step 1) setting-up point be -30~-38 DEG C,
Condensation reaction time is 100~160min, and the transfer time of 6-amino-penicillanic acid salting liquid is 20~28min, when 6- amino
When the residual quantity of penicillanic acid≤0.5%, stop reaction.
Technical solution of the present invention further improvement lies in that: the system of the 6-amino-penicillanic acid salting liquid in the step 1)
Preparation Method is even after dissolving 10~20min specifically, 6-amino-penicillanic acid is added in 0~6 DEG C of dichloromethane solvent
Water and triethylamine is added in speed, and control mixing temperature is 0~3 DEG C, after 20~30min of hybrid reaction, by 6-amino-penicillanic acid salt
Solution is cooled to -15 DEG C, keeps the temperature spare.
Technical solution of the present invention further improvement lies in that: 6- aminopenicillanic in the 6-amino-penicillanic acid salting liquid
Acid and the mass ratio of methylene chloride are 1:1.5~1:1.8, and the mass ratio of 6-amino-penicillanic acid and water is 1:0.15~1:
0.20, the molar ratio of 6-amino-penicillanic acid and triethylamine is 1:1.05~1:1.15.
Technical solution of the present invention further improvement lies in that: D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts in the step 1)
Mixed anhydride solution preparation method specifically, it is 10~15 DEG C that D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts, which are added to temperature,
It in methylene chloride and quickly stirs, while n,N-dimethylacetamide is added, and cooling processing is carried out to solution, when cooling to 0
DEG C when, be added 2,6- lutidines, continue to be cooled to -30~-38 DEG C, at the uniform velocity addition pivaloyl chloride, control solution temperature -
15~-20 DEG C, 40~80min of insulation reaction is carried out, -50 DEG C are cooled to after heat preservation and isooctyl acid is added, obtains D- (-) -
The mixed anhydride solution of para hydroxybenzene acid anhydride propylhomoserin dane potassium salts, -50 DEG C of heat preservations are spare.
Technical solution of the present invention further improvement lies in that: the D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride is molten
The mass ratio of D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and methylene chloride is 1:4~1:5, D- (-)-para hydroxybenzene acid anhydride ammonia in liquid
Sour dane potassium salts and the mass ratio of n,N-dimethylacetamide are 1:0.40~1:0.50, D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts
Mass ratio with 2,6- lutidines is 1:0.025~1:0.03, D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and pivaloyl
The molar ratio of chlorine is 1:1.0~1:1.1, and the mass ratio of D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and isooctyl acid is 1:0.024
~1:0.028.
Technical solution of the present invention further improvement lies in that: the dilution temperature of condensation reaction mixed liquor is in the step 2)
10~15 DEG C, the temperature of hydrolysis is 5~10 DEG C, and the time of hydrolysis is 5~10min, detection aqueous pH values are 1.0~
When 1.2, stop hydrolysis.
Technical solution of the present invention further improvement lies in that: buffer in the step 3) is the phosphoric acid of pH5.0~5.1
Potassium dihydrogen buffer, buffer solution additional amount are 1%~5% of water phase volume in step 2), the concentration of the ammonium hydroxide is 10~
15% and the addition speed of ammonium hydroxide is controlled, the pH in crystallization kettle is made to be maintained at 5.0~5.1, during control plus ammonium hydroxide in crystallization kettle
Temperature be 0~10 DEG C, it is described cooling crystallization temperature be 5~20 DEG C, 1~2h of mixing time, 0.5~3h of time of repose, take out
After considering washing, 3~6h is dried in vacuo at a temperature of 40~65 DEG C.
Technical solution of the present invention further improvement lies in that: in the step 4) temperature of dehydrated alcohol be 0~5 DEG C, institute
The mass ratio for stating Amoxicillin and dehydrated alcohol is 1:2.0~1:2.3, the mass ratio of Amoxicillin and triethylamine be 1:0.4~
The mass ratio of 1:0.5, the sodium iso-octoate and Amoxicillin is 0.65:1~0.75:1, the quality of sodium iso-octoate and methyl acetate
Than for 1:3.8~1:4.2.
Technical solution of the present invention further improvement lies in that: crystallization temperature in the step 5) is 0~15 DEG C, when heat preservation
Between be 10~30min, continuations mixing time is 1~2h, and the drying temperature of crystal is 40~65 DEG C, drying pressure≤-
0.06MPa, drying time are 3~6h, and the Amoxicillin Sodium crystal seed is D50≤7.5 μm, D90≤18 μm, TOP≤40 μm；Ah
The mass ratio of Amdinocillin sodium crystal seed and Amoxicillin sodium solution is 0.001:1~0.005:1, the concentration of the aqueous sodium carbonate
It is 20~24%, the mass ratio of the aqueous sodium carbonate and Amoxicillin sodium solution is 0.005:1~0.05:1.
By adopting the above-described technical solution, the technological progress achieved by the present invention is:
The present invention overcomes existing injection preparation purity bottom, stability is poor, impurity is more, is easy the disadvantages of allergy, so that
Amoxicillin sodium and clavulanate potassium powder needle and the stability for injecting solution are improved, and save rubescent will not become for a long time
Color effectively reduces the allergy risk of preparation.
Amoxicillin sodium for injection potassium clavulanate preparation pharmacological property prepared by the present invention is stablized, and is packed using 25ml bottle,
Every bottle packs amoxicillin sodium and clavulanate potassium preparation 1.2g, and clinic prepares note using the scheme of making up a prescription of 20ml injection water dissolution
Solution is penetrated, after making up a prescription after 10min, clavulanic acid stability is better than other 17% or more schemes of making up a prescription, and Amoxicillin stability is excellent
In other 10% or more schemes of making up a prescription.
Emphasis of the present invention improves the purity and crystal size of crystallised sodium amoxycillin, high-purity Amoxicillin Sodium obtained
Crystal has many advantages, such as purity is high, and impurity is few,
The present invention is by improving the concrete technology of condensation reaction in the preparation process of Amoxicillin, such as: improving mixed anhydride
The holding temperature of solution shortens 6-amino-penicillanic acid salting liquid and is added to D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride
The time of solution improves setting-up point etc., shortens the time of condensation reaction, reduces by-product, improves reaction yield.
The present invention is improved by the concrete technology to hydrolysis in the preparation process of Amoxicillin, such as: control dilution
Temperature, hydrolysis temperature, hydrolysis time quickly stir, and time etc. is added in control hydrochloric acid, hydrolytic process can be made not have crystallization, mentioned
High yield quality and yield.
The present invention is controlled by the process conditions of the crystallization process to Amoxicillin, as: pH is 5.0~5.1
It is carried out in potassium phosphate buffer, control ammonium hydroxide rate of addition makes pH be maintained at 5.0~5.1 etc., and crystallization can be made to obtain
The advantages that Amoxicillin has purity is high, and impurity is few, and stability is good.
The present invention is controlled by the process conditions of preparation process and crystallization process to Amoxicillin Sodium, such as: in Ah
The Amoxicillin Sodium crystal seed filtered out is added when Amdinocillin sodium crystallizes, limits the grain size parameter of crystal seed, crystallization can be made to obtain
Amoxicillin Sodium has purity is high, and impurity is few, and stability is good, it is not easy to the advantages that allergy.The present invention overcomes dry problem, realizes
Three-in-one device close drying.Amoxicillin Sodium granularity increases to 30 μm or so by 15 μm.
Specific embodiment
Embodiment of the present invention is described in detail combined with specific embodiments below.It should be appreciated that reality of the invention
It applies and is not limited by the following examples, the accommodation in any form and/or change made to the present invention fall within this hair
Bright protection scope.
The preparation of 1 high-purity crystallised sodium amoxycillin of embodiment.
The preparation method of high-purity crystallised sodium amoxycillin, including condensation reaction, hydrolysis, Amoxicillin crystallization,
The preparation of Amoxicillin Sodium, Amoxicillin Sodium five processing steps of crystallization, it is specific as follows.
1) condensation reaction.
6-amino-penicillanic acid salting liquid is prepared first.Detailed process is, according to 6-amino-penicillanic acid and methylene chloride
Mass ratio be 1:1.5, weigh 200g reaction raw materials 6-amino-penicillanic acid and 300g dichloromethane solvent, it is green according to 6- amino
The mass ratio of mould alkanoic acid and water is 1:0.20, weighs 40g water, is 1 according to the molar ratio of 6-amino-penicillanic acid and triethylamine:
1.05, weigh 98.3g triethylamine.
Methylene chloride is cooled to 0~6 DEG C, after stirring and dissolving 20min, at the uniform velocity addition water and triethylamine, control mixing temperature
Degree is 0~3 DEG C, and after hybrid reaction 30min, sampling observation 6-amino-penicillanic acid dissolves situation, complete to 6-amino-penicillanic acid
After fully dissolved, 6-amino-penicillanic acid salting liquid is cooled to -15 DEG C, is kept the temperature spare.
Then D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride solution is prepared.Detailed process is, right according to D- (-)-
The mass ratio of hydroxyl phthalic anhydride propylhomoserin dane potassium salts and methylene chloride is 1:4, weighs 300g reaction raw materials D- (-)-para hydroxybenzene acid anhydride ammonia
Sour dane potassium salts and 1200g dichloromethane solvent, according to D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and n,N-dimethylacetamide
Mass ratio be 1:0.40, weigh 120gN, N- dimethyl acetamide, according to D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and 2,
The mass ratio of 6- lutidines is 1:0.025, weighs 7.5g2,6- lutidines, according to D- (-)-para hydroxybenzene acid anhydride propylhomoserin
The molar ratio of dane potassium salts and pivaloyl chloride is 1:1.0,119g pivaloyl chloride is weighed, according to D- (-)-para hydroxybenzene acid anhydride propylhomoserin Deng's potassium
The molar ratio of salt and isooctyl acid is 1:0.024, weighs 7.2g isooctyl acid.
D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts are added in the methylene chloride that temperature is 10 DEG C and are quickly stirred, together
When n,N-dimethylacetamide is added, and cooling processing is carried out to solution, when cooling to 0 DEG C, 2,6- lutidines is added,
Continue to be cooled to -30 DEG C, pivaloyl chloride is at the uniform velocity added in 10min, controls solution temperature at -15 DEG C, carry out insulation reaction
60min is cooled to -50 DEG C and isooctyl acid is added after heat preservation, obtain D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride
Solution, -50 DEG C of heat preservations are spare.
6-amino-penicillanic acid salting liquid is transferred to D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride in 20min
In solution, -30 DEG C at a temperature of carry out condensation reaction 120min, when the residual quantity of 6-amino-penicillanic acid≤0.5%, stop
It only reacts, obtains condensation reaction mixed liquor.
2) hydrolysis.
It takes 2400ml water to be cooled to 15 DEG C in advance, the condensation reaction mixed liquor that step 1) obtains is added to the water dilution, 10
Hydrochloric acid is at the uniform velocity added in minute, reaction is hydrolyzed, the temperature of hydrolysis is 5~10 DEG C, after stirring hydrolysis 10min, detects water
Phase pH value be 1.0~1.2 when, stop hydrolysis, after stratification, fetch water it is mutually stand-by.
3) crystallization of Amoxicillin.
According to buffer solution additional amount be step 2) in water phase volume 3%, in crystallization kettle be added 200mlpH5.0~
5.1 potassium phosphate buffer, the ammonium hydroxide that the water phase and concentration under stiring obtaining step 2) are 10% slowly add simultaneously
Enter into the crystallization kettle for filling buffer, control the addition speed of ammonium hydroxide, so that the pH in crystallization kettle is maintained at 5.0~5.1, control
Adding the temperature during ammonium hydroxide in crystallization kettle is 10 DEG C, and adding the time of ammonium hydroxide is about 120min, is cooled to 5 DEG C of analysis after adding ammonium hydroxide
Crystalline substance stirs 1h, stands 1h, filters, then washed respectively with water and isopropanol, be dried in vacuo 3h at a temperature of 45 DEG C, obtain A Moxi
Woods crystal 354g.
4) preparation of Amoxicillin Sodium.
Be 1:2.0 according to the mass ratio of Amoxicillin and dehydrated alcohol, weigh in 100g step 3) gained Amoxicillin with
And 200g dehydrated alcohol, it is 1:0.5 according to the mass ratio of Amoxicillin and triethylamine, 50g triethylamine is weighed, according to sodium iso-octoate
Mass ratio with Amoxicillin is 0.65:1, weighs 65g sodium iso-octoate, is 1 according to the mass ratio of sodium iso-octoate and methyl acetate:
4.0, weigh 260g methyl acetate.
Triethylamine is added into dehydrated alcohol, stirs evenly, cools to 0 DEG C, Amoxicillin is added, stirs to completely molten
Solution, obtains Amoxicillin solution after membrane filtration degerming, spare.
Sodium iso-octoate is added in methyl acetate, stirring is to being completely dissolved, and after membrane filtration degerming, obtained solution is added
Into Amoxicillin solution, reaction obtains Amoxicillin sodium solution.
5) crystallization of Amoxicillin Sodium.
It is 0.001:1 according to the mass ratio of Amoxicillin Sodium crystal seed and Amoxicillin sodium solution, weighs Amoxicillin Sodium crystalline substance
Kind 0.1g, the partial size of Amoxicillin Sodium crystal seed are D50≤7.5 μm, D90≤18 μm, TOP≤40 μm.Preparing concentration is 20%
Aqueous sodium carbonate is 0.009:1 according to the mass ratio of aqueous sodium carbonate and Amoxicillin sodium solution, it is water-soluble to weigh sodium carbonate
Liquid 6g.
Amoxicillin sodium solution in step 4) is cooled to 0~5 DEG C, Amoxicillin Sodium crystal seed is added, keeps the temperature 0~5 DEG C
And 30min is stirred, aqueous sodium carbonate is added dropwise when having crystal precipitation, continues to stir 2h, filter, filter cake 250ml acetic acid first
Ester washing, three-in-one device close drying, drying temperature are 40 DEG C, and drying pressure is -0.09MPa, and drying time 6h is obtained white
Color crystallised sodium amoxycillin 84.2g.
The content of crystallised sodium amoxycillin obtained in the present embodiment is 99.5%, and partial size is 27~32 μm.
The preparation of 2 high-purity crystallised sodium amoxycillin of embodiment.
The preparation method of high-purity crystallised sodium amoxycillin, including condensation reaction, hydrolysis, Amoxicillin crystallization,
The preparation of Amoxicillin Sodium, Amoxicillin Sodium five processing steps of crystallization, it is specific as follows.
1) condensation reaction.
6-amino-penicillanic acid salting liquid is prepared first.Detailed process is, according to 6-amino-penicillanic acid and methylene chloride
Mass ratio be 1:1.75,200g reaction raw materials 6-amino-penicillanic acid and 350g dichloromethane solvent are weighed, according to 6- amino
The mass ratio of penicillanic acid and water is 1:0.175, weighs 35g water, the molar ratio according to 6-amino-penicillanic acid and triethylamine is
1:1.10 weighing 103.0g triethylamine.
Methylene chloride is cooled to 0~6 DEG C, after stirring and dissolving 10min, at the uniform velocity addition water and triethylamine, control mixing temperature
Degree is 0~3 DEG C, and after hybrid reaction 20min, sampling observation 6-amino-penicillanic acid dissolves situation, complete to 6-amino-penicillanic acid
After fully dissolved, 6-amino-penicillanic acid salting liquid is cooled to -10 DEG C, is kept the temperature spare.
Then D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride solution is prepared.Detailed process is, right according to D- (-)-
The mass ratio of hydroxyl phthalic anhydride propylhomoserin dane potassium salts and methylene chloride is 1:4.5, weighs 300g reaction raw materials D- (-)-para hydroxybenzene acid anhydride
Propylhomoserin dane potassium salts and 1350g dichloromethane solvent, according to D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and N, N- dimethylacetamide
The mass ratio of amine is 1:0.45, weighs 135gN, N- dimethyl acetamide, according to D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts with
The mass ratio of 2,6- lutidines is 1:0.03, weighs 9.0g2,6- lutidines, according to D- (-)-para hydroxybenzene acid anhydride ammonia
The molar ratio of sour dane potassium salts and pivaloyl chloride is 1:1.1,131.0g pivaloyl chloride is weighed, according to D- (-)-para hydroxybenzene acid anhydride propylhomoserin
The molar ratio of dane potassium salts and isooctyl acid is 1:0.025, weighs 7.5g isooctyl acid.
D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts are added in the methylene chloride that temperature is 15 DEG C and are quickly stirred, together
When n,N-dimethylacetamide is added, and cooling processing is carried out to solution, when cooling to 0 DEG C, 2,6- lutidines is added,
Continue to be cooled to -35 DEG C, pivaloyl chloride is at the uniform velocity added in 10min, controls solution temperature at -20 DEG C, carry out insulation reaction
70min is cooled to -50 DEG C and isooctyl acid is added after heat preservation, obtain D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride
Solution, -50 DEG C of heat preservations are spare.
6-amino-penicillanic acid salting liquid is transferred to D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride in 20min
In solution, -35 DEG C at a temperature of carry out condensation reaction 100min, when the residual quantity of 6-amino-penicillanic acid≤0.5%, stop
It only reacts, obtains condensation reaction mixed liquor.
2) hydrolysis.
It takes 2400ml water to be cooled to 10 DEG C in advance, the condensation reaction mixed liquor that step 1) obtains is added to the water dilution, 10
Hydrochloric acid is at the uniform velocity added in minute, reaction is hydrolyzed, the temperature of hydrolysis is 5~10 DEG C, after stirring hydrolysis 5min, detects water
Phase pH value be 1.0~1.2 when, stop hydrolysis, after stratification, fetch water it is mutually stand-by.
3) crystallization of Amoxicillin.
According to buffer solution additional amount be step 2) in water phase volume 2%, in crystallization kettle be added 400mlpH5.0~
5.1 potassium phosphate buffer, the ammonium hydroxide that the water phase and concentration under stiring obtaining step 2) are 10% slowly add simultaneously
Enter into the crystallization kettle for filling buffer, control the addition speed of ammonium hydroxide, so that the pH in crystallization kettle is maintained at 5.0~5.1, control
Adding the temperature during ammonium hydroxide in crystallization kettle is 10 DEG C, and adding the time of ammonium hydroxide is about 100min, is cooled to 10 DEG C of analysis after adding ammonium hydroxide
Crystalline substance stirs 2h, stands 2h, filters, then washed respectively with water and isopropanol, be dried in vacuo 4h at a temperature of 60 DEG C, obtain A Moxi
Woods crystal 350g.
4) preparation of Amoxicillin Sodium.
Be 1:2.3 according to the mass ratio of Amoxicillin and dehydrated alcohol, weigh in 100g step 3) gained Amoxicillin with
And 230g dehydrated alcohol, it is 1:0.4 according to the mass ratio of Amoxicillin and triethylamine, 40g triethylamine is weighed, according to sodium iso-octoate
Mass ratio with Amoxicillin is 0.70:1, weighs 70g sodium iso-octoate, is 1 according to the mass ratio of sodium iso-octoate and methyl acetate:
4.2, weigh 294g methyl acetate.
Triethylamine is added into dehydrated alcohol, stirs evenly, cools to 0 DEG C, Amoxicillin is added, stirs to completely molten
Solution, obtains Amoxicillin solution after membrane filtration degerming, spare.
Sodium iso-octoate is added in methyl acetate, stirring is to being completely dissolved, and after membrane filtration degerming, obtained solution is added
Into Amoxicillin solution, reaction obtains Amoxicillin sodium solution.
5) crystallization of Amoxicillin Sodium.
It is 0.002:1 according to the mass ratio of Amoxicillin Sodium crystal seed and Amoxicillin sodium solution, weighs Amoxicillin Sodium crystalline substance
Kind 0.2g, the partial size of Amoxicillin Sodium crystal seed are D50≤7.5 μm, D90≤18 μm, TOP≤40 μm.Preparing concentration is 22%
Aqueous sodium carbonate is 0.02:1 according to the mass ratio of aqueous sodium carbonate and Amoxicillin sodium solution, it is water-soluble to weigh sodium carbonate
Liquid 14g.
Amoxicillin sodium solution in step 4) is cooled to 5~10 DEG C, Amoxicillin Sodium crystal seed, heat preservation 5~10 is added
DEG C and stir 20min, aqueous sodium carbonate is added dropwise when having crystal precipitation, continue stir 1.5h, filter, filter cake 250ml second
The washing of sour methyl esters, three-in-one device close drying, drying temperature are 60 DEG C, and drying pressure is -0.0085MPa, and drying time is
5h obtains white crystallised sodium amoxycillin 83.7g.
The content of crystallised sodium amoxycillin obtained in the present embodiment is 99.6%, and partial size is 28~33 μm.
The preparation of 3 amoxicillin sodium for injection potassium clavulanate preparation of embodiment.
The amoxicillin sodium for injection potassium clavulanate preparation of the present embodiment includes that the Amoxicillin Sodium that weight ratio is 5:1 is brilliant
Body and potassium clavulanate.The granularity of crystallised sodium amoxycillin is 25~35 μm, is made by above-described embodiment 1 or embodiment 2.
The preparation method of the amoxicillin sodium for injection potassium clavulanate preparation of the present embodiment comprises the following steps that,
A the crystallised sodium amoxycillin that granularity is 25~35 μm) is made according to the processing step of embodiment 1 or embodiment 2.
B) crystallised sodium amoxycillin is uniformly mixed with potassium clavulanate according to mass ratio 5:1.
C it) is packed using 25ml bottle, the content of active constituent in every bottle packaging amoxicillin sodium and clavulanate potassium preparation
For 1.2g, amoxicillin sodium for injection potassium clavulanate powder needle is obtained；This product is compound preparation, is contained in the preparation that specification is 1.2g
Amoxicillin 1.0g contains clavulanic acid 0.2g.
D when) clinical, every bottle amoxicillin sodium for injection potassium clavulanate powder needle is made up a prescription using the dissolution of 20ml injection water
Scheme obtains amoxicillin sodium and clavulanate potassium injection solution.
The preparation of 4 amoxicillin sodium for injection potassium clavulanate preparation of embodiment.
The amoxicillin sodium for injection potassium clavulanate preparation of the present embodiment includes that the Amoxicillin Sodium that weight ratio is 5:1 is brilliant
Body and potassium clavulanate.The granularity of crystallised sodium amoxycillin is 25~35 μm, is made by above-described embodiment 1 or embodiment 2.
The preparation method of the amoxicillin sodium for injection potassium clavulanate preparation of the present embodiment comprises the following steps that,
A the crystallised sodium amoxycillin that granularity is 25~35 μm) is made according to the processing step of embodiment 1 or embodiment 2.
B) crystallised sodium amoxycillin is uniformly mixed with potassium clavulanate according to mass ratio 5:1.
C it) is packed using 25ml bottle, the content of active constituent in every bottle packaging amoxicillin sodium and clavulanate potassium preparation
For 0.6g, amoxicillin sodium for injection potassium clavulanate powder needle is obtained.This product is compound preparation, is contained in the preparation that specification is 0.6g
Amoxicillin 0.5g contains clavulanic acid 0.1g.
D when) clinical, every bottle amoxicillin sodium for injection potassium clavulanate powder needle is made up a prescription using the dissolution of 20ml injection water
Scheme obtains amoxicillin sodium and clavulanate potassium injection solution.
The preparation of 5 amoxicillin sodium for injection potassium clavulanate preparation of embodiment.
The amoxicillin sodium for injection potassium clavulanate preparation of the present embodiment includes the Amoxicillin Sodium that weight ratio is 10:1
Crystal and potassium clavulanate.The granularity of crystallised sodium amoxycillin is 25~35 μm, is made by above-described embodiment 1 or embodiment 2.
The preparation method of the amoxicillin sodium for injection potassium clavulanate preparation of the present embodiment comprises the following steps that,
A the crystallised sodium amoxycillin that granularity is 25~35 μm) is made according to the processing step of embodiment 1 or embodiment 2；
B) crystallised sodium amoxycillin is uniformly mixed with potassium clavulanate according to mass ratio 10:1；
C it) is packed using 25ml bottle, the content of active constituent in every bottle packaging amoxicillin sodium and clavulanate potassium preparation
For 1.1g, amoxicillin sodium for injection potassium clavulanate powder needle is obtained；This product is compound preparation, is contained in the preparation that specification is 1.1g
Amoxicillin 1.0g contains clavulanic acid 0.1g.
D when) clinical, every bottle amoxicillin sodium for injection potassium clavulanate powder needle is made up a prescription using the dissolution of 20ml injection water
Scheme obtains amoxicillin sodium and clavulanate potassium injection solution.
In 3~embodiment of above-described embodiment 5, active constituent in amoxicillin sodium for injection potassium clavulanate preparation refers to
After being configured to injection solution, Amoxicillin and clavulanic acid in solution.
6 amoxicillin sodium and clavulanate potassium of embodiment injects solution stability testing.
The amoxicillin sodium for injection potassium clavulanate formulation samples prepared in 3 batches of embodiments 3 are taken, Amoxicillin is configured to
Sodium and clavulanate potassium injects solution, and at 30 DEG C ± 2 DEG C of temperature, relative humidity 65% ± 5% is investigated 6 months, after placement
Sampling in 1st, 2,3,6 month is investigated, and is compared with 0 month investigation data, test result see the table below 1, table 2.
The solution stability testing comparison table one of 1 amoxicillin sodium for injection potassium clavulanate preparation of table
The solution stability testing comparison table two of 2 amoxicillin sodium for injection potassium clavulanate preparation of table
The result shows that: pass through the detection to high spot reviews project, the results showed that 3 batches of samples investigate 6 in the above conditions
Month character, clarity (just, falling), basicity, solution colour, labelled amount, moisture, content, related substance comply with standard regulation, because
This this product be it is highly stable, stability is much higher than commercially available amoxicillin sodium for injection potassium clavulanate.
The solution stability testing of the commercially available amoxicillin sodium for injection potassium clavulanate preparation of comparative example 1.
The amoxicillin sodium and clavulanate potassium product that main raw medicine manufacturer is dispensed at present is chosen, different volumes are added
Water for injection, test clavulanic acid and A Moxi respectively 0 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 60 minutes
The content of woods, the experimental data are shown in the following table 3, table 4.
The solution stability testing comparison table one of the commercially available amoxicillin sodium for injection potassium clavulanate preparation of table 3
The solution stability testing comparison table two of the commercially available amoxicillin sodium for injection potassium clavulanate preparation of table 4
Note: it with testing result when 0 is result after 100% conversion that above data, which is by content,.
It can be seen from the above result that with the increase of drug solution concentration, degradation speed is obviously accelerated.
Currently, commercially available other producer's amoxicillin sodium for injection potassium clavulanates be all made of bottle capacity be 7mL or
10mL bottle at most can only add 5mL or 10mL water for injection to be dissolved in clinical use, and the pharmacy product in North China uses
Bottle capacity be 25mL, it is desirable that when clinical use be added water for injection 20mL dissolved, this is also the product of North China pharmacy
Clinical use stability be higher than other producers the reason of one of.
Claims (8)
1. amoxicillin sodium for injection potassium clavulanate preparation, it is characterised in that: the A Moxi that the preparation is 5:1 by mass ratio
Woods sodium crystal and potassium clavulanate composition, the granularity of the crystallised sodium amoxycillin are 25 ~ 35 μm；
Preparation method comprises the following steps that,
A) the crystallised sodium amoxycillin that prepared sizes are 25 ~ 35 μm；
B) crystallised sodium amoxycillin is uniformly mixed with potassium clavulanate according to fixed mass ratio；
C it) is packed using 25ml bottle, the content of active constituent is in every bottle packaging amoxicillin sodium and clavulanate potassium preparation
0.6 ~ 1.2g obtains amoxicillin sodium for injection potassium clavulanate powder needle；
D when) clinical, every bottle amoxicillin sodium for injection potassium clavulanate powder needle is filled a prescription using the dissolution of 20ml injection water
Case obtains amoxicillin sodium and clavulanate potassium injection solution；
The step A) in the preparation of crystallised sodium amoxycillin include following process steps,
1) 6-amino-penicillanic acid salting liquid is transferred to D- (-)-para hydroxybenzene acid anhydride propylhomoserin Deng by condensation reaction within a certain period of time
In the mixed anhydride solution of sylvite, condensation reaction is carried out, condensation reaction mixed liquor is obtained；
Setting-up point is -35 DEG C, condensation reaction time 100min；
6-amino-penicillanic acid specifically, is added to 0 ~ 6 DEG C of dichloromethane by the preparation method of 6-amino-penicillanic acid salting liquid
In alkane solvents, after dissolving 10min, at the uniform velocity addition water and triethylamine, control mixing temperature are 0 ~ 3 DEG C, after hybrid reaction 20min,
6-amino-penicillanic acid salting liquid is cooled to -15 DEG C, is kept the temperature spare；
The mass ratio of 6-amino-penicillanic acid and methylene chloride is 1:1.75,6- amino mould in 6-amino-penicillanic acid salting liquid
The mass ratio of alkanoic acid and water is 1:0.15 ~ 1:0.20, and the molar ratio of 6-amino-penicillanic acid and triethylamine is 1:1.10；
2) the condensation reaction mixed liquor that step 1) obtains is added to the water dilution, and hydrochloric acid is added and is hydrolyzed by hydrolysis
Reaction, stratification after stirring hydrolysis, fetches water mutually stand-by；
3) water phase and ammonium hydroxide that step 2 obtains while being slowly added into is filled the crystallization kettle of buffer by the crystallization of Amoxicillin
In, the crystallization that cools down after ammonium hydroxide is added, is stirred, stands, filters, then washed respectively with water and isopropanol, vacuum drying obtains A Moxi
Woods crystal；
The concentration of the ammonium hydroxide is 10% and controls the addition speed of ammonium hydroxide, and the temperature during control plus ammonium hydroxide in crystallization kettle is 10
DEG C, the temperature of the cooling crystallization is 10 DEG C, mixing time 2h, time of repose 2h；
4) Amoxicillin crystal obtained in step 3) is added to the dehydrated alcohol containing triethylamine by the preparation of Amoxicillin Sodium
In, it stirs to being completely dissolved, Amoxicillin solution is obtained after membrane filtration degerming, the methyl acetate solution of sodium iso-octoate is added to
In the solution of Amoxicillin, reaction obtains Amoxicillin sodium solution；
5) the Amoxicillin sodium solution in step 4) is transferred to crystallization, washing, dries three-in-one set by the crystallization of Amoxicillin Sodium
In standby, first cool to crystallization temperature and Amoxicillin Sodium crystal seed is added, keep the temperature and stir, sodium carbonate is added dropwise when having crystal precipitation
Aqueous solution continues to stir, and completely rear suction filtration to be crystallized, filter cake is washed with methyl acetate, and last close drying obtains Amoxicillin Sodium
Crystal；
Crystallization temperature is 5 ~ 10 DEG C, soaking time 20min, and continuation mixing time is 1.5h；
The mass ratio of Amoxicillin Sodium crystal seed and Amoxicillin sodium solution is 0.002:1, and the concentration of the aqueous sodium carbonate is
22%, the mass ratio of the aqueous sodium carbonate and Amoxicillin sodium solution is 0.005:1 ~ 0.05:1.
2. amoxicillin sodium for injection potassium clavulanate preparation according to claim 1, it is characterised in that: the step 1)
The transfer time of middle 6-amino-penicillanic acid salting liquid is 20 ~ 28min, when the residual quantity of 6-amino-penicillanic acid≤0.5%,
Stop reaction.
3. amoxicillin sodium for injection potassium clavulanate preparation according to claim 2, it is characterised in that: the step 1)
The preparation method of middle D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride solution is specifically, by D- (-)-para hydroxybenzene acid anhydride propylhomoserin
Dane potassium salts are added in the methylene chloride that temperature is 10 ~ 15 DEG C and quickly stir, while n,N-dimethylacetamide are added, and right
Solution carries out cooling processing, when cooling to 0 DEG C, be added 2,6- lutidines, continue to be cooled to -30 ~ -38 DEG C, at the uniform velocity plus
Enter pivaloyl chloride, controls solution temperature at -15 ~ -20 DEG C, carry out 40 ~ 80min of insulation reaction, be cooled to -50 DEG C after heat preservation
And isooctyl acid is added, D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts mixed anhydride solution is obtained, -50 DEG C of heat preservations are spare.
4. amoxicillin sodium for injection potassium clavulanate preparation according to claim 3, it is characterised in that: the D- (-)-
D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and methylene chloride mass ratio in the mixed anhydride solution of para hydroxybenzene acid anhydride propylhomoserin dane potassium salts
For 1:4 ~ 1:5, the mass ratio of D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and n,N-dimethylacetamide is 1:0.40 ~ 1:
0.50, D- (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and 2, the mass ratio of 6- lutidines are 1:0.025 ~ 1:0.03, D-
The molar ratio of (-)-para hydroxybenzene acid anhydride propylhomoserin dane potassium salts and pivaloyl chloride is 1:1.0 ~ 1:1.1, D- (-)-para hydroxybenzene acid anhydride propylhomoserin
The mass ratio of dane potassium salts and isooctyl acid is 1:0.024 ~ 1:0.028.
5. amoxicillin sodium for injection potassium clavulanate preparation according to claim 1, it is characterised in that: the step 2
The dilution temperature of middle condensation reaction mixed liquor is 10 ~ 15 DEG C, and the temperature of hydrolysis is 5 ~ 10 DEG C, the time of hydrolysis is 5 ~
10min stops hydrolysis when detection aqueous pH values are 1.0 ~ 1.2.
6. amoxicillin sodium for injection potassium clavulanate preparation according to claim 1, it is characterised in that: the step 3)
In buffer be pH5.0 ~ 5.1 potassium phosphate buffer, buffer solution additional amount be water phase volume in step 2 1% ~
5%, so that the pH in crystallization kettle is maintained at 5.0 ~ 5.1, after filtering and washing, 3 ~ 6h is dried in vacuo at a temperature of 40 ~ 65 DEG C.
7. amoxicillin sodium for injection potassium clavulanate preparation according to claim 1, it is characterised in that: the step 4)
The temperature of middle dehydrated alcohol is 0 ~ 5 DEG C, and the mass ratio of the Amoxicillin and dehydrated alcohol is 1:2.0 ~ 1:2.3, Amoxicillin
It is 1:0.4 ~ 1:0.5 with the mass ratio of triethylamine, the mass ratio of the sodium iso-octoate and Amoxicillin is 0.65:1 ~ 0.75:1,
The mass ratio of sodium iso-octoate and methyl acetate is 1:3.8 ~ 1:4.2.
8. amoxicillin sodium for injection potassium clavulanate preparation according to claim 1, it is characterised in that: the step 5)
In crystal drying temperature be 40 ~ 65 DEG C, drying pressure≤- 0.06MPa, drying time be 3 ~ 6h, the Amoxicillin Sodium
Crystal seed is D50≤7.5 μm, D90≤18 μm, TOP≤40 μm.
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