CN109160921A - A kind of 1/2 water ceftizoxime sodium compound - Google Patents
A kind of 1/2 water ceftizoxime sodium compound Download PDFInfo
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- CN109160921A CN109160921A CN201710619708.9A CN201710619708A CN109160921A CN 109160921 A CN109160921 A CN 109160921A CN 201710619708 A CN201710619708 A CN 201710619708A CN 109160921 A CN109160921 A CN 109160921A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of 1/2 water ceftizoxime sodium compound and its preparation method, it is a kind of white crystalline powder that every mole of ceftizoxime sodium, which contains 1/2 mole of water, its corresponding 2 angle θ of main X-ray characteristic diffraction peak is at 11.43 ± 0.2 °, 13.24 ± 0.2 °, 16.54 ± 0.2 °, 17.85 ± 0.2 °, 19.46 ± 0.2 °, 20.66 ± 0.2 °, 22.33 ± 0.2 °, 23.30 ± 0.2 °, there is characteristic diffraction peak at 23.65 ± 0.2 °, 24.60 ± 0.2 °.1/2 water ceftizoxime sodium compound prepared by the method for the present invention, it is with good stability and meet requirement as preparation raw material.
Description
Technical field
The invention belongs to chemical engineering medicine crystallization technique fields, and in particular to a kind of 1/2 water ceftizoxime sodium compound
And its preparation method.
Background technique
Ceftizoxime sodium is developed by Japanese Fujisawa Pharmaceutical Co., Ltd earliest, and in nineteen eighty-two first in Japan
Listing, trade name epocelin, to belong to third-generation cephalosporin antibiotic, mechanism of action is by inhibiting bacteria cell wall viscous
The biosynthesis of peptide and reach bactericidal effect, have the characteristics that wide spectrum, efficient, resistance to enzyme, low toxicity and blood-brain barrier can be penetrated.Cephalo
The spectrum beta-lactamase that azoles oxime sodium generates various gram-positive bacterias and Gram-negative bacteria is stablized；To escherichia coli,
The enterobacteriaceae lactobacteriaceaes such as Klebsiella Pneumoniae, proteus mirabilis have powerful antibacterial action, the pseudomonads such as green copper pseudomonad
Belong to and acinetobacter is poor to this product sensibility；There is good antibacterial action to haemophilus influenzae and neisseria gonorrhoeae；To gold
The effect of staphylococcus aureus and staphylococcus epidermis is poor, methicillin-resistant staphylococcus Portugal compared with the first, second generation cephalosporin
To this product drug resistance, various streptococcus are highly sensitive to this product for grape coccus and enterococcus spp；Peptococcus, peptostreptococcus and portion
Divide the anaerobic bacterias such as Bacteroides is in sensitive to this product more.Clinically ceftizoxime sodium is for treating lower respiratory tract caused by sensitive bacteria
Infection, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, streptococcus pneumonia
Or meningitis caused by haemophilus influenzae and Simple gonorrhea.
Synthesis in relation to ceftizoxime sodium, three synthetic routes of document report, (one) with 7- phenylacetylamino -3- cephalo
Rhzomorph -4- carboxylic acid is raw material to methoxybenzyl ester, is repeatedly sloughed blocking group, then ceftizoxime sodium is made with salt forming agent, this road
Line reaction step is long, increases operation sequence and production cost, and by-product is more.(2) with 7- amino -3- demethyl -3- head
Spore alkanoic acid (7-ANCA) is raw material and cefotaxime acetic acid direct polycondensation, and then again at salt, this route side reaction is more, products therefrom
A large amount of eluant, eluent need to be also used through alumina column chromatography column purification, it is at high cost, complicated for operation and pollute the environment, no
It is suitble to industrialized production.(3) using 7-ANCA as raw material, with 2- (2- amino -4- thiazolyl) -2- methoxy imino-acetyl-benzo
Thiazole thioesters, which is condensed, is made Ceftizoxime acid, then ceftizoxime sodium is reacted to obtain with salt forming agent.
The ceftizoxime sodium compound of above method preparation, there is poor storage stability, thermal decomposition temperature is low, mobility
Serious problems poor, easy to moisture absorption etc..To influence product quality, formulation products are caused not clarify, turbidity is unqualified, and reduces
The stability of preparation, in order to obtain a kind of ceftizoxime sodium compound that performance is more excellent, the present invention is specifically proposed.
Summary of the invention
The invention discloses a kind of solvates that ceftizoxime sodium is new, more specifically close for 1/2 water Ceftizoxime sodium
Object, i.e. every mole of ceftizoxime sodium compound contain 1/2 mole of water, molecular formula C13H12N5NaO5S2·1/2H2O, molecular weight
414.38 structural formula are as follows:
Karl_Fischer method be containing one of the most single-minded, accurate method in moisture method in various measurement substances, by
It is classified as the basic skills of determination of moisture in many substances, especially to organic compound, as a result accurately and reliably.It is disclosed by the invention
1/2 water ceftizoxime sodium compound Karl_Fischer method measures moisture content between 2.13%-2.22%, 1/2 head spore azoles
Oxime sodium compound theory moisture content is 2.17%, it may be determined that ceftizoxime sodium compound of the present invention contains 1/2 mole of water.
1/2 water ceftizoxime sodium compound of the present invention, TG analysis the results show that percentage loss of weight be computed can
Know about 2.19%, the theoretical percentage composition of water is 2.17% in Ceftizoxime sodium molecule, measures cephalo azoles referring to expense Xiu Shi method
Oxime sodium moisture content is 2.13~2.22%, and it is 2.19% that experiment, which measures TG weightlessness, is consistent substantially with theoretical water content.Therefore
Deducibility ceftizoxime sodium TG weightlessness is caused by removing water, and every mole of ceftizoxime sodium contains 1/2 mole of water.As shown in Fig. 1.
Data are obtained by heat analysis-mass spectrometer (NETZSCH STA 449C) analysis.Analysis condition are as follows: 2~10mg of sample, oxidation
Aluminium crucible, high pure nitrogen do reaction gas and protection gas, and flow is respectively 40ml/min and 30ml/min, heating rate 10K/min,
Temperature test range is 25~400 DEG C.Sample decomposition starting temperature is 59.2 DEG C, and temperature is higher than 258.5 DEG C, and sample quickly divides
Solution.
1/2 water ceftizoxime sodium compound of the present invention, x-ray diffractogram of powder spectrum are in 2 θ of the angle of diffraction
11.43 ± 0.2 °, 13.24 ± 0.2 °, 16.54 ± 0.2 °, 17.85 ± 0.2 °, 19.46 ± 0.2 °, 20.66 ± 0.2 °, 22.33
There are characteristic diffraction peak, the opposite diffracted intensity of the angle of diffraction at ± 0.2 °, 23.30 ± 0.2 °, 23.65 ± 0.2 °, 24.60 ± 0.2 °
Respectively 89.67,39.41,19.06,46.51,100,22.11,46.76,38.69,40.87,24.76.As shown in Fig. 2.X
Ray powder diffraction test condition: EMPYREAN (sharp shadow) X-ray diffractometer of Dutch Panalytical company, CuK α radiation,
Light pipe voltage 40kV, heater current 300mA, continuous scanning, 0.02 ° of step-length, 8 °/min of scanning speed, scanning range is 2~
50°。
Document has been reported that the different crystal forms of same substance, the different solvents compound of same substance have identical powder X-ray to penetrate more
Line diffraction spectrogram has the identical powder x-ray diffraction spectrogram in part, and it is therefore necessary to according to " the quality control of polymorphic drug
Technology and method guideline processed ", provide other discrimination methods proof this patent reports is new hydrate.
1/2 water ceftizoxime sodium compound of the present invention, Fourier transform infrared spectroscopy are 3425.9 in wave number
±2cm-1, 3239.6 ± 2cm-1, 1746.3 ± 2cm-1, 1648.1 ± 2cm-1, 1537.9 ± 2cm-1, 1414.7 ± 2cm-1,
1365.2±2cm-1, 1180.9 ± 2cm-1, 1034.0 ± 2cm-1, 992.5 ± 2cm-1, 811.0 ± 2cm-1There is characteristic absorption at place
Peak, as shown in Fig. 3.Examination of infrared spectrum condition are as follows: Agilent Cary 630, pressing potassium bromide troche.
1/2 water ceftizoxime sodium compound of the present invention, dsc analysis is the results show that have heat absorption at about 73.9 DEG C
There is exothermic peak at peak at about 264.9 DEG C.As shown in Fig. 4.DSC data is by heat analysis-mass spectrometer (NETZSCH STA
449C) analysis obtains, analysis condition are as follows: 2~10mg of sample, alumina crucible, high pure nitrogen do reaction gas and protection gas, flow
Respectively 40ml/min and 30ml/min.10 DEG C/min of heating rate, 25~400 DEG C of temperature range.
1/2 water ceftizoxime sodium compound of the present invention, specific preparation method include:
(1) 7-ANCA is added in chloroform, stirs into suspension, is slowly added to triethylamine, stirred, add AE-
Active ester reaction, end of reaction reduce temperature, and water is added and extracts, separates water phase, and active carbon, stirring and adsorbing is added, and filtering is washed
It washs, merging filtrate, adjusts filtrate pH value with hydrochloric acid solution, stirred crystallization filters, and chloroform washing, vacuum drying obtains cephalo
Azoles oxime acid；
(2) Ceftizoxime acid is added in purified water, stirs into suspension, reduced temperature, be slowly added to triethylamine, stirred
Dissolution adds active carbon stirring decoloration, and filtering purifies water washing, keeps temperature, be slowly added to the ethanol water of sodium iso-octoate,
Stirring, adds alcohol crystal, is slowly stirred crystallization, filters, ethanol washing, and vacuum drying obtains 1/2 water ceftizoxime sodium compound.
In above-mentioned preparation method, the reaction temperature after addition 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester described in step (1) is 30-35 DEG C, described
Addition 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester after the reaction time be 4-5h, the reduction is cooled to 10-15 DEG C, the addition hydrochloric acid solution tune
PH value is saved to 2.0-2.5, the crystallization temperature is 10-15 DEG C, and the crystallization time is 1-2h, and the drying temperature is
30-40℃。
In above-mentioned preparation method, to 5-10 DEG C, the ethanol water is reduction temperature described in step (2)
The reaction time of the ethanol water of 50%-70%, the Ceftizoxime acid and sodium iso-octoate is 30min-1h, and described stirs
Mixing crystallization time is 1-2h, and the drying temperature is 30-40 DEG C.
The preparation method advantage of 1/2 water ceftizoxime sodium compound provided by the invention is high income, at low cost, product product
Matter is stablized；1/2 prepared water ceftizoxime sodium compound high performance liquid chromatography content meets States Pharmacopoeia specifications.
1/2 water ceftizoxime sodium compound thermal stability provided by the invention is good, and differential thermal analysis shows it about 73.9
DEG C there is endothermic peak, has exothermic peak at about 264.9 DEG C.Accelerated stability test shows 1/2 water ceftizoxime sodium compound of the invention
Stability be better than ceftizoxime sodium anhydride.1/2 water ceftizoxime sodium compound provided by the invention and ceftizoxime sodium without
Water object is compared to less easy to moisture absorption.Therefore 1/2 water ceftizoxime sodium compound provided by the invention is excellent in terms of stability, moisture resistance
In ceftizoxime sodium anhydride, there is wider application prospect.
Further purpose of the invention provides a kind of pharmaceutical composition containing 1/2 water ceftizoxime sodium compound.It is excellent
Selection of land, described pharmaceutical composition include 1/2 water ceftizoxime sodium compound and the excipient pharmaceutically received.It is highly preferred that medicine
Compositions are selected from pharmaceutically acceptable dosage form.
Further purpose of the invention, provides 1/2 water ceftizoxime sodium compound of one kind and its pharmaceutical composition exists
Prepare the application in antibacterials.
Detailed description of the invention
The TG of 1/2 water ceftizoxime sodium compound of Fig. 1 schemes；
The X-ray powder diffraction of 1/2 water ceftizoxime sodium compound of Fig. 2 composes (XRD) figure；
Fourier transform infrared spectroscopy (FT-IR) figure of 1/2 water ceftizoxime sodium compound of Fig. 3；
Differential thermal analysis (DSC) figure of 1/2 water ceftizoxime sodium compound of Fig. 4.
Specific embodiment
Below will by specific embodiment, the present invention will be further described, but therefore do not limit the present invention to institute
In the scope of embodiments stated, it should be understood by those skilled in the art that changing to the equivalent replacement that the content of present invention is done, or accordingly
Into still falling within protection scope of the present invention.
The preparation of 1 1/2 water ceftizoxime sodium compound of embodiment
(1) 100g 7-ANCA is added in 2L chloroform, stirs into suspension, is slowly added to 200ml triethylamine, stirs
20min to be mixed, 30 DEG C of reaction 4h of 193gAE- active ester are added, end of reaction reduces temperature to 10 DEG C, and 4L water is added and extracts, point
From water phase, 20g active carbon is added, stirring and adsorbing 30min is filtered, washing, merging filtrate, is adjusted with the hydrochloric acid solution of 2mol/L
To 2.0,10 DEG C of stirred crystallization 1h, filtering, chloroform washing, 30 DEG C are dried in vacuo 20 minutes pH value, obtain Ceftizoxime acid
169.3g；
(2) Ceftizoxime acid is added in 500ml purified water, stirs into suspension, reduced temperature to 5 DEG C, be slowly added to
70ml triethylamine, stirring and dissolving, be added 5g active carbon stirring decoloration 20min, filtering, purify water washing, be slowly added to dissolved with
The ethanol water 200ml of the 50% of 100g sodium iso-octoate is stirred to react 30min, and 5L ethyl alcohol is added, and is slowly stirred crystallization 1h,
Filtering, ethanol washing, 30 DEG C are dried in vacuo 30 minutes, obtain 1/2 water ceftizoxime sodium compound 161.1g.
X-ray powder diffraction pattern 2 θ of the angle of diffraction be 11.43 °, 13.24 °, 16.54 °, 17.85 °, 19.46 °,
There is characteristic diffraction peak at 20.66 °, 22.33 °, 23.30 °, 23.65 °, 24.60 °, the opposite diffracted intensity of the angle of diffraction is respectively
89.67,39.41,19.06,46.51,100,22.11,46.76,38.69,40.87,24.76.
FTIR spectrum is 3425.9cm in wave number-1, 3239.6cm-1, 1746.3cm-1, 1648.1cm-1,
1537.9cm-1, 1414.7cm-1, 1365.2cm-1, 1180.9cm-1, 1034.0cm-1, 992.5cm-1, 811.0cm-1There is feature at place
Peak, the corresponding characteristic peak of each wave number is almost the same, all within the scope of.
It is 99.69% that HPLC method, which detects purity,；It is 2.17% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
2.19%, it is almost the same with the result (theoretical value 2.17%) of 1/2 water contained in this way；Elemental Analysis theory are as follows: C:
37.68%, H:3.16%, N:16.90%, Na:5.55%, O:21.24%, S:15.47%；Measured value are as follows: C:37.63%,
H:3.17%, N:16.92%, Na:5.54%, O:21.25%, S:15.49%.
The preparation of 2 1/2 water ceftizoxime sodium compound of embodiment
(1) 120g 7-ANCA is added in 2.5L chloroform, stirs into suspension, is slowly added to 240ml triethylamine,
20min is stirred, 35 DEG C of reaction 5h of 232g 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester are added, end of reaction reduces temperature to 15 DEG C, and 5L water is added and mentions
It takes, separates water phase, 20g active carbon is added, stirring and adsorbing 30min is filtered, washing, merging filtrate, with the hydrochloric acid solution of 2mol/L
PH value is adjusted to 2.5,10 DEG C of stirred crystallization 1h, filtering, chloroform washing, 30 DEG C are dried in vacuo 25 minutes, obtain Ceftizoxime
Sour 211.8g；
(2) Ceftizoxime acid is added in 500ml purified water, stirs into suspension, reduced temperature to 10 DEG C, be slowly added to
100ml triethylamine, stirring and dissolving, be added 5g active carbon stirring decoloration 20min, filtering, purify water washing, be slowly added to dissolved with
The ethanol water 250ml of the 70% of 125g sodium iso-octoate is stirred to react 1h, and 6L ethyl alcohol is added, and is slowly stirred crystallization 2h, mistake
Filter, ethanol washing, 40 DEG C are dried in vacuo 20 minutes, obtain 1/2 water ceftizoxime sodium compound 207.3g.
X-ray powder diffraction pattern 2 θ of the angle of diffraction be 11.44 °, 13.20 °, 16.57 °, 17.86 °, 19.42 °,
There is characteristic diffraction peak at 20.68 °, 22.35 °, 23.33 °, 23.66 °, 24.62 °, the opposite diffracted intensity of the angle of diffraction is respectively
88.40,39.89,19.77,45.50,100,23.09,45.19,37.63,39.28,25.70.
FTIR spectrum is 3426.3cm in wave number-1, 3239.9cm-1, 1746.6cm-1, 1648.2cm-1,
1537.5cm-1, 1414.4cm-1, 1365.6cm-1, 1180.3cm-1, 1034.5cm-1, 992.7cm-1, 811.2cm-1There is feature at place
Peak, the corresponding characteristic peak of each wave number is almost the same, all within the scope of.
It is 99.72% that HPLC method, which detects purity,；It is 2.13% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
2.16%, it is almost the same with the result (theoretical value 2.17%) of 1/2 water contained in this way；Elemental Analysis theory are as follows: C:
37.68%, H:3.16%, N:16.90%, Na:5.55%, O:21.24%, S:15.47%；Measured value are as follows: C:37.66%,
H:3.16%, N:16.91%, Na:5.57%, O:21.23%, S:15.47%.
The preparation of 3 1/2 water ceftizoxime sodium compound of embodiment
(1) 90g 7-ANCA is added in 1.5L chloroform, stirs into suspension, is slowly added to 180ml triethylamine, stirs
20min is mixed, 35 DEG C of reaction 4.5h of 174g 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester are added, end of reaction reduces temperature to 12 DEG C, and 4L water is added and mentions
It takes, separates water phase, 20g active carbon is added, stirring and adsorbing 20min is filtered, washing, merging filtrate, with the hydrochloric acid solution of 2mol/L
PH value is adjusted to 2.2,12 DEG C of stirred crystallization 1.5h, filtering, chloroform washing, 35 DEG C are dried in vacuo 20 minutes, obtain cephalo azoles
Oxime acid 152.4g；
(2) Ceftizoxime acid is added in 400ml purified water, stirs into suspension, reduced temperature to 8 DEG C, be slowly added to
5g active carbon stirring decoloration 20min is added in 90ml triethylamine, stirring and dissolving, and filtering purifies water washing, is slowly added to dissolved with 90g
The ethanol water 200ml of the 60% of sodium iso-octoate is stirred to react 1h, and 4L ethyl alcohol is added, and is slowly stirred crystallization 1.5h, filters,
Ethanol washing, 35 DEG C are dried in vacuo 25 minutes, obtain 1/2 water ceftizoxime sodium compound 149.6g.
X-ray powder diffraction pattern 2 θ of the angle of diffraction be 11.40 °, 13.22 °, 16.55 °, 17.89 °, 19.45 °,
There is characteristic diffraction peak at 20.66 °, 22.31 °, 23.35 °, 23.64 °, 24.68 °, the opposite diffracted intensity of the angle of diffraction is respectively
89.52,38.17,20.25,43.91,100,22.63,44.31,36.09,38.74,24.99.
FTIR spectrum is 3426.0cm in wave number-1, 3239.2cm-1, 1747.1cm-1, 1648.5cm-1,
1538.2cm-1, 1414.6cm-1, 1365.2cm-1, 1180.5cm-1, 1034.3cm-1, 992.2cm-1, 811.0cm-1There is feature at place
Peak, the corresponding characteristic peak of each wave number is almost the same, all within the scope of.
It is 99.66% that HPLC method, which detects purity,；It is 2.22% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
2.20%, it is almost the same with the result (theoretical value 2.17%) of 1/2 water contained in this way；Elemental Analysis theory are as follows: C:
37.68%, H:3.16%, N:16.90%, Na:5.55%, O:21.24%, S:15.47%；Measured value are as follows: C:37.70%,
H:3.15%, N:16.88%, Na:5.56%, O:21.25%, S:15.46%.
The preparation of 1 ceftizoxime sodium compound of comparative example
The method of " discussion of the synthesis technology about ceftizoxime sodium " in reference literature " Heilungkiang scientific and technological information " report
Prepare ceftizoxime sodium compound
(1) 120g 7-ANCA is added in 3L isopropanol, stirring adds 232g 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, stirs evenly, and delays
Slow that 2500ml triethylamine is added, after reaction solution clarification, the reaction was continued 1h is added 4L water and extracts, separates water phase, water phase isopropanol
20g active carbon is added in washing, and stirring and adsorbing 20min, filtering, filtrate is using Al2O31.2L acetone is added in water layer after column chromatography,
It is slowly added to the hydrochloric acid solution of 2mol/L, when crystal solution muddiness starts growing the grain 30min, continues plus the hydrochloric acid solution of 2mol/L is adjusted
To 2.5,8 DEG C of stirred crystallization 1h, filtering, ethyl acetate washing, 40 DEG C are dried in vacuo 20 minutes pH value, obtain Ceftizoxime acid
164.1g；
(2) Ceftizoxime acid is added in 500ml purified water, 100g anhydrous sodium acetate is added and stirs to solution clarification, adds
Enter 6g active carbon and stir the 30min that decolourizes, filtering, purifying washes charcoal cake, adds acetone to precipitation is crystallized in filtrate, be slowly stirred growing the grain
1h, continues plus acetone is to 15L, is cooled to 10 DEG C, stirred crystallization 1h, filtering, acetone washing, 40 DEG C are dried in vacuo 50 minutes, obtain
Ceftizoxime sodium compound 171.5g.
It is 99.21% that HPLC method, which detects purity,；It is 4.31% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
4.40%；Elemental Analysis theory are as follows: C:38.52%, H:2.98%, N:17.28%, Na:5.67%, O:19.73%, S:
15.82%；Measured value are as follows: C:38.50%, H:2.99%, N:17.30%, Na:5.64%, O:19.74%, S:15.83%.
The preparation of 2 ceftizoxime sodium of comparative example, 1.75 hydrate
Using 1.75 hydrate of ceftizoxime sodium of the method preparation of embodiment 1 in patent CN101781316A
In 500ml triangular flask plus Ceftizoxime acid 100g, water 200ml, stirring make into suspension, three are added dropwise at 5 DEG C
Ethamine 40ml, stirring and dissolving add active carbon 1g, stir 30 minutes, filter, and wash, and filter, and 200ml is added dropwise in filtrate at 5 DEG C
Sodium iso-octoate and alcohol mixeding liquid (containing sodium iso-octoate 65g), stirring, glacial acetic acid adjusts pH to 7.0, and acetone 500ml is slowly added dropwise
With ethyl alcohol 1500ml mixed liquor, 5 DEG C arranged below, and solid is precipitated sufficiently, filters, and a small amount of ethyl alcohol is washed 3 times, filters, and gained is solid
Body is recrystallized with water-ethanol-acetone mixed solvent, and 5 DEG C arranged below, makes to crystallize abundant wash-off, is filtered, 40 DEG C of vacuum drying
4h obtains off-white color crystallization 60.3g.
It is 99.08% that HPLC method, which detects purity,；It is 7.25% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
7.19%；Elemental Analysis theory are as follows: C:35.74%, H:3.58%, N:16.03%, Na:5.26%, O:24.72%, S:
14.68%；Measured value are as follows: C:35.71%, H:3.59%, N:16.05%, Na:5.24%, O:24.73%, S:14.69%.
Test example 1: stability test
The 1/2 water ceftizoxime sodium compound and the preparation of comparative example 1~2 that the present inventor prepares the embodiment of the present invention 1~3
Ceftizoxime sodium compound carried out accelerated stability investigate test.Investigation condition is 40 DEG C ± 2 DEG C of temperature, is placed 6 months,
It is sampled respectively at 0,1,2,3,6 the end of month.Inspection target is character, clarity, solution colour, moisture, pH value, content, cephalo
Azoles oxime polymer and related substance.Accelerated test is investigated result and be see the table below.
Conclusion: from the above results, by 6 months accelerated tests, sample prepared by the embodiment of the present invention 1~3 was every
Testing index is substantially better than the product of comparative example 1~2, has absolutely proved 1/2 water ceftizoxime sodium compound prepared by the present invention
Stability is more preferable, and quality is better than similar product, while the moisture of Examples 1 to 3 and comparative example 2 pushes away substantially without significant change
The water that it contains that breaks is the crystallization water, and non-adsorbed water；The moisture of comparative example 1 is decreased obviously, and infers the water that it contains for absorption
Water.
Test example 2: wettability test
Cephalo azoles prepared by 1/2 water ceftizoxime sodium compound and comparative example 1~2 prepared by the embodiment of the present invention 1~3
Oxime sodium compound is placed in dynamic vapor sorption instrument under the conditions of 40 DEG C, the weight change in record three hours, and test result is as follows:
| Relative humidity RH/% | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 |
| 0 | 0 | 0 | 0 | 0 | 0 |
| 10 | 0 | 0 | 0 | 0 | 0 |
| 20 | 0 | 0.01 | 0 | 0 | 0 |
| 30 | 0 | 0.02 | 0 | 0.02 | 0.03 |
| 40 | 0 | 0.02 | 0.01 | 0.08 | 0.05 |
| 50 | 0 | 0.02 | 0.02 | 0.25 | 0.18 |
| 60 | 0.01 | 0.05 | 0.03 | 0.56 | 0.33 |
| 70 | 0.67 | 0.58 | 0.60 | 0.98 | 0.87 |
Conclusion: 1/2 water ceftizoxime sodium compound provided by the invention is less easy to moisture absorption.
Test example 3: fluidity test
The present inventor takes funnel method to survey ceftizoxime sodium prepared by the embodiment of the present invention 1~3 and comparative example 1~2
Determine angle of repose, the mobility of ceftizoxime sodium is studied.Angle of repose testing result:
Angle of repose testing result:
| Embodiment | Angle of repose θ |
| Embodiment 1 | 28.2° |
| Embodiment 2 | 27.9° |
| Embodiment 3 | 27.6° |
| Comparative example 1 | 34.6° |
| Comparative example 2 | 35.2° |
As a result: the mobility of 1/2 water ceftizoxime sodium compound prepared by the present invention is apparently higher than 1~2 cephalo of comparative example
Azoles oxime sodium compound can satisfy the needs of different preparation preparations.
The verifying of 4 crystallization water of test example is investigated
It is the crystallization water to sufficiently verify 1/2 water in ceftizoxime sodium compound of the present invention, the present inventor passes through thermogravimetric
Three kinds of analytic approach, 60 DEG C of thermal stability 10 days, vacuum freezedrying weight-loss method methods, investigate the moisture of each embodiment and comparative example
As a result, specific as follows:
4, thermogravimetry
Thermogravimetric analysis is the weightlessness before sample decomposes at high operating temperatures, is the important side for verifying the crystallization water or adsorbing water
Method, the present inventor have carried out thermogravimetric analysis to the ceftizoxime sodium compound of each embodiment and comparative example preparation respectively, have as a result converged
It is total as follows:
| Embodiment | Thermogravimetry weightlessness (%) |
| Embodiment 1 | 2.19 |
| Embodiment 2 | 2.16 |
| Embodiment 3 | 2.20 |
| Comparative example 1 | 4.40 |
| Comparative example 2 | 7.19 |
As a result, the 1/2 water ceftizoxime sodium compound weightlessness and the result of 1/2 water contained of Examples 1 to 3 preparation
(theoretical value 2.17%) is almost the same；Ceftizoxime sodium weightlessness prepared by comparative example 1 is larger；Ceftizoxime prepared by comparative example 2
Sodium compound weightlessness and the result (theoretical value 7.21%) of 1.75 water contained are almost the same.Infer the embodiment of the present invention 1~3
The aqueous ceftizoxime sodium compound institute prepared for the crystallization water, comparative example 1 of ceftizoxime sodium compound institute prepared with comparative example 2
Aqueous is absorption water.
2,60 DEG C thermal stability 10 days
Ceftizoxime sodium prepared by 1/2 water ceftizoxime sodium compound of preparation of the embodiment of the present invention and comparative example 1~2
Compound is respectively placed in 60 DEG C of baking ovens 10 days, detects moisture with Karl_Fischer method respectively at 0,10 day, as a result as follows:
| Embodiment | 0 day (%) | 10 days (%) |
| Embodiment 1 | 2.17 | 2.15 |
| Embodiment 2 | 2.13 | 2.10 |
| Embodiment 3 | 2.22 | 2.21 |
| Comparative example 1 | 4.31 | 0.51 |
| Comparative example 2 | 7.25 | 7.18 |
As a result, 60 DEG C of high temperature are placed 10 days, 1/2 water ceftizoxime sodium compound moisture of Examples 1 to 3 preparation does not have substantially
There is significant change, ceftizoxime sodium moisture prepared by comparative example 1 is substantially reduced, ceftizoxime sodium compound prepared by comparative example 2
Moisture does not have significant change.Ceftizoxime sodium compound institute prepared by the deduction embodiment of the present invention 1~3 and comparative example 2 is aqueous to be
The crystallization water, ceftizoxime sodium compound institute prepared by comparative example 1 are aqueous for absorption water.
3, vacuum freezedrying 10 hours
Ceftizoxime sodium prepared by 1/2 water ceftizoxime sodium compound of preparation of the embodiment of the present invention and comparative example 1~2
Compound, which is respectively placed in -45 DEG C of freeze driers, to be vacuumized 10 hours, detects water with Karl_Fischer method respectively at 0,10 hour
Point, it is as a result as follows:
| Embodiment | 0 hour (%) | 10 hours (%) |
| Embodiment 1 | 2.17 | 2.14 |
| Embodiment 2 | 2.13 | 2.11 |
| Embodiment 3 | 2.22 | 2.19 |
| Comparative example 1 | 4.31 | 0.42 |
| Comparative example 2 | 7.25 | 7.20 |
As a result, -45 DEG C of vacuum freezedryings of low temperature 10 hours, 1/2 water Ceftizoxime sodium of Examples 1 to 3 preparation is closed
Object moisture is substantially without significant change, and ceftizoxime sodium moisture prepared by comparative example 1 is substantially reduced, cephalo prepared by comparative example 2
Azoles oxime sodium compound moisture does not have significant change.Infer Ceftizoxime sodium prepared by the embodiment of the present invention 1~3 and comparative example 2
It is the crystallization water that it is aqueous, which to close object institute, and ceftizoxime sodium compound institute prepared by comparative example 1 is aqueous for absorption water.
Claims (6)
1. a kind of 1/2 water ceftizoxime sodium compound, it is characterised in that every mole of ceftizoxime sodium contains 1/2 mole of water, molecular formula
C13H12N5NaO5S2·1/2H2O, molecular weight 414.38, structural formula are as follows:
2. a kind of pharmaceutical composition, it is characterised in that include 1/2 water ceftizoxime sodium compound described in claim 1.
3. a kind of pharmaceutical composition, it is characterised in that include 1/2 water ceftizoxime sodium compound described in claim 1 and pharmacy
Upper acceptable excipient.
4. pharmaceutical composition according to claim 3, it is characterised in that described pharmaceutical composition is selected from pharmaceutically acceptable
Dosage form.
5. application of the 1/2 water ceftizoxime sodium compound described in claim 1 in preparation antibacterials.
6. application of the described in any item pharmaceutical compositions of claim 2-4 in preparation antibacterials.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109160920A (en) * | 2017-07-20 | 2019-01-08 | 海南美大制药有限公司 | An a kind of water ceftizoxime sodium compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781316A (en) * | 2010-03-17 | 2010-07-21 | 刘力 | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof |
| CN103044450A (en) * | 2013-01-05 | 2013-04-17 | 黄金秀 | Ceftizoxime sodium compound and preparation method and drug composition of ceftizoxime sodium compound |
| CN103524532A (en) * | 2013-10-31 | 2014-01-22 | 浙江亚太药业股份有限公司 | Ceftizoxime sodium compound crystal form, and preparing method and pharmaceutical preparation thereof |
| CN105622635A (en) * | 2016-03-10 | 2016-06-01 | 重庆福安药业集团庆余堂制药有限公司 | Ceftizoxime sodium novel crystal form capable of reducing anaphylactic reactions and preparation thereof |
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2017
- 2017-07-26 CN CN201710619708.9A patent/CN109160921A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781316A (en) * | 2010-03-17 | 2010-07-21 | 刘力 | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof |
| CN103044450A (en) * | 2013-01-05 | 2013-04-17 | 黄金秀 | Ceftizoxime sodium compound and preparation method and drug composition of ceftizoxime sodium compound |
| CN103524532A (en) * | 2013-10-31 | 2014-01-22 | 浙江亚太药业股份有限公司 | Ceftizoxime sodium compound crystal form, and preparing method and pharmaceutical preparation thereof |
| CN105622635A (en) * | 2016-03-10 | 2016-06-01 | 重庆福安药业集团庆余堂制药有限公司 | Ceftizoxime sodium novel crystal form capable of reducing anaphylactic reactions and preparation thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109160920A (en) * | 2017-07-20 | 2019-01-08 | 海南美大制药有限公司 | An a kind of water ceftizoxime sodium compound |
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