CN109134502A - A kind of 1/2 water cefuroxime sodium compound - Google Patents
A kind of 1/2 water cefuroxime sodium compound Download PDFInfo
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- CN109134502A CN109134502A CN201710454614.0A CN201710454614A CN109134502A CN 109134502 A CN109134502 A CN 109134502A CN 201710454614 A CN201710454614 A CN 201710454614A CN 109134502 A CN109134502 A CN 109134502A
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- water
- cefuroxime sodium
- cefuroxime
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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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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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
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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
- C07—ORGANIC CHEMISTRY
- 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 cefuroxime sodium compound, every mole of Cefuroxime Sodium contains 1/2 mole of water.1/2 water cefuroxime sodium compound prepared by the method for the present invention, with thermal stability is good, good fluidity, remarkable advantage not easy to moisture absorption and meets 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 cefuroxime sodium compound
And its preparation method.
Background technique
Cefuroxime Sodium, English name Cefuroxime Sodium, also known as Zinacef, cefuroxime, Chinese nickname:
(6R, 7R) -7- [2- furyl (methoxyimino) acetylamino] -3- carbamoyloxymethyl -8- oxo -5- thia -1- nitrogen
Miscellaneous two ring [4.2.0] oct-2-ene -2- sodium formate, molecular weight: 446.37, molecular formula: C16H15N4NaO8S。
Cefuroxime Sodium is white, off-white color or micro-yellow powder or crystalline powder；It is odorless, bitter；Have draw it is moist,
Readily soluble in water, slightly molten in methyl alcohol, insoluble in ethyl alcohol or chloroform, in every 1ml in the solution containing 10mg, specific rotation is+55 °
To+65 °；It is measured using according to spectrophotometry, trap is measured at the wavelength of 274nm, absorption coefficient (E1cm1%) is 390-
425。
Cefuroxime Sodium is the classic two generations cephalosporin for having the first generation Yu third generation cephalosporin advantage, not only
There is stronger antibacterial activity to gram-positive cocci, and also have good antibacterial activity to certain gramnegative bacteriums,
Especially in the treatment of Gram-positive and gramnegative bacterium mixed infection, the drug even more preferentially selected.Cefuroxime
Sodium is suitable for respiratory tract infection, urinary system infection contamination, ear since has a broad antifungal spectrum, internal wide, tissue concentration height, the toxicity of being distributed are low
The infection of nose larynx, Skin and soft tissue infection, gynecological infections, stranguria syndrome, septicemia, meningitis and inside and outside postoperative infection etc..Cephalo
Cefuroxime sodium be applied not only to operation in anti-infective therapy, and after surgery anti-infective therapy and surgical prophylaxis infection in curative effect very
Obviously.Cefuroxime Sodium in vivo not by liver metabolism, therefore to liver nontoxicity；It is drained from urine with original shape through kidney, therefore
To the almost non-toxic side effect of kidney, so its medication is very safe, there are good pharmacokinetics and safety to newborn.The medicine
Above-mentioned advantage becomes the preferred medication of Gram-negative bacteria or gram-negative positive bacteria mixed infection.
The initial preparation route of Cefuroxime Sodium is proposed by the Glax company of Britain, passes through 8 steps by 7-amino-cephalosporanic acid
Reaction preparation mainly due to the blocking group for introducing amino and carboxyl in intermediate steps, but needs finally to slough protecting group,
Yield is lower, and impurity is more.Then there are many other preparation methods, is such as first reacted with SMIF-C1 by 7-ACA and generate 7-
[(z) -2- furyl -2- methoxy imino acetylamino] -3- acetyl-o-methyl -3- cephalo alkane 7-FCA), then with sodium hydroxide water
Solution generates 7-FHCA, then reacts with trichloroacetyl isocyanate and generates cefuroxime acid, is finally converted by salification process
Cefuroxime Sodium.Cefuroxime Sodium stability is poor, and refrigeration need to be sealed under the conditions of 2-8 DEG C, stores or transport improper be easy out
, when examining according to standards of pharmacopoeia, often there is the underproof problem of color of solution in existing solid color burn.
The Cefuroxime Sodium product clinically used at present is anhydride, due to Material synthesis technique and drug nature
Influence, there is unstable quality, thermal decomposition temperature is low, poor fluidity, serious problems easy to moisture absorption etc..To influence product
Quality causes formulation products not clarify, and turbidity is unqualified, and reduces the stability of preparation.
Therefore, it is necessary to invent, a kind of preparation process is simple, high income；Thermal stability is good, good fluidity, not easy to moisture absorption
Cefuroxime sodium hydrate, to meet requirement and the clinic needs of pharmaceutical formulations.
Summary of the invention
The object of the present invention is to provide a kind of novel solvent compounds of Cefuroxime Sodium, are more specifically 1/2 head spore
Cefuroxime sodium compound, i.e. every mole of Cefuroxime Sodium contain 1/2 mole of water, molecular formula C16H15N4NaO8S·1/2H2O, molecular weight
It is 455.38, structural formula are as follows:
1/2 water cefuroxime sodium compound of the present invention, specific preparation method include:
(1) under room temperature, cefuroxime acid and sodium acetate are added in the mixed solution of water and organic solvent, stirring,
Reaction, obtains cefuroxime sodium solution；
(2) crystal seed is added in above-mentioned cefuroxime sodium solution, reduces temperature, be slowly added to organic solvent, stirring knot
Crystalline substance, filtering；
(3) above-mentioned filtrate is soluble in water, active carbon is added, stirring and adsorbing filters, organic solvent is added in filtrate,
Reduce temperature, stirred crystallization, filtration；Organic solvent washing filtrate, vacuum drying, obtains 1/2 water cefuroxime sodium compound.
In above-mentioned preparation method, wherein the organic solvent is selected from methanol, ethyl alcohol, chloroform, methylene chloride, acetic acid
One of ethyl ester or any two kinds of mixed solution.
In above-mentioned preparation method, the volume ratio of water described in step (1) and organic solvent is 1:(1-1.5).
In above-mentioned preparation method, crystal seed form described in step (2) be aciculiform, ellipse or it is one of amorphous or its
Mixture.
In above-mentioned preparation method, wherein the reduction temperature is to -5 DEG C -0 DEG C.
In above-mentioned preparation method, wherein the crystallization mixing speed is 150-500rpm.
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.Cephalo of the invention
Cefuroxime sodium compound Karl_Fischer method measures moisture content between 1.90%-2.07%, and theoretical moisture content is 1.98%,
It can determine that cefuroxime sodium compound of the present invention contains 1/2 water.
1/2 water cefuroxime sodium compound of the present invention, infrared spectroscopy are 3528.1 ± 2cm in wave number-1,
3366.5±2cm-1, 3256.6 ± 2cm-1, 1757.7 ± 2cm-1, 1698.9 ± 2cm-1, 1667.1 ± 2cm-1, 1627.0 ±
2cm-1, 1402.3 ± 2cm-1, 1334.3 ± 2cm-1, 1082.6 ± 2cm-1, 1061.5 ± 2cm-1, 1011.7 ± 2cm-1There is spy at place
Absorption peak is levied, as shown in Fig. 1.Examination of infrared spectrum condition are as follows: Agilent Cary 630, pressing potassium bromide troche.
1/2 water cefuroxime sodium compound of the present invention, x-ray diffractogram of powder spectrum are in 2 θ of the angle of diffraction
There is spy at 10.18 ± 0.2 °, 11.30 ± 0.2 °, 13.30 ± 0.2 °, 18.90 ± 0.2 °, 19.21 ± 0.2 °, 21.30 ± 0.2 °
Diffraction maximum is levied, the opposite diffracted intensity of the angle of diffraction is respectively 100,20.35,38.51,78.97,97.08,10.81, such as attached drawing 2
It is shown.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 °.
1/2 water cefuroxime sodium compound of the present invention, TG analysis is the results show that cefuroxime sodium compound
Percentage loss of weight calculated result is it is found that weightlessness about 2.0%, and the theoretical percentage composition of water is 1.98% in cefuroxime sodium molecule,
Measuring Cefuroxime Sodium moisture content referring to expense Xiu Shi method is 1.90~2.07%, and it is 2.0% that experiment, which measures TG weightlessness, with reason
It is consistent substantially by water content.It can be inferred that Cefuroxime Sodium TG weightlessness is caused by removing water, and every mole of Cefuroxime Sodium contains
1/2 mole of water.As shown in Fig. 3.Data are obtained by heat analysis-mass spectrometer (NETZSCH STA449C) analysis.Analyze item
Part are as follows: 2~10mg of sample, alumina crucible, high pure nitrogen do reaction gas and protection gas, flow be respectively 40ml/min and
30ml/min, heating rate 10K/min, temperature test range are 25~400 DEG C.Sample decomposition starting temperature is 150.2 DEG C, temperature
Degree is higher than 227.6 DEG C, sample fast decoupled.
1/2 water cefuroxime sodium compound of the present invention, dsc analysis is the results show that have heat absorption at about 160.2 DEG C
There is exothermic peak at peak at about 249.7 DEG C.As shown in Fig. 4.DSC data is by heat analysis-mass spectrometer (NETZSCH
STA449C) analysis obtains, analysis condition are as follows: and 2~10mg of sample, alumina crucible, high pure nitrogen do reaction gas and protection gas,
Flow is respectively 40ml/min and 30ml/min.10 DEG C/min of heating rate, 25~400 DEG C of temperature range.
The preparation method advantage of 1/2 water cefuroxime sodium compound provided by the invention are as follows: easy to operate, solvent consumption；
Crystallization, filtering, rate of drying are fast, and time-consuming short, high-efficient, low energy consumption；The 1/2 prepared efficient liquid of water cefuroxime sodium compound
Phase chromatographic content meets States Pharmacopoeia specifications in 100% or so (in terms of anhydride).
1/2 water cefuroxime sodium compound thermal stability provided by the invention is good, and dsc analysis shows it at about 160.2 DEG C
There is endothermic peak, has exothermic peak at about 249.7 DEG C.Accelerated stability test shows 1/2 water cefuroxime sodium compound of the invention
Stability is better than 0.25 hydrate of Cefuroxime Sodium anhydride and Cefuroxime Sodium.1/2 water Cefuroxime Sodium provided by the invention
Compound is less easy to moisture absorption compared with Cefuroxime Sodium anhydride, 0.25 hydrate of Cefuroxime Sodium.Therefore provided by the invention
1/2 water cefuroxime sodium compound is better than Cefuroxime Sodium anhydride and Cefuroxime Sodium 0.25 in terms of stability, moisture resistance
Hydrate has wider application prospect.
Further purpose of the invention provides a kind of pharmaceutical composition containing 1/2 water cefuroxime sodium compound.It is excellent
Selection of land, described pharmaceutical composition include 1/2 water cefuroxime sodium compound and the excipient pharmaceutically received.More electedly, medicine
Compositions are selected from pharmaceutically acceptable dosage form.
Detailed description of the invention
Fig. 1 is the FTIR spectrum figure of 1/2 water cefuroxime sodium compound.
Fig. 2 is the X ray diffracting spectrum of 1/2 water cefuroxime sodium compound.
Fig. 3 is the TG analysis chart of 1/2 water cefuroxime sodium compound.
Fig. 4 is the dsc analysis figure of 1/2 water cefuroxime sodium compound.
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 cefuroxime sodium compound of embodiment
(1) under room temperature, water (2L) and ethyl alcohol (2L) is added in 848.8g cefuroxime acid and 272.2g sodium acetate
In mixed solution, 150rpm stirring reacts 2h, obtains cefuroxime sodium solution；
(2) 10g crystal seed is added in above-mentioned cefuroxime sodium solution, reduces temperature to -5 DEG C, is slowly added to ethyl alcohol,
150rpm stirred crystallization, filtering；
(3) above-mentioned filtrate is dissolved in 2L water, 1g active carbon is added, stirring and adsorbing 30min is filtered, in filtrate slowly
3L ethyl alcohol is added, reduces temperature to -5 DEG C, 150rpm stirred crystallization 1h, filters；With ethanol washing filtrate, 40 DEG C of vacuum drying
1 hour, obtain 1/2 water cefuroxime sodium compound 846.3g.
Testing result:
X-ray powder diffraction pattern 2 θ of the angle of diffraction be 10.18 °, 11.30 °, 13.30 °, 18.90 °, 19.21 °,
There is characteristic diffraction peak at 21.30 °, the opposite diffracted intensity of the angle of diffraction is respectively 100,20.35,38.51,78.97,97.08,
10.81。
FTIR spectrum is 3528.1cm in wave number-1, 3366.5cm-1, 3256.6cm-1, 1757.7cm-1,
1698.9cm-1, 1667.1cm-1, 1627.0cm-1, 1402.3cm-1, 1334.3cm-1, 1082.6cm-1, 1061.5cm-1,
1011.7cm-1There is a characteristic peak at place, and the corresponding characteristic peak of each wave number is almost the same, all within the scope of.
It is 99.67% that HPLC method, which detects purity,；It is 1.90% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
2.00%, it is almost the same with the result (theoretical value 1.98%) of 1/2 water contained in this way；Elemental Analysis theory are as follows: C:
42.20%, H:3.54%, N:12.30%, Na:5.05%, O:29.86%, S:7.04%；Measured value are as follows: C:42.14%, H:
3.55%, N:12.33%, Na:5.06%, O:29.85%, S:7.06%.
The preparation of 2 1/2 water cefuroxime sodium compound of embodiment
(1) under room temperature, water (2L) and methanol (2.5L) is added in 849.6g cefuroxime acid and 274.1g sodium acetate
Mixed solution in, 500rpm stirring, react 2h, obtain cefuroxime sodium solution；
(2) 10g crystal seed is added in above-mentioned cefuroxime sodium solution, reduces temperature to 0 DEG C, is slowly added to 2L methanol,
500rpm stirred crystallization, filtering；
(3) above-mentioned filtrate is dissolved in 3L water, 1.5g active carbon is added, stirring and adsorbing 30min is filtered, and is delayed in filtrate
It is slow that 3L methanol is added, temperature is reduced to 0 DEG C, 500rpm stirred crystallization 1h, is filtered；Filtrate is washed with methanol, 40 DEG C of vacuum are dry
Dry 1 hour, obtain 1/2 water cefuroxime sodium compound 851.1g.
Testing result:
X-ray powder diffraction pattern 2 θ of the angle of diffraction be 10.12 °, 11.33 °, 13.36 °, 18.94 °, 19.22 °,
There is characteristic peak at 21.39 °, the opposite diffracted intensity of the angle of diffraction is respectively 100,21.44,37.86,77.52,98.22,11.12.
FTIR spectrum is 3528.2cm in wave number-1, 3366.3cm-1, 3258.1cm-1, 1758.5cm-1,
1699.0cm-1, 1667.2cm-1, 1627.9cm-1, 1402.4cm-1, 1334.2cm-1, 1082.3cm-1, 1061.6cm-1,
1011.0cm-1There is a characteristic peak at place, and the corresponding characteristic peak of each wave number is almost the same, all within the scope of.
It is 99.71% that HPLC method, which detects purity,；It is 2.07% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
2.02%, it is almost the same with the result (theoretical value 1.98%) of 1/2 water contained in this way；Elemental Analysis theory are as follows: C:
42.20%, H:3.54%, N:12.30%, Na:5.05%, O:29.86%, S:7.04%；Measured value are as follows: C:42.21%, H:
3.54%, N:12.34%, Na:5.03%, O:29.84%, S:7.05%.
The preparation of 3 1/2 water cefuroxime sodium compound of embodiment
(1) under room temperature, water (2L) and ethyl acetate is added in 906.2g cefuroxime acid and 285.3g sodium acetate
In the mixed solution of (2L), 300rpm stirring reacts 1h, obtains cefuroxime sodium solution；
(2) 10g crystal seed is added in above-mentioned cefuroxime sodium solution, reduces temperature to -1 DEG C, is slowly added to 2L acetic acid
Ethyl ester, 300rpm stirred crystallization, filtering；
(3) above-mentioned filtrate is dissolved in 2L water, 2g active carbon is added, stirring and adsorbing 30min is filtered, in filtrate slowly
3L ethyl acetate is added, reduces temperature to -1 DEG C, 300rpm stirred crystallization 1h, filters；Filtrate is washed with ethyl acetate, 40 DEG C
Vacuum drying 1 hour, obtains 1/2 water cefuroxime sodium compound 877.5g.
Testing result:
X-ray powder diffraction pattern 2 θ of the angle of diffraction be 10.10 °, 11.36 °, 13.39 °, 18.99 °, 19.26 °,
There is characteristic peak at 21.41 °, the opposite diffracted intensity of the angle of diffraction is respectively 100,22.32,36.25,76.10,97.23,10.45.
FTIR spectrum is 3529.0cm in wave number-1, 3365.8cm-1, 3257.6cm-1, 1759.0cm-1,
1698.4cm-1, 1667.5cm-1, 1627.1cm-1, 1402.6cm-1, 1334.0cm-1, 1082.8cm-1, 1061.2cm-1,
1011.1cm-1There is a characteristic peak at place, and the corresponding characteristic peak of each wave number is almost the same, all within the scope of.
It is 99.63% that HPLC method, which detects purity,；It is 1.95% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
1.99%, it is almost the same with the result (theoretical value 1.98%) of 1/2 water contained in this way；Elemental Analysis theory are as follows: C:
42.20%, H:3.54%, N:12.30%, Na:5.05%, O:29.86%, S:7.04%；Measured value are as follows: C:42.18%, H:
3.53%, N:12.33%, Na:5.06%, O:29.88%, S:7.02%.
Comparative example 1 prepares Cefuroxime Sodium (anhydride) according to existing technical literature CN101475579A
Using the identical preparation method of document embodiment 1: 0.35g citric acid is dissolved in 4ml water, 95% second of 25ml
In the mixed solution of pure and mild 120ml acetone, cefuroxime 10g is added, stirring to dissolved clarification is added active carbon 0.6g and stirs 30 points
Clock filters carbon removal, washes charcoal with proper amount of acetone, merging filtrate and washes charcoal liquid, and 40 DEG C of temperature control, by 70% sodium lactate of 5g and 50ml second
The solution stirring of pure and mild 10ml acetone is added in above-mentioned amalgamation liquid, is finished, and stirring 30 minutes is continued, and filtering is collected, washing knot
Crystalline substance, vacuum drying is at 45 DEG C to get stable Cefuroxime Sodium (anhydride) 10.22g, yield 97.1%.
It is 98.15% that HPLC method, which detects purity,；It is 0.33% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.38%, it is little with anhydride theoretical value difference in this way；Elemental Analysis theory are as follows: C:43.05%, H:3.39%, N:
12.55%, Na:5.15%, O:28.67%, S:7.18%；Measured value are as follows: C:42.99%, H:3.42%, N:12.51%,
Na:5.18%, O:28.70%, S:7.19%.
Comparative example 2 prepares 0.25 hydrate of Cefuroxime Sodium according to existing technical literature CN104072519A
Using the identical preparation method of patent document embodiment 1.At room temperature, increase the head of purity in 500ml flask
Spore cefuroxime acid 10.6g, acetone 180ml, ethyl alcohol 10ml, water 5ml, are stirred to dissolve, and add active carbon 0.06g, stir 30 minutes, take out
It filters, sodium iso-octoate and alcohol mixed solution (containing sodium iso-octoate 4.72g) 60ml is added dropwise at 4 DEG C in filtrate, stirs, 4 DEG C or less
It places, solid is precipitated sufficiently, filter, a small amount of chloroform is washed twice, and a small amount of ethyl alcohol is washed twice, is filtered, a small amount of water of obtained solid
Dissolution, then with ethyl alcohol 260ml, isopropanol 20ml, acetone 20ml be that solvent is recrystallized, 4 DEG C are arranged below, keep crystallization abundant
Be precipitated, filter, a small amount of ethyl alcohol and chloroform replace rinse, filter, obtained solid 20 DEG C or so forced air drying 1 day, then 25 DEG C of left sides
Right vacuum is sufficiently 1 day dry, and 40 DEG C of vacuum drying 4h or so obtain off-white color crystalline powder 5.78g.
It is 97.96% that HPLC method, which detects purity,；It is 1.03% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
1.00%, in this way with it is almost the same with the result (theoretical value 0.99%) of 0.25 water contained；Elemental Analysis theory are as follows: C:
42.62%, H:3.46%, N:12.43%, Na:5.10%, O:29.27%, S:7.11%；Measured value are as follows: C:42.60%, H:
3.47%, N:12.46%, Na:5.12%, O:29.25%, S:7.09%.
1 study on the stability of test example
Prepared by the 1/2 water cefuroxime sodium compound and comparative example 1 that the present inventor prepares the embodiment of the present invention 1~3
0.25 hydrate of Cefuroxime Sodium prepared by Cefuroxime Sodium anhydride and comparative example 2 has carried out accelerated stability and has investigated examination
It tests.Investigation condition is 40 DEG C ± 2 DEG C of temperature, is placed 6 months, is sampled respectively at 0,1,2,3,6 the end of month.Inspection target be character,
Clarity, solution colour, moisture, pH value, content and polymer.
2 hygroscopicity of test example is investigated
By 1/2 water cefuroxime sodium compound prepared by the embodiment of the present invention 1~3 and cefuroxime prepared by comparative example 1
0.25 hydrate of Cefuroxime Sodium prepared by sodium anhydride and comparative example 2 is placed in dynamic vapor sorption instrument under the conditions of 40 DEG C,
Weight change in record three hours, test result are as follows:
Conclusion: 1/2 water cefuroxime sodium compound provided by the invention and Cefuroxime Sodium prepared by comparative example 1 are anhydrous
0.25 hydrate of Cefuroxime Sodium prepared by object and comparative example 2 is compared to less easy to moisture absorption.
3 mobility of test example is investigated
The present inventor prepares 1/2 water cefuroxime sodium compound prepared by the embodiment of the present invention 1~3 with comparative example 1
0.25 hydrate of Cefuroxime Sodium prepared by Cefuroxime Sodium anhydride and comparative example 2 takes funnel method to measure angle of repose, right
The mobility of Cefuroxime Sodium is studied.Angle of repose testing result:
Angle of repose testing result:
| Embodiment | Angle of repose θ |
| Embodiment 1 | 28.8° |
| Embodiment 2 | 29.1° |
| Embodiment 3 | 30.2° |
| Comparative example 1 | 35.2° |
| Comparative example 2 | 34.8° |
Conclusion: the mobility of 1/2 water cefuroxime sodium compound prepared by the present invention is apparently higher than comparative example 1 and comparative example
2 Cefuroxime Sodium can satisfy the needs of different preparation preparations.
4 dissolubility of test example is investigated
By 1/2 water cefuroxime sodium compound prepared by the embodiment of the present invention 1~3 and cefuroxime prepared by comparative example 1
0.25 hydrate of Cefuroxime Sodium prepared by sodium anhydride and comparative example 2 is dissolved in aqueous solution respectively, is shaked 20min, is passed through
Detection level calculates Examples 1 to 3, the solubility of comparative example 1 and comparative example 2 in water.
Solubility testing result
| Embodiment | Solubility |
| Embodiment 1 | 0.89g/ml |
| Embodiment 2 | 0.91g/ml |
| Embodiment 3 | 0.86g/ml |
| Comparative example 1 | 0.41g/ml |
| Comparative example 2 | 0.42g/ml |
Conclusion: the dissolubility of 1/2 water cefuroxime sodium compound prepared by the embodiment of the present invention 1~3 is significantly better than comparison
The Cefuroxime Sodium of example 1 and comparative example 2.
The verifying of 5 crystallization water of test example is investigated
It is the crystallization water to sufficiently verify 1/2 water in cefuroxime 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:
1, 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 cefuroxime 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 | 2.00 |
| Embodiment 2 | 2.02 |
| Embodiment 3 | 1.99 |
| Comparative example 1 | 0.38 |
| Comparative example 2 | 1.00 |
As a result, the 1/2 water cefuroxime sodium compound weightlessness and the result of 1/2 water contained of Examples 1 to 3 preparation
(theoretical value 1.98%) is almost the same；0.25 hydrate weightlessness of Cefuroxime Sodium prepared by comparative example 2 and 0.25 water contained
Result (theoretical value 0.99%) it is almost the same；Cefuroxime Sodium anhydride weightlessness and anhydride theoretical value prepared by comparative example 1
Difference is little.Infer that water contained by the cefuroxime sodium compound of the embodiment of the present invention 1~3 and the preparation of comparative example 2 is the crystallization water, it is right
Water contained by cefuroxime sodium compound prepared by ratio 1 is absorption water.
2,60 DEG C thermal stability 10 days
By 1/2 water cefuroxime sodium compound of preparation of the embodiment of the present invention and the Cefuroxime Sodium for preparing of comparative example 1 without
0.25 hydrate of Cefuroxime Sodium prepared by water object and comparative example 2 was respectively placed in 60 DEG C of baking ovens 10 days, respectively at 0,10 day
Moisture is detected with Karl_Fischer method, as a result as follows:
| Embodiment | 0 day (%) | 10 days (%) |
| Embodiment 1 | 1.90 | 1.87 |
| Embodiment 2 | 2.07 | 2.02 |
| Embodiment 3 | 1.95 | 1.93 |
| Comparative example 1 | 0.33 | 0.10 |
| Comparative example 2 | 1.03 | 0.99 |
As a result, 60 DEG C of high temperature are placed 10 days, the 1/2 water cefuroxime sodium compound and comparative example 2 of Examples 1 to 3 preparation
The Cefuroxime Sodium anhydride that the 0.25 hydrate moisture of Cefuroxime Sodium of preparation is prepared without significant change, comparative example 1 substantially
Moisture is substantially reduced, and infers that water contained by the cefuroxime sodium compound of the embodiment of the present invention 1~3 and the preparation of comparative example 2 is crystallization
Water, comparative example 1 prepare cefuroxime sodium compound contained by water be absorption water.
3, vacuum freezedrying 10 hours
By 1/2 water cefuroxime sodium compound of preparation of the embodiment of the present invention and the Cefuroxime Sodium for preparing of comparative example 1 without
0.25 hydrate of Cefuroxime Sodium prepared by water object and comparative example 2 is respectively placed in -45 DEG C of freeze driers that vacuumize 10 small
When, moisture was detected with Karl_Fischer method respectively at 0,10 hour, as a result as follows:
| Embodiment | 0 hour (%) | 10 hours (%) |
| Embodiment 1 | 1.90 | 1.88 |
| Embodiment 2 | 2.07 | 2.05 |
| Embodiment 3 | 1.95 | 1.90 |
| Comparative example 1 | 0.33 | 0.14 |
| Comparative example 2 | 1.03 | 0.96 |
As a result, -45 DEG C of vacuum freezedryings of low temperature 10 hours, 1/2 water cefuroxime sodium of Examples 1 to 3 preparation is closed
The cephalo furan that 0.25 hydrate moisture of Cefuroxime Sodium prepared by object and comparative example 2 is prepared without significant change, comparative example 1 substantially
Pungent sodium anhydride moisture is substantially reduced, and infers cefuroxime sodium compound institute prepared by the embodiment of the present invention 1~3 and comparative example 2
Aqueous is the crystallization water, and water contained by cefuroxime sodium compound prepared by comparative example 1 is absorption water.
Claims (6)
1. a kind of 1/2 water cefuroxime sodium compound, which is characterized in that every mole of Cefuroxime Sodium contains 1/2 mole of water, molecular formula
For C16H15N4NaO8S·1/2H2O, molecular weight 455.38, structural formula are as follows:
2. a kind of pharmaceutical composition, it is characterised in that include 1/2 water cefuroxime sodium compound described in claim 1.
3. a kind of pharmaceutical composition, it is characterised in that include 1/2 water cefuroxime sodium compound described in claim 1 and pharmacy
The excipient of upper receiving.
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 cefuroxime sodium compound described in claim 1 in preparation antibacterials.
6. application of the pharmaceutical composition described in claim 2 or 3 in preparation antibacterials.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109096307A (en) * | 2017-06-20 | 2018-12-28 | 赵建宇 | One kind 33/4Water ceftriaxone sodium compound |
| CN109096306A (en) * | 2017-06-20 | 2018-12-28 | 樊艳芳 | A kind of 1/2 water Cefazolin sodium compound |
| CN109096308A (en) * | 2017-06-20 | 2018-12-28 | 海南灵康制药有限公司 | 1/4 water cefmenoxime hydrochloride compound of one kind and its pharmaceutical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072519A (en) * | 2014-07-04 | 2014-10-01 | 刘力 | Cefuroxime sodium compound entity and application thereof |
| CN106699775A (en) * | 2017-01-18 | 2017-05-24 | 海南美大制药有限公司 | 1/5 water cefamandole sodium compound |
| CN106831821A (en) * | 2017-01-04 | 2017-06-13 | 海南灵康制药有限公司 | 1/4 water Cefamandole nafate compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072519A (en) * | 2014-07-04 | 2014-10-01 | 刘力 | Cefuroxime sodium compound entity and application thereof |
| CN106831821A (en) * | 2017-01-04 | 2017-06-13 | 海南灵康制药有限公司 | 1/4 water Cefamandole nafate compounds |
| CN106699775A (en) * | 2017-01-18 | 2017-05-24 | 海南美大制药有限公司 | 1/5 water cefamandole sodium compound |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109096307A (en) * | 2017-06-20 | 2018-12-28 | 赵建宇 | One kind 33/4Water ceftriaxone sodium compound |
| CN109096306A (en) * | 2017-06-20 | 2018-12-28 | 樊艳芳 | A kind of 1/2 water Cefazolin sodium compound |
| CN109096308A (en) * | 2017-06-20 | 2018-12-28 | 海南灵康制药有限公司 | 1/4 water cefmenoxime hydrochloride compound of one kind and its pharmaceutical composition |
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Effective date of registration: 20190808 Address after: 710399 Standardized Workshop Phase I Construction Zone of Fengjing Industrial Park, Xi'an City, Shaanxi Province Applicant after: SHAANXI DUNSI PHARMACEUTICAL CO.,LTD. Applicant after: Yining Elxing Intellectual Property Service Co.,Ltd. Address before: 570216 No. 16 Yaogu Erheng Road, Yaogu Industrial Park, Haikou National High-tech Industrial Development Zone, Hainan Province Applicant before: Hainan Lingkang Pharmaceutical Co.,Ltd. |
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Application publication date: 20190104 |