CN103145735B - Cefmenoxime hydrochloride compound for injection and pharmaceutical composition thereof - Google Patents
Cefmenoxime hydrochloride compound for injection and pharmaceutical composition thereof Download PDFInfo
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- CN103145735B CN103145735B CN201310092270.5A CN201310092270A CN103145735B CN 103145735 B CN103145735 B CN 103145735B CN 201310092270 A CN201310092270 A CN 201310092270A CN 103145735 B CN103145735 B CN 103145735B
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Abstract
The invention relates to a cefmenoxime hydrochloride compound for injection. The cefmenoxime hydrochloride compound is a crystal; an X-ray powder diffraction pattern measured by Cu-Kalpha rays is shown in a figure 1; and the crystal main granularity of the hydrochloric cefmenoxime is 195-230 microns, and the distribution width is between 150 and 280 microns. The invention also relates to a pharmaceutical composition of the cefmenoxime hydrochloride compound, which comprises 10 parts by weight of hydrochloric cefmenoxime crystal, and 1.5-2.0 parts by weight of anhydrous sodium carbonate, preferably 10 parts by weight of the hydrochloric cefmenoxime crystal and 1.75 parts by weight of anhydrous sodium carbonate. The injection prepared by using the cefmenoxime hydrochloride compound is quickly dissolved, and is good in flowability, good in stability and safe and reliable in clinical application.
Description
Technical field
The present invention relates to a kind of Cefmenoxime Hemihydrochloride, specifically, relate to a kind of Cefmenoxime hydrochloride compound used for injection and pharmaceutical composition thereof.
Background technology
Cefmenoxime Hemihydrochloride (cefmenoxime hydrochloride) molecular formula is (C
16h
17n
9o
5s
3)
2hCl, its structural formula is:
But water-soluble very poor due to Cefmenoxime Hemihydrochloride, slightly soluble only in water, gives in practical application and has brought a lot of difficulties.At present, people have done a lot of research for the preparation of Cefmenoxime Hemihydrochloride.
A kind of synthetic method of Cefmenoxime Hemihydrochloride is disclosed in " preparation of Cefmenoxime Hemihydrochloride " (Heilungkiang scientific and technical information the 8th phase in 2008) literary composition, be specially: will in cefmenoxime acid, add sodium bicarbonate to dissolving, then add hydrochloric acid and ethanol, 5 ℃ of stirred crystallization 2 hours, filter, filtrate water and ethanol wash respectively, and vacuum-drying obtains crystalline powder." synthesizing of Cefmenoxime Hemihydrochloride " (fine chemistry industry, in January, 2009) a kind of synthetic method of Cefmenoxime Hemihydrochloride is disclosed in a literary composition, be specially: cefmenoxime is dissolved in anhydrous sodium carbonate, through decolouring, filtration, washing, with salt acid for adjusting pH value to 1.5, stir growing the grain 2 hours, filter, washing, the vacuum drying crystalline powder to Cefmenoxime Hemihydrochloride.The dissolution time of the cefmenoxime hydrochloride injection that Cefmenoxime Hemihydrochloride prepared by above-mentioned technique prepares is longer, and clinical application is very inconvenient.
A kind of preparation technology of instant Cefmenoxime Hemihydrochloride is disclosed in patent ZL200910114629.8 " preparation technology of instantly-dissolving cefmenoxime hydrochloride ", Cefmenoxime Hemihydrochloride crude product is added to water and be mixed with suspension, add sodium carbonate, obtain clear liquor, decolouring, filter, with salt acid for adjusting pH value, be 0.8～1.2 after washing, collect filtrate, then by weakly alkaline, to dissolve adjusting pH value be 1.3～1.75, stirred crystallization, obtains a kind of Cefmenoxime Hemihydrochloride of instant type.The preparation of the Cefmenoxime Hemihydrochloride that the method prepares can dissolve about 30 seconds, but its solubility property and stability etc. still have much room for improvement.
In patent ZL200910303437.1, disclose a kind of cefmenoxime hydrochloride composition powder injection, this powder pin utilizes acetone recrystallization by Cefmenoxime Hemihydrochloride, then is ground to 400～600 orders, is then prepared into powder pin.This patent adopts acetone, as solvent, Cefmenoxime Hemihydrochloride is carried out to recrystallization, there is certain potential safety hazard, in addition, the method that has adopted first recrystallization to grind again in this patent, processing step is comparatively complicated, reduced the yield of Cefmenoxime Hemihydrochloride, its solubility property and stability etc. also have much room for improvement.
The cefmenoxime hydrochloride compound that patent application 201210332727.0 discloses described in a kind of unformed cefmenoxime hydrochloride compound is measured by powdery diffractometry assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is without notable feature diffraction peak.Possess polymolecularity feature, be conducive to drug absorption, improve clinical adaptability.Cefmenoxime hydrochloride compound is the unformed powder of micro-yellow; The purity of the cefmenoxime hydrochloride compound of this application is higher, but the yield of this unformed powder preparation is lower, and the solubleness of this unformed powder also awaits further raising.
Patent application 201210137852.6 discloses a kind of cefmenoxime hydrochloride compound and micronized method thereof, comprise the following steps: dried Cefmenoxime Hemihydrochloride crystalline powder raw material, after accelerating with supersonic airstream in micronizer mill, mutually collide and pulverize, supersonic airstream is that the compressed-air actuated pressure by 0.4～0.8MPa promotes, compressed-air actuated temperature≤40 ℃; Pulverized material enters graded region with air-flow, meets the material of granularity requirements by setting the grading wheel of rotating speed, and the material that does not meet granularity requirements returns to disintegrating area to be continued to pulverize; But its solubility property and stability etc. also have much room for improvement.
For this reason, the present invention proposes a kind of new compound that is suitable for preparing the Cefmenoxime Hemihydrochloride of preparation.
Summary of the invention
The first goal of the invention of the present invention is to provide a kind of compound of Cefmenoxime Hemihydrochloride.
The second goal of the invention of the present invention is to provide the pharmaceutical composition of the compound of this Cefmenoxime Hemihydrochloride.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of Cefmenoxime hydrochloride compound used for injection, described cefmenoxime hydrochloride compound is crystal, uses Cu-K α
As shown in Figure 1, its structural formula is suc as formula shown in I for the X-ray powder diffraction pattern that radionetric survey obtains:
" mouthful., on " the white CH of Mk makes H3 mono-H be from Lu 7O "." H9 is@
(I)o
The first optimal technical scheme of the present invention is: the main granularity of crystal of described Cefmenoxime Hemihydrochloride is 180～240 μ m, and Tile Width is 120～300 μ m; Preferred main granularity is 195～230 μ m, and Tile Width is 150～280 μ m.
The second optimal technical scheme of the present invention is that the preparation method of described cefmenoxime hydrochloride compound crystal comprises the following steps:
(1) get Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, under 0～5 ℃ of condition, adding mass percent is 15% sodium hydroxide solution, and stirring and dissolving, obtains clear liquor, then adds the mixing solutions of Virahol and ethyl acetate;
(2) clear liquor being added to mass percent is 0.01～0.02% activated carbon decolorizing, stirs the filtrate of filtering after 0.5～1.5 hour;
(3) solution step (2) being obtained is warming up to 20～25 ℃, the hydrochloric acid that adds while stirring 0～5 ℃, regulating pH value is 1.8, after hydrochloric acid adds, stop stirring, continue solution to be cooled to 0～5 ℃, standing growing the grain 1～3 hour, obtain filtering after crystal, washing, vacuum-drying 2～6 hours, obtains Cefmenoxime Hemihydrochloride crystal.
The 3rd optimal technical scheme of the present invention is: to add the volume ratio of Virahol and ethyl acetate in Virahol and ethyl acetate mixture be 1:0.5～1, preferably 1:0.5～0.85, more preferably 1:0.5～0.75.
The 4th optimal technical scheme of the present invention is: add Virahol and ethyl acetate mixed solvent and Cefmenoxime Hemihydrochloride solid solution volume ratio be 0.2～0.5:1, preferred 0.45～0.5:1.
The 5th optimal technical scheme of the present invention is: the stirring velocity while adding hydrochloric acid be 90～120 revs/min.
The invention still further relates to a kind of medicinal composition for injections of cefmenoxime hydrochloride compound, described pharmaceutical composition comprises: Cefmenoxime Hemihydrochloride crystal 10 weight parts, anhydrous sodium carbonate 1.5～2.0 weight parts; Preferably comprise Cefmenoxime Hemihydrochloride crystal 10 weight parts, anhydrous sodium carbonate 1.75 weight parts.
Described in described pharmaceutical composition, in composition, also contain and can add at least one in stablizer or antioxidant.
Below further explanation and description of the technical solution of the present invention are carried out:
The present invention relates to a kind of Cefmenoxime hydrochloride compound used for injection, described cefmenoxime hydrochloride compound is crystal, the X-ray powder diffraction pattern that use Cu-K alpha-ray measures as shown in Figure 1, measuring its fusing point is 171～175 ℃, proterties is yellowish crystalline powder, through sem observation and particle size analyzer, measure, the main granularity of crystal of this Cefmenoxime Hemihydrochloride is 180～240 μ m, and Tile Width is 120～300 μ m; Preferred main granularity is 195～230 μ m, and Tile Width is 150～280 μ m.Crystal size of the present invention is moderate, thereby the productive rate of its compound crystal in preparation process is improved, and can reach 97.5%; And purity to 99.98%, its structure is confirmed through proton nmr spectra.
The preparation method of cefmenoxime hydrochloride compound of the present invention is simple, efficient, and method is simple, and productive rate is high, purity is high; Most suitable large-scale industrial production.
The preparation method of cefmenoxime hydrochloride compound crystal of the present invention comprises the following steps:
The preparation method of cefmenoxime hydrochloride compound crystal comprises the following steps:
(1) get Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, under 0～5 ℃ of condition, adding mass percent is 15% sodium hydroxide solution, and stirring and dissolving, obtains clear liquor, then adds the mixing solutions of Virahol and ethyl acetate; The volume ratio of Virahol and ethyl acetate is 1:0.5～1, preferably 1:0.5～0.85, more preferably 1:0.5～0.75; The volume ratio of Virahol and ethyl acetate mixed solvent and Cefmenoxime Hemihydrochloride solid solution is 0.2～0.5:1, preferably 0.45～0.5:1;
(2) clear liquor being added to mass percent is 0.01～0.02% activated carbon decolorizing, stirs the filtrate of filtering after 0.5～1.5 hour;
(3) solution step (2) being obtained is warming up to 20～25 ℃, adds while stirring the hydrochloric acid of 0～5 ℃, and regulating pH value is 1.8, and stirring velocity is 90～120 revs/min; After hydrochloric acid adds, stop stirring, continue solution to be cooled to 0～5 ℃, standing growing the grain 1～3 hour, obtains filtering after crystal, washing, and vacuum-drying 2～6 hours, obtains Cefmenoxime Hemihydrochloride crystal.
The present invention is by the condition of crystallization control, prepared a kind of new Cefmenoxime Hemihydrochloride crystal, the present invention is by the control to temperature, pH value, flow acceleration, stirring velocity, the crystallisation process of stricter control solution, obtained a kind of brand-new Cefmenoxime Hemihydrochloride crystalline compounds, through stability test, confirm, the stability of this crystalline compounds is fine, is highly suitable for pharmaceutical compositions, safe and reliable.
Consisting of of the pharmaceutical composition of cefmenoxime hydrochloride compound of the present invention: Cefmenoxime Hemihydrochloride crystal 10 weight parts, anhydrous sodium carbonate 1.5～2.0 weight parts; Preferably comprise Cefmenoxime Hemihydrochloride crystal 10 weight parts, anhydrous sodium carbonate 1.75 weight parts.Those skilled in the art can also according to specific needs, add stablizer, antioxidant etc. in composition.
Preparation method of the present invention can adopt other conventional preparation method's preparations of this area, and can its condition be optimized by the experiment of limited number of time.According to the general knowledge of this area, can in the pharmaceutical composition of Cefmenoxime Hemihydrochloride of the present invention, further add stablizer, oxidation inhibitor or sanitas etc., thereby further improve the character of composition of the present invention.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern that the Cu-K alpha-ray of the Cefmenoxime Hemihydrochloride crystal of embodiment 1 preparation measures.
The specific embodiment of the present invention only limits to content of the present invention to make further explanation, not to Composition of contents restriction of the present invention.In the present invention, all adopt commercial reagent.
Embodiment
The preparation of embodiment 1 cefmenoxime hydrochloride compound
(1) get Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, under 1 ℃ of condition, adding mass percent is 15% sodium hydroxide solution, and stirring and dissolving, obtains clear liquor, then adds the mixing solutions of Virahol and ethyl acetate; The volume ratio of Virahol and ethyl acetate is 1:0.75; Add Virahol and ethyl acetate mixed solvent and Cefmenoxime Hemihydrochloride solid solution volume ratio be 0.45:1;
(2) clear liquor being added to mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 1 hour;
(3) solution step (2) being obtained is warming up to 20 ℃, adds while stirring the hydrochloric acid of 1 ℃, and regulating pH value is 1.8, and stirring velocity is 90 revs/min; After hydrochloric acid adds, stop stirring, continue solution to be cooled to 1 ℃, standing growing the grain 1 hour, obtains filtering after crystal, washing, and vacuum-drying 4 hours, obtains Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray preparing measures as shown in Figure 1, measuring its fusing point is 172 ℃, proterties is yellowish crystalline powder, through sem observation and particle size analyzer, measure, the main granularity of crystal of this Cefmenoxime Hemihydrochloride is 195～230 μ m, and Tile Width is 150～280 μ m; Productive rate is 97.5%, and purity is 99.99%.
The preparation of embodiment 2 cefmenoxime hydrochloride compounds
(1) get Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, under 0 ℃ of condition, adding mass percent is 15% sodium hydroxide solution, and stirring and dissolving, obtains clear liquor, then adds the mixing solutions of Virahol and ethyl acetate; The volume ratio of Virahol and ethyl acetate is 1:0.5; Add Virahol and ethyl acetate mixed solvent and Cefmenoxime Hemihydrochloride solid solution volume ratio be 0.45:1;
(2) clear liquor being added to mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 1.5 hours;
(3) solution step (2) being obtained is warming up to 25 ℃, adds while stirring the hydrochloric acid of 1 ℃, and regulating pH value is 1.8, and stirring velocity is 120 revs/min; After hydrochloric acid adds, stop stirring, continue solution to be cooled to 0 ℃, standing growing the grain 2 hours, obtains filtering after crystal, washing, and vacuum-drying 4 hours, obtains Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray preparing measures as shown in Figure 1, measuring its fusing point is 171～175 ℃, proterties is yellowish crystalline powder, through sem observation and particle size analyzer, measure, the main granularity of crystal of this Cefmenoxime Hemihydrochloride is 195～230 μ m, and Tile Width is 150～280 μ m; Productive rate is 97.5%, and purity is 99.98%.
The preparation of embodiment 3 cefmenoxime hydrochloride compounds
(1) get Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, under 5 ℃ of conditions, adding mass percent is 15% sodium hydroxide solution, and stirring and dissolving, obtains clear liquor, then adds the mixing solutions of Virahol and ethyl acetate; The volume ratio of Virahol and ethyl acetate is 1:0.85; Add Virahol and ethyl acetate mixed solvent and Cefmenoxime Hemihydrochloride solid solution volume ratio be 0.2:1;
(2) clear liquor being added to mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 0.5 hour;
(3) solution step (2) being obtained is warming up to 25 ℃, adds while stirring the hydrochloric acid of 5 ℃, and regulating pH value is 1.8, and stirring velocity is 120 revs/min; After hydrochloric acid adds, stop stirring, continue solution to be cooled to 5 ℃, standing growing the grain 3 hours, obtains filtering after crystal, washing, and vacuum-drying 6 hours, obtains Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray preparing measures as shown in Figure 1, measuring its fusing point is 171～175 ℃, proterties is yellowish crystalline powder, through sem observation and particle size analyzer, measure, the main granularity of crystal of this Cefmenoxime Hemihydrochloride is 195～230 μ m, and Tile Width is 150～280 μ m; Productive rate is 97.3%, and purity is 99.98%.
The preparation of embodiment 4 cefmenoxime hydrochloride compounds
(1) get Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, under 2 ℃ of conditions, adding mass percent is 15% sodium hydroxide solution, and stirring and dissolving, obtains clear liquor, then adds the mixing solutions of Virahol and ethyl acetate; The volume ratio of Virahol and ethyl acetate is 1:0.5; Add Virahol and ethyl acetate mixed solvent and Cefmenoxime Hemihydrochloride solid solution volume ratio be 0.2:1;
(2) clear liquor being added to mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 1 hour;
(3) solution step (2) being obtained is warming up to 22 ℃, adds while stirring the hydrochloric acid of 2 ℃, and regulating pH value is 1.8, and stirring velocity is 120 revs/min; After hydrochloric acid adds, stop stirring, continue solution to be cooled to 2 ℃, standing growing the grain 2 hours, obtains filtering after crystal, washing, and vacuum-drying 4 hours, obtains Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray preparing measures as shown in Figure 1, measuring its fusing point is 171～175 ℃, proterties is yellowish crystalline powder, through sem observation and particle size analyzer, measure, the main granularity of crystal of this Cefmenoxime Hemihydrochloride is 195～230 μ m, and Tile Width is 150～280 μ m; Productive rate is 97.2%, and purity is 99.99%.
The preparation of embodiment 5 cefmenoxime hydrochloride compounds
(1) get Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, under 4 ℃ of conditions, adding mass percent is 15% sodium hydroxide solution, and stirring and dissolving, obtains clear liquor, then adds the mixing solutions of Virahol and ethyl acetate; The volume ratio of Virahol and ethyl acetate is 1:1; Add Virahol and ethyl acetate mixed solvent and Cefmenoxime Hemihydrochloride solid solution volume ratio be 0.5:1;
(2) clear liquor being added to mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 1.5 hours;
(3) solution step (2) being obtained is warming up to 22 ℃, adds while stirring the hydrochloric acid of 4 ℃, and regulating pH value is 1.8, and stirring velocity is 120 revs/min; After hydrochloric acid adds, stop stirring, continue solution to be cooled to 2 ℃, standing growing the grain 2 hours, obtains filtering after crystal, washing, and vacuum-drying 4 hours, obtains Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray preparing measures as shown in Figure 1, measuring its fusing point is 171～175 ℃, proterties is yellowish crystalline powder, through sem observation and particle size analyzer, measure, the main granularity of crystal of this Cefmenoxime Hemihydrochloride is 195～230 μ m, and Tile Width is 150～280 μ m; Productive rate is 92.1%, and purity is 99.98%.
The preparation of the injection of embodiment 6 cefmenoxime hydrochloride compounds
Consisting of of this injection: Cefmenoxime Hemihydrochloride crystal 10 weight parts of the embodiment of the present invention 1～5 preparation, anhydrous sodium carbonate 1.75 weight parts.
Preparation method is:
(1) take in proportion Cefmenoxime Hemihydrochloride and anhydrous sodium carbonate, fully mix;
(2) divide in the cillin bottle being filled to after sterilizing and jump a queue.
Experimental example 1 stability test
Three batches 101,102,103 of Cefmenoxime Hemihydrochloride crystal that adopt embodiment 1 preparation, are prepared into preparation according to the method for embodiment 6, carry out stability test:
1. high temperature test
Get preparation simulation listing packing, at 60 ℃ of temperature, place 10 days, in the 5th day and sampling in the 10th day, by stability high spot reviews project, detect.Particulate matter adopts microscopic counting to detect.
2. high humidity test
Get preparation simulation listing packing, put in constant humidity encloses container, under the condition of 25 ℃ of relative humidity 90% ± 5%, place 10 days, in the 5th day and sampling in the 10th day, by stability high spot reviews project, detect.Particulate matter adopts microscopic counting to detect.
3. strong illumination test
Get preparation simulation listing packing, put in sealing clean container, be placed under the condition that illumination is 4500lx ± 500lx and place 10 days, in the 5th day and sampling in the 10th day, by stability high spot reviews project, detect.Particulate matter adopts microscopic counting to detect.
Influence factor test-results sees the following form 1.
Table 1: Cefmenoxime Hemihydrochloride crystal influence factor test-results
Result shows: the injection of preparing of the present invention, under the condition of simulation listing packing, under illumination, hot conditions, to place 10 days, and indices is without considerable change.
The Cefmenoxime Hemihydrochloride crystal that other embodiment of the present invention is prepared has also carried out identical test, has obtained similar result.
Experimental example 2: accelerate experiment
Three batches 201,202,203 of the Cefmenoxime Hemihydrochloride crystalline compounds that the embodiment of the present invention 2 is prepared, method according to embodiment 6 is prepared into preparation, simulation listing packing, carry out following stability test: in 40 ℃ ± 2 ℃, under the condition of 75% ± 5%RH, place 6 months, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.Particulate matter adopts microscopic counting to detect.Experimental result is as shown in table 2.
Table 2: accelerated test result:
From accelerated test result, Cefmenoxime Hemihydrochloride crystal of the present invention is prepared preparation, through accelerated test, within 6 months, investigates, and related substance and content slightly change, and considerable change does not occur all the other indices.Confirm that Cefmenoxime Hemihydrochloride crystalchecked performance of the present invention is good.
The Cefmenoxime Hemihydrochloride crystalline compounds that other embodiment of the present invention is prepared has also carried out identical test, and the result of its acquisition is similar.
Experimental example 3: test of long duration
According to experimental example 6 methods, prepare preparation for 3 batches 301,302,303 of the Cefmenoxime Hemihydrochloride crystalline compounds that the embodiment of the present invention 3 is prepared, simulation listing packing, carry out following stability test: put in sealing clean container, at 30 ℃ ± 2 ℃, under 60% ± 5%RH part, place 24 months, at duration of test respectively at the 3rd, 6,9,12,18 samplings at the end of month once, each stability high spot reviews project is tested, particulate matter adopts microscopic counting to detect.Test-results is as shown in table 3:
Table 3: long-term test results
From long-term test results, Cefmenoxime Hemihydrochloride crystal formulations of the present invention is investigated through test of long duration for 18 months, and considerable change does not all occur indices, confirms that the stability of Cefmenoxime Hemihydrochloride crystal formulations of the present invention is good.
The Cefmenoxime Hemihydrochloride crystal that other embodiment of the present invention is prepared has also carried out test of long duration, has obtained identical test-results.
Experimental example 4: stability comparison test
The Cefmenoxime Hemihydrochloride crystal that adopts embodiment 1 preparation, is prepared into preparation according to the method for embodiment 6;
The preparation method of Comparative formulation 1,2,3,4 is:
Comparative example 1 preparation method: the preparation that adopts common commercially available Cefmenoxime Hemihydrochloride raw material (Liaoning Hasco Pharmaceutical Co., Ltd., the accurate word H20123248 of traditional Chinese medicines) to prepare according to the method for embodiment 6;
Comparative example 2 preparation methods: prepare Cefmenoxime Hemihydrochloride according to ZL200910114629.8 embodiment 4, the preparation of preparing according to the method for embodiment 6;
The preparation method of comparative example 3: prepare Cefmenoxime Hemihydrochloride crystal according to ZL201110320076.9 embodiment 1, the preparation of preparing according to the method for embodiment 6;
The preparation method of comparative example 4, according to the unformed Cefmenoxime Hemihydrochloride of patent application 201210332727.0 embodiment 1 preparation, the preparation of preparing according to the method for embodiment 6;
Above-mentioned preparation is carried out under identical condition to stability comparison test:
1. high temperature test
Get preparation prepared by Comparative formulation 1～4 and the compounds of this invention, simulation listing packing is placed 10 days at 60 ℃ of temperature, in the 5th day and sampling in the 10th day, by stability high spot reviews project, detects.Particulate matter adopts microscopic counting to detect.
2. high humidity test
Get preparation prepared by Comparative formulation 1～4 and the compounds of this invention, simulation listing packing, puts in constant humidity encloses container, places 10 days under the condition of 25 ℃ of relative humidity 90% ± 5%, in the 5th day and sampling in the 10th day, by stability high spot reviews project, detects.Particulate matter adopts microscopic counting to detect.
3. strong illumination test
Get preparation prepared by Comparative formulation 1～4 and the compounds of this invention, simulation listing packing, puts in sealing clean container, is placed under the condition that illumination is 4500lx ± 500lx and places 10 days, in the 5th day and sampling in the 10th day, by stability high spot reviews project, detects.Particulate matter adopts microscopic counting to detect.
Influence factor test-results sees the following form 8.
Table 4: Cefmenoxime Hemihydrochloride crystal influence factor test-results
Result shows: this product, under the condition of simulation listing packing, is placed 10 days under high temperature, high humidity, illumination condition, and except related substance slightly increases, outside content slightly reduces, other indices are without considerable change.And the appearance having in drugs compared the underproof situation of insoluble particle, and its related substances all increases to some extent, medicament contg all decreases.
Experimental example 5: Accelerated stability test
According to the method for embodiment 4, prepare comparative example preparation and preparation of the present invention, at the same terms, press and carry out Accelerated stability test: difference sample thief, under 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% condition, place 6 months, at duration of test respectively at the 1st, 3,6 samplings at the end of month once, each stability high spot reviews project is tested.Particulate matter adopts microscopic counting to detect.Test-results is in Table 5.
Table 5:
Result shows: this product, under the condition of simulation listing packing, is placed 3 months under acceleration environment, and except related substance slightly increases, outside content slightly reduces, other indices are without considerable change.And the content of related substance in drugs compared obviously raises, medicament contg obviously reduces, and underproof situation appears in particulate matter.The stability that proves preparation prepared by crystal of the present invention is better than prior art.
Experimental example 6: the impact of the ratio of solvent on Cefmenoxime Hemihydrochloride crystalline compounds in investigation reaction
Adopt the preparation condition of embodiment 1, comparison of design example 1a～8a, only changes listed condition in table, and all the other steps and condition are with embodiment 1; Specifically as shown in table 6,7.
Table 6:
Table 7:
From above-mentioned experiment, the condition of employing of the present invention makes purity and two index optimizations of yield.
Experimental example 7: the screening experiment of activated carbon concentration
Other processing parameter, all with embodiment 1, selects respectively the injection gac of different concns to adsorb, and take Cefmenoxime Hemihydrochloride crystal yield, purity as investigating index, the consumption of screening gac.The inspection of clarity adopts two clarity test procedures of Chinese Pharmacopoeia version in 2000, the results are shown in Table 8:
Table 8: activated carbon dosage shaker test
| Concentration of activated carbon (%) | Productive rate (%) | Purity (%) |
| 0.1 | 90.2 | 99.72 |
| 0.05 | 92.6 | 99.80 |
| 0.03 | 94.2 | 99.92 |
| 0.02 | 95.5 | 99.95 |
| 0.01 | 97.5 | 99.98 |
In table, draw, it is best that the purity that 0.01% gac can Cefmenoxime Hemihydrochloride crystal and yield reach, less to main ingredient absorption, and pollute minimumly, so select concentration, is 0.01%(g/ml) gac adsorb.
Experimental example 8: solvability contrast experiment
The cefmenoxime hydrochloride compound that adopts embodiment 1～5 preparation, is prepared into preparation according to the method for embodiment 6, according to the method for embodiment 4, prepares comparative example preparation, under identical condition, tests.
Get injection 1g prepared by each preparation, add the water for injection of 10ml, according to the jolting of obtain solution general method, under identical experiment condition, its dissolving situation is measured, experimental result is in Table 9;
Table 9:
| ? | 25 ℃ of dissolution times (s) | 1 ℃ of dissolution time (s) |
| The preparation of embodiment 1 compound | Within 3 seconds, dissolve solution clarification completely | Within 6 seconds, dissolve solution clarification completely |
| The preparation of embodiment 2 compounds | Within 3 seconds, dissolve solution clarification completely | Within 6 seconds, dissolve solution clarification completely |
| The preparation of embodiment 3 compounds | Within 3 seconds, dissolve solution clarification completely | Within 6 seconds, dissolve solution clarification completely |
| The preparation of embodiment 4 compounds | Within 3 seconds, dissolve solution clarification completely | Within 6 seconds, dissolve solution clarification completely |
| The preparation of embodiment 5 compounds | Within 4 seconds, dissolve solution clarification completely | Within 7 seconds, dissolve solution clarification completely |
| Comparative example 1 | Within 3 minutes, do not dissolve completely yet | Within 5 minutes, do not dissolve completely yet |
| Comparative example 2 | Within 8 seconds, dissolve solution clarification completely | Within 45 seconds, dissolve solution clarification completely |
| Comparative example 3 | Within 5 seconds, dissolve solution clarification completely | Within 18 seconds, dissolve solution clarification completely |
| Comparative example 4 | Within 10 seconds, dissolve solution clarification completely | Within 31 seconds, dissolve solution clarification completely |
Known according to dissolution experiment, the preparation of cefmenoxime hydrochloride compound prepared by the present invention, under normal temperature condition, dissolution rate is rapid, far away higher than adopting the prepared preparation of disclosed Cefmenoxime Hemihydrochloride in prior art.Under cold condition, crystal prepared by the present invention still can dissolve rapidly, and preparation in comparative example dissolution rate at low temperatures obviously slows down.
Experimental example 9: mobility experiment
This experimental example detects the mobility of the cefmenoxime hydrochloride compound of the embodiment of the present invention 1, adopt fixed funnel method, funnel is placed in to the suitable height on graph paper, make cefmenoxime hydrochloride compound from flare opening Free-flow, until the cone top forming contacts with flare opening, measure hypotenuse and the horizontal angle (slope of repose θ) of cefmenoxime hydrochloride compound accumulation horizon.
Table 10: cefmenoxime hydrochloride compound mobility experimental result
| Batch | 1 | 2 | 3 | 4 | 5 | Mean value |
| θ（°） | 35 | 35 | 36 | 35 | 36 | 35.4 |
From the interpretation of table 10, the mobility of the cefmenoxime hydrochloride compound that the embodiment of the present invention 1 prepares is fine, and the cefmenoxime hydrochloride compound of the embodiment of the present invention 2～4 is also detected, and has obtained similar experimental result.
Experimental example 10
This experimental example detects the mobility of the cefmenoxime hydrochloride composition preparation of the embodiment of the present invention 6, adopt fixed funnel method, funnel is placed in to the suitable height on graph paper, make cefmenoxime hydrochloride composition preparation from flare opening Free-flow, until the cone top forming contacts with flare opening, measure hypotenuse and the horizontal angle (slope of repose θ) of cefmenoxime hydrochloride composition preparation accumulation horizon.
Table 11: the mobility experimental result of cefmenoxime hydrochloride composition preparation
| Batch | 1 | 2 | 3 | 4 | 5 | Mean value |
| θ（°） | 35 | 34 | 34 | 34 | 35 | 34.4 |
From the interpretation of table 11, the mobility of the cefmenoxime hydrochloride composition preparation that the embodiment of the present invention 6 prepares is fine, clinical easy to use and reliable.
Claims (13)
1. a Cefmenoxime hydrochloride compound used for injection, is characterized in that, described cefmenoxime hydrochloride compound is crystal, and as shown in Figure 1, its structural formula is suc as formula shown in I for the X-ray powder diffraction pattern that use Cu-K alpha-ray measures:
2. Cefmenoxime hydrochloride compound used for injection according to claim 1, is characterized in that, the main granularity of crystal of described cefmenoxime hydrochloride compound is 180～240 μ m, and Tile Width is 120～300 μ m.
3. Cefmenoxime hydrochloride compound used for injection according to claim 2, is characterized in that, the main granularity of crystal of described cefmenoxime hydrochloride compound is 195～230 μ m, and Tile Width is 150～280 μ m.
4. Cefmenoxime hydrochloride compound used for injection according to claim 1, is characterized in that, the preparation method of described cefmenoxime hydrochloride compound comprises the following steps:
(1) get Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, under 0～5 ℃ of condition, adding mass percent is 15% sodium hydroxide solution, and stirring and dissolving, obtains clear liquor, then adds the mixing solutions of Virahol and ethyl acetate;
(2) clear liquor being added to mass percent is 0.01～0.02% activated carbon decolorizing, stirs the filtrate of filtering after 0.5～1.5 hour;
(3) solution step (2) being obtained is warming up to 20～25 ℃, the hydrochloric acid that adds while stirring 0～5 ℃, regulating pH value is 1.8, after hydrochloric acid adds, stop stirring, continue solution to be cooled to 0～5 ℃, standing growing the grain 1～3 hour, obtain filtering after crystal, washing, vacuum-drying 2～6 hours, obtains Cefmenoxime Hemihydrochloride crystal.
5. Cefmenoxime hydrochloride compound used for injection according to claim 4, is characterized in that, to add the volume ratio of Virahol and ethyl acetate in Virahol and ethyl acetate mixture be 1:0.5～1.
6. Cefmenoxime hydrochloride compound used for injection according to claim 5, is characterized in that, to add the volume ratio of Virahol and ethyl acetate in Virahol and ethyl acetate mixture be 1:0.5～0.85.
7. Cefmenoxime hydrochloride compound used for injection according to claim 6, is characterized in that, to add the volume ratio of Virahol and ethyl acetate in Virahol and ethyl acetate mixture be 1:0.5～0.75.
8. Cefmenoxime hydrochloride compound used for injection according to claim 4, is characterized in that, add Virahol and ethyl acetate mixed solvent and Cefmenoxime Hemihydrochloride solid solution volume ratio be 0.2～0.5:1.
9. Cefmenoxime hydrochloride compound used for injection according to claim 8, is characterized in that, add Virahol and ethyl acetate mixed solvent and Cefmenoxime Hemihydrochloride solid solution volume ratio be 0.45～0.5:1.
10. Cefmenoxime hydrochloride compound used for injection according to claim 4, is characterized in that, the stirring velocity while adding hydrochloric acid be 90～120 revs/min.
11. 1 kinds of medicinal composition for injections that comprise cefmenoxime hydrochloride compound claimed in claim 1, is characterized in that, described pharmaceutical composition comprises: Cefmenoxime Hemihydrochloride crystal 10 weight parts, anhydrous sodium carbonate 1.5～2.0 weight parts.
The medicinal composition for injections of 12. cefmenoxime hydrochloride compounds according to claim 11, is characterized in that, described pharmaceutical composition comprises: Cefmenoxime Hemihydrochloride crystal 10 weight parts, anhydrous sodium carbonate 1.75 weight parts.
The pharmaceutical composition of 13. cefmenoxime hydrochloride compounds according to claim 11, is characterized in that, also contains at least one in stablizer, antioxidant described in described pharmaceutical composition in composition.
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| CN103432078B (en) * | 2013-08-28 | 2015-06-17 | 芦红代 | Medicinal composition of cefmenoxime hydrochloride |
| CN105566352A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
| CN106117246B (en) * | 2016-06-13 | 2018-02-27 | 芦红代 | A kind of preparation method of Cefmenoxime Hcl raw material |
| CN109134504A (en) * | 2017-06-16 | 2019-01-04 | 陈立平 | 1/2 water cefmenoxime hydrochloride compound of one kind and its drug combination preparation |
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| CN101735249A (en) * | 2009-12-12 | 2010-06-16 | 桂林澳林制药有限责任公司 | Process for preparing instantly-dissolving cefmenoxime hydrochloride |
| CN101798314A (en) * | 2010-03-24 | 2010-08-11 | 海南数尔药物研究有限公司 | High-purity cefmenoxime hydrochloride compound |
| CN102329329A (en) * | 2011-07-15 | 2012-01-25 | 海南灵康制药有限公司 | Novel method for preparing cefmenoxime hydrochloride compound |
| CN102408439A (en) * | 2011-10-20 | 2012-04-11 | 桂林澳林制药有限责任公司 | Cefmenoxime hydrochloride compound used for injection |
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| CN101735249A (en) * | 2009-12-12 | 2010-06-16 | 桂林澳林制药有限责任公司 | Process for preparing instantly-dissolving cefmenoxime hydrochloride |
| CN101798314A (en) * | 2010-03-24 | 2010-08-11 | 海南数尔药物研究有限公司 | High-purity cefmenoxime hydrochloride compound |
| CN102329329A (en) * | 2011-07-15 | 2012-01-25 | 海南灵康制药有限公司 | Novel method for preparing cefmenoxime hydrochloride compound |
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