CN103145735A - 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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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 is given in practical application and has been brought a lot of difficulties.At present, people have done a lot of researchs 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 add sodium bicarbonate to dissolving in cefmenoxime acid, 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, stirred growing the grain 2 hours, filter, washing, vacuum drying crystalline powder to Cefmenoxime Hemihydrochloride.The dissolution time of the cefmenoxime hydrochloride injection that the Cefmenoxime Hemihydrochloride of above-mentioned technique preparation 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 ", the Cefmenoxime Hemihydrochloride crude product is added water be mixed with suspension, add sodium carbonate, obtain clear liquor, be 0.8～1.2 with the salt acid for adjusting pH value after decolouring, filtration, washing, collect filtrate, then be 1.3～1.75 with weakly alkaline dissolving adjusting pH value, 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 remain to be improved.
Disclose a kind of cefmenoxime hydrochloride composition powder injection in patent ZL200910303437.1, this powder pin utilizes acetone recrystallization with Cefmenoxime Hemihydrochloride, then is ground to 400～600 orders, then is prepared into the powder pin.This patent adopts acetone as solvent, Cefmenoxime Hemihydrochloride to be carried out recrystallization, has 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 has much room for improvement.
Patent application 201210332727.0 discloses the described cefmenoxime hydrochloride compound of a kind of unformed cefmenoxime hydrochloride compound and has measured with the powdery diffractometry assay method, and the X-ray powder diffraction collection of illustrative plates that represents with 2 θ ± 0.2 ° diffraction angle is without the notable feature diffraction peak.Possess the polymolecularity characteristics, be conducive to drug absorption, improve clinical adaptability.Cefmenoxime hydrochloride compound is the unformed powder of little 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, mutually collide and pulverize after accelerating with supersonic airstream in micronizer mill, 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 purpose 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
The X-ray powder diffraction pattern that radionetric survey obtains as shown in Figure 1, its structural formula is suc as formula shown in I:
" mouthful., on " the white CH of Mk makes H3 one H be from Lu 7O "." H9 is@
(I)o
The first optimal technical scheme of the present invention is: the crystal master granularity 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 preparation method that the second optimal technical scheme of the present invention is described cefmenoxime hydrochloride compound crystal comprises the following steps:
(1) get the Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, adding mass percent under 0～5 ℃ of condition 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 mass percent is 0.01～0.02% activated carbon decolorizing, stirs the filtrate of filtering after 0.5～1.5 hour;
(3) solution that step (2) is obtained is warming up to 20～25 ℃, the hydrochloric acid that adds while stirring 0～5 ℃, regulating the pH value is 1.8, stop after hydrochloric acid adds 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 the Cefmenoxime Hemihydrochloride crystal.
The 3rd optimal technical scheme of the present invention is: add that in Virahol and ethyl acetate mixture, the volume ratio of Virahol and ethyl acetate is 1:0.5～1, preferred 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 when adding hydrochloric acid be 90～120 rev/mins.
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.
Also contain in the described composition of described pharmaceutical composition and can add at least a 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, measure through sem observation and particle size analyzer, the crystal master granularity 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 proved conclusively 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 the Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, adding mass percent under 0～5 ℃ of condition 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, preferred 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, preferred 0.45～0.5:1;
(2) clear liquor being added mass percent is 0.01～0.02% activated carbon decolorizing, stirs the filtrate of filtering after 0.5～1.5 hour;
(3) solution that step (2) is obtained is warming up to 20～25 ℃, adds while stirring the hydrochloric acid of 0～5 ℃, and regulating the pH value is 1.8, and stirring velocity is 90～120 rev/mins; Stop after hydrochloric acid adds stirring, continue solution is cooled to 0～5 ℃, standing growing the grain 1～3 hour obtains filtering after crystal, washing, and vacuum-drying 2～6 hours obtains the 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, confirm that through stability test this crystalline compounds stable 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 this area other preparation method's preparations commonly used, and can its condition be optimized by the experiment of limited number of time.According to the general knowledge of this area, can further add stablizer, oxidation inhibitor or sanitas etc. in the pharmaceutical composition of Cefmenoxime Hemihydrochloride of the present invention, thereby further improve the character of composition of the present invention.
Description of drawings
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 is made further explanation, not to Composition of contents restriction of the present invention.All adopt the commercial reagent in the present invention.
Embodiment
The preparation of embodiment 1 cefmenoxime hydrochloride compound
(1) get the Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, adding mass percent under 1 ℃ of condition 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 mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 1 hour;
(3) solution that step (2) is obtained is warming up to 20 ℃, adds while stirring the hydrochloric acid of 1 ℃, and regulating the pH value is 1.8, and stirring velocity is 90 rev/mins; Stop after hydrochloric acid adds stirring, continue solution is cooled to 1 ℃, standing growing the grain 1 hour obtains filtering after crystal, washing, and vacuum-drying 4 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray for preparing measures as shown in Figure 1, measuring its fusing point is 172 ℃, proterties is yellowish crystalline powder, measure through sem observation and particle size analyzer, the crystal master granularity 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 the Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, adding mass percent under 0 ℃ of condition 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 mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 1.5 hours;
(3) solution that step (2) is obtained is warming up to 25 ℃, adds while stirring the hydrochloric acid of 1 ℃, and regulating the pH value is 1.8, and stirring velocity is 120 rev/mins; Stop after hydrochloric acid adds stirring, continue solution is cooled to 0 ℃, standing growing the grain 2 hours obtains filtering after crystal, washing, and vacuum-drying 4 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray for preparing measures as shown in Figure 1, measuring its fusing point is 171～175 ℃, proterties is yellowish crystalline powder, measure through sem observation and particle size analyzer, the crystal master granularity 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 the Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, adding mass percent under 5 ℃ of conditions 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 mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 0.5 hour;
(3) solution that step (2) is obtained is warming up to 25 ℃, adds while stirring the hydrochloric acid of 5 ℃, and regulating the pH value is 1.8, and stirring velocity is 120 rev/mins; Stop after hydrochloric acid adds stirring, continue solution is cooled to 5 ℃, standing growing the grain 3 hours obtains filtering after crystal, washing, and vacuum-drying 6 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray for preparing measures as shown in Figure 1, measuring its fusing point is 171～175 ℃, proterties is yellowish crystalline powder, measure through sem observation and particle size analyzer, the crystal master granularity 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 the Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, adding mass percent under 2 ℃ of conditions 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 mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 1 hour;
(3) solution that step (2) is obtained is warming up to 22 ℃, adds while stirring the hydrochloric acid of 2 ℃, and regulating the pH value is 1.8, and stirring velocity is 120 rev/mins; Stop after hydrochloric acid adds stirring, continue solution is cooled to 2 ℃, standing growing the grain 2 hours obtains filtering after crystal, washing, and vacuum-drying 4 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray for preparing measures as shown in Figure 1, measuring its fusing point is 171～175 ℃, proterties is yellowish crystalline powder, measure through sem observation and particle size analyzer, the crystal master granularity 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 the Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, adding mass percent under 4 ℃ of conditions 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 mass percent is 0.01% activated carbon decolorizing, stirs the filtrate of filtering after 1.5 hours;
(3) solution that step (2) is obtained is warming up to 22 ℃, adds while stirring the hydrochloric acid of 4 ℃, and regulating the pH value is 1.8, and stirring velocity is 120 rev/mins; Stop after hydrochloric acid adds stirring, continue solution is cooled to 2 ℃, standing growing the grain 2 hours obtains filtering after crystal, washing, and vacuum-drying 4 hours obtains the Cefmenoxime Hemihydrochloride crystal.
The X-ray powder diffraction pattern that the Cefmenoxime Hemihydrochloride crystal use Cu-K alpha-ray for preparing measures as shown in Figure 1, measuring its fusing point is 171～175 ℃, proterties is yellowish crystalline powder, measure through sem observation and particle size analyzer, the crystal master granularity 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.
The preparation method is:
(1) take in proportion Cefmenoxime Hemihydrochloride and anhydrous sodium carbonate, fully mix;
(2) divide in the cillin bottle that is filled to after sterilization and jump a queue.
Experimental example 1 stability test
Adopt three batches 101,102,103 of Cefmenoxime Hemihydrochloride crystal of embodiment 1 preparation, be prepared into preparation according to the method for embodiment 6, carry out stability test:
1. high temperature test
Get preparation simulation listing packing, placed 10 days at 60 ℃ of temperature, in the 5th day and sampling in the 10th day, detect by stable high spot reviews project.Particulate matter adopts microscopic counting to detect.
2. high humidity test
Get preparation simulation listing packing, put in the constant humidity encloses container, placed 10 days under the condition of 25 ℃ of relative humidity 90% ± 5%, in the 5th day and sampling in the 10th day, detect by stable high spot reviews project.Particulate matter adopts microscopic counting to detect.
3. strong illumination test
Get preparation simulation listing packing, put in the sealing clean container, be placed under the condition that illumination is 4500lx ± 500lx and placed 10 days, in the 5th day and sampling in the 10th day, detect by stable high spot reviews project.Particulate matter adopts microscopic counting to detect.
The influence factor test-results sees the following form 1.
Table 1: Cefmenoxime Hemihydrochloride crystal influence factor test-results
Result shows: preparation injection of the present invention, under the condition of simulation listing packing, to place 10 days under illumination, hot conditions, 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 ℃, placed 6 months under the condition of 75% ± 5%RH, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stable 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:
By the accelerated test result as can be known, Cefmenoxime Hemihydrochloride crystal of the present invention prepares preparation, investigates in 6 months through accelerated test, 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
3 batches 301,302,303 of the Cefmenoxime Hemihydrochloride crystalline compounds that the embodiment of the present invention 3 is prepared prepare preparation according to experimental example 6 methods, simulation listing packing, carry out following stability test: put in the sealing clean container, at 30 ℃ ± 2 ℃, placed 24 months under 60% ± 5%RH spare, at duration of test respectively at the 3rd, 6,9,12,18 sampling at the end of month once, each stable 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
By long-term test results as can be known, Cefmenoxime Hemihydrochloride crystal formulations of the present invention was investigated through test of long duration in 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: stable comparison test
Adopt the Cefmenoxime Hemihydrochloride crystal of embodiment 1 preparation, be prepared into preparation according to the method for embodiment 6;
Comparative formulation 1,2,3,4 preparation method are:
Comparative Examples 1 preparation method: adopt common commercially available Cefmenoxime Hemihydrochloride raw material (Liaoning Hasco Pharmaceutical Co., Ltd., the accurate word H20123248 of traditional Chinese medicines) according to the preparation of the method preparation of embodiment 6;
Comparative Examples 2 preparation methods: according to ZL200910114629.8 embodiment 4 preparation Cefmenoxime Hemihydrochlorides, according to the preparation of the method preparation of embodiment 6;
The preparation method of Comparative Examples 3: according to ZL201110320076.9 embodiment 1 preparation Cefmenoxime Hemihydrochloride crystal, according to the preparation of the method preparation of embodiment 6;
The preparation method of Comparative Examples 4 is according to the patent application 201210332727.0 unformed Cefmenoxime Hemihydrochlorides of embodiment 1 preparation, according to the preparation of the method preparation of embodiment 6;
Above-mentioned preparation is carried out stable comparison test under identical condition:
1. high temperature test
Get the preparation of Comparative formulation 1～4 and the compounds of this invention preparation, simulation listing packing was placed 10 days at 60 ℃ of temperature, in the 5th day and sampling in the 10th day, detected by stable high spot reviews project.Particulate matter adopts microscopic counting to detect.
2. high humidity test
Get the preparation of Comparative formulation 1～4 and the compounds of this invention preparation, simulation listing packing is put in the 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, detects by stable high spot reviews project.Particulate matter adopts microscopic counting to detect.
3. strong illumination test
Get the preparation of Comparative formulation 1～4 and the compounds of this invention preparation, simulation listing packing is put in the 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, detects by stable high spot reviews project.Particulate matter adopts microscopic counting to detect.
The influence factor test-results sees the following form 8.
Table 4: Cefmenoxime Hemihydrochloride crystal influence factor test-results
Result shows: this product was placed 10 days under high temperature, high humidity, illumination condition under the condition of simulation listing packing, and except related substance slightly increases, outside content slightly reduced, other indices were without considerable change.And the appearance that has 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
Method according to embodiment 4 prepares Comparative Examples preparation and preparation of the present invention, press at the same terms and carry out Accelerated stability test: the difference sample thief, placed 6 months under 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% condition, at duration of test respectively at the 1st, 3,6 sampling at the end of month once, each stable high spot reviews project is tested.Particulate matter adopts microscopic counting to detect.Test-results sees Table 5.
Table 5:
Result shows: this product was placed 3 months under acceleration environment under the condition of simulation listing packing, and except related substance slightly increases, outside content slightly reduced, other indices were without considerable change.And the content of the related substance in drugs compared obviously raises, and medicament contg obviously reduces, and underproof situation appears in particulate matter.The stability that proves the preparation of crystal preparation of the present invention is better than prior art.
Experimental example 6: investigate the ratio of solvent in reaction to the impact of Cefmenoxime Hemihydrochloride crystalline compounds
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:
By above-mentioned experiment as can be known, 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 selects respectively the injection gac of different concns to adsorb all with embodiment 1, take Cefmenoxime Hemihydrochloride crystal yield, purity as investigating index, the consumption of screening gac.Two clarity test procedures of Chinese Pharmacopoeia version in 2000 are adopted in the inspection of clarity, 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 |
By drawing in table, it is best that the purity that 0.01% gac can the Cefmenoxime Hemihydrochloride crystal and yield reach, less to main ingredient absorption, and pollute minimumly, is 0.01%(g/ml so select concentration) gac adsorb.
Experimental example 8: solvability contrast experiment
Adopt the cefmenoxime hydrochloride compound of embodiment 1～5 preparation, be prepared into preparation according to the method for embodiment 6, prepare the Comparative Examples preparation according to the method for embodiment 4, test under identical condition.
Get the injection 1g of each preparation 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 sees Table 9;
Table 9:
| ? | 25 ℃ of dissolution times (s) | 1 ℃ of dissolution time (s) |
| The preparation of embodiment 1 compound | Dissolving fully in 3 seconds, the solution clarification | Dissolving fully in 6 seconds, the solution clarification |
| The preparation of embodiment 2 compounds | Dissolving fully in 3 seconds, the solution clarification | Dissolving fully in 6 seconds, the solution clarification |
| The preparation of embodiment 3 compounds | Dissolving fully in 3 seconds, the solution clarification | Dissolving fully in 6 seconds, the solution clarification |
| The preparation of embodiment 4 compounds | Dissolving fully in 3 seconds, the solution clarification | Dissolving fully in 6 seconds, the solution clarification |
| The preparation of embodiment 5 compounds | Dissolving fully in 4 seconds, the solution clarification | Dissolving fully in 7 seconds, the solution clarification |
| Comparative Examples 1 | Dissolving fully not yet in 3 minutes | Dissolving fully not yet in 5 minutes |
| Comparative Examples 2 | Dissolving fully in 8 seconds, the solution clarification | Dissolving fully in 45 seconds, the solution clarification |
| Comparative Examples 3 | Dissolving fully in 5 seconds, the solution clarification | Dissolving fully in 18 seconds, the solution clarification |
| Comparative Examples 4 | Dissolving fully in 10 seconds, the solution clarification | Dissolving fully in 31 seconds, the solution clarification |
According to dissolution experiment as can be known, the preparation of the cefmenoxime hydrochloride compound of the present invention's preparation, 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, the crystal of the present invention's preparation still can dissolve rapidly, and the dissolution rate at low temperatures of the preparation in Comparative Examples is obviously slowed 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 the fixed funnel method, funnel is placed in suitable height on graph paper, make cefmenoxime hydrochloride compound under the flare opening Free-flow, until the cone top that forms 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 the fixed funnel method, funnel is placed in suitable height on graph paper, make the cefmenoxime hydrochloride composition preparation under the flare opening Free-flow, until the cone top that forms 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, and is clinical easy to use and reliable.
Claims (8)
1. a Cefmenoxime hydrochloride compound used for injection, is characterized in that, described cefmenoxime hydrochloride compound is crystal, uses
The X-ray powder diffraction pattern that the Cu-K alpha-ray measures as shown in Figure 1, its structural formula is suc as formula shown in I:
2. Cefmenoxime hydrochloride compound used for injection according to claim 1, is characterized in that, described Cefmenoxime Hemihydrochloride chemical combination
The crystal master granularity of thing is 180～240 μ m, and Tile Width is 120～300 μ m; Preferred main granularity is 195～230 μ m, minute
The cloth width is 150～280 μ m.
3. 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 the Cefmenoxime Hemihydrochloride solid and add water and stir and to make suspension, adding mass percent under 0～5 ℃ of condition 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 mass percent is 0.01～0.02% activated carbon decolorizing, stirs the filtrate of filtering after 0.5～1.5 hour;
(3) solution that step (2) is obtained is warming up to 20～25 ℃, the hydrochloric acid that adds while stirring 0～5 ℃, regulating the pH value is 1.8, stop after hydrochloric acid adds 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 the Cefmenoxime Hemihydrochloride crystal.
4. Cefmenoxime hydrochloride compound used for injection according to claim 3, it is characterized in that, add that in Virahol and ethyl acetate mixture, the volume ratio of Virahol and ethyl acetate is 1:0.5～1, preferred 1:0.5～0.85, more preferably 1:0.5～0.75.
5. Cefmenoxime hydrochloride compound used for injection according to claim 3, is characterized in that, 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.
6. Cefmenoxime hydrochloride compound used for injection according to claim 3, is characterized in that, the stirring velocity when adding hydrochloric acid be 90～120 rev/mins.
7. a medicinal composition for injections that comprises 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; Preferably comprise Cefmenoxime Hemihydrochloride crystal 10 weight parts, anhydrous sodium carbonate 1.75 weight parts.
8. the pharmaceutical composition of cefmenoxime hydrochloride compound according to claim 7, is characterized in that, also contains at least a in stablizer, antioxidant in the described composition of described pharmaceutical composition.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432078A (en) * | 2013-08-28 | 2013-12-11 | 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 |
| CN106117246A (en) * | 2016-06-13 | 2016-11-16 | 芦红代 | A kind of preparation method of Abbott 50192 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2013
- 2013-03-21 CN CN201310092270.5A patent/CN103145735B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 李爱军等: "盐酸头孢甲肟的合成", 《中国抗生素杂志》, vol. 30, no. 3, 31 March 2005 (2005-03-31) * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432078A (en) * | 2013-08-28 | 2013-12-11 | 芦红代 | Medicinal composition of cefmenoxime hydrochloride |
| 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 |
| CN106117246A (en) * | 2016-06-13 | 2016-11-16 | 芦红代 | A kind of preparation method of Abbott 50192 raw material |
| 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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