CN104610283A - Cefepime dihydrochloride compound and pharmaceutical composition thereof - Google Patents
Cefepime dihydrochloride compound and pharmaceutical composition thereof Download PDFInfo
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- CN104610283A CN104610283A CN201510047901.0A CN201510047901A CN104610283A CN 104610283 A CN104610283 A CN 104610283A CN 201510047901 A CN201510047901 A CN 201510047901A CN 104610283 A CN104610283 A CN 104610283A
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Abstract
The invention discloses a cefepime dihydrochloride compound. The cefepime dihydrochloride compound is prepared by a following method comprising the following steps: (1) dissolving a cefepime dihydrochloride crude product into water and performing membrane separation and impurity removal by selecting a separating membrane with the molecular weight cut off of 500-3000; (2) adding the impurity-removed solution into an organic solvent, then adding active carbon into the obtained solution, stirring, filtering the solution to remove charcoal, and collecting the filter solution; (3) separating and purifying the filter solution with a chromatographic column, wherein a mobile phase is a mixed solvent of isopropanol and acetonitrile, and a stationary phase filler is silica gel or aluminum oxide; and (4) concentrating the separated and purified filter solution, and performing spray-drying to obtain the cefepime dihydrochloride compound. The invention also discloses a pharmaceutical composition containing the cefepime dihydrochloride compound, wherein the pharmaceutical composition is sterile powder for injection. The cefepime dihydrochloride compound and the pharmaceutical composition disclosed by the invention have low impurity content and few toxic and side effects, so that the medication safety of the patient is greatly improved.
Description
Technical field
The present invention relates to a kind of cefepime hydrochloride compound prepared and pharmaceutical composition, belong to field of pharmaceutical chemistry technology.
Background technology
Cefepime is wide spectrum forth generation cynnematin, reaches germicidal action by the biosynthesizing of anti-bacteria cell walls.In vitro tests shows, all has effect to gram-positive microorganism and negative bacterium.The avidity of this product to the β-lactamase that bacterial chromosome is encoded is low, can the hydrolysis of the most β-lactamase of quite tolerant, and can infiltrate rapidly in the cell of gram-negative bacteria.In somatic cells, its target molecule is penicillin-binding protein (PBP).Molecular formula: C
19h
25clN
6o
5s
2hClH
2o is white or off-white powder; Micro-smelly, tasteless.
Cefepime is a kind of thermally labile and water-soluble very large neutral inner salt, there is carboxyl negative ion in cefepime, combine with the proton in the aqueous solution, impel water dissociation to balance produce more alkali ion and make solution be weakly alkaline, but easily there is the reactions such as degraded and open loop in it under weak basic condition, cause content to decline, impurity increases, yield is low, product purity is low.
In prior art, the preparation of high-purity hydrochloric acid cefepime adopts the method for recrystallization more.Improvement (the Meng Hong etc. of such as cefepime Hydrochloride synthetic method, China's microbiotic magazine, in August, 2005), in the publication in disclosed method, to, in cefepime Hydrochloride crystallisation process, adopt acetone and water as solvent, after crystallization obtains cefepime Hydrochloride crude product, again through boiling process, obtain the cefepime Hydrochloride that purity is 99.8% (HPLC).Such as patent application 201110444957.1 discloses a kind of synthetic method of cefepime Hydrochloride again, also be add acetone to carry out crystallization in the crystallisation step of this synthetic method, the cefepime Hydrochloride purity adopting the method to prepare is up to 99.7% (HPLC).
Summary of the invention
It is cefepime hydrochloride compound prepared that the object of the invention there is provided prepared by a kind of novel method, makes cefepime hydrochloride compound preparedly to have the advantages such as purity is high, impurity is low, toxic side effect is little.
In order to realize foregoing invention object, this invention takes following technical scheme: a kind of cefepime hydrochloride compound prepared, described cefepime hydrochloride compound prepared structural formula is:
This is cefepime hydrochloride compound prepared standby in order to below legal system: (1), by soluble in water for cefepime Hydrochloride crude product, select molecular weight cut-off be 500 ~ 3000 separatory membrane, under 0.1 ~ 0.5MPa working pressure condition, carry out membrane separation for removing impurities;
(2), be added in organic solvent by the cefepime Hydrochloride solution of step (1), in gained solution, add gac, 40 ~ 50 DEG C are stirred 20 ~ 30min, filtering decarbonization, collect filtrate;
(3), the filtrate of step (2) is carried out chromatographic column separation and purification; The condition of described chromatographic column separation and purification is: moving phase is the Virahol of volume ratio 1: 2.5 ~ 4 and the mixed solvent of acetonitrile, and fixed phase stuffing is silica gel or aluminum oxide, and flow velocity is 3 ~ 4.5ml/min, column temperature 30 ~ 40 DEG C;
(4), the filtrate after separation and purification is condensed into the concentrated solution of 20 ~ 40 degree Beaume 60 DEG C time, spray-dried, to obtain final product.
As preferably, the film that in described step (1), separation, impurity removal uses is aromatic polyamide membrane, sulfonated polysulfone membrane or polysulfone membrane.
As preferably, in described step (1), the working pressure of membrane separation for removing impurities is 0.3MPa.
As preferably, in described step (2), organic solvent is volume ratio is the hexanaphthene of 1:2 and the mixed solvent of acetonitrile.
As preferably, in described step (2), the add-on of gac is 2.5 ~ 10% of cefepime Hydrochloride crude product.
As preferably, in described step (2), the add-on of gac is 7.5% of cefepime Hydrochloride crude product.
As preferably, in described step (3), the condition of chromatographic column separation and purification is: moving phase is the Virahol of volume ratio 1: 3 and the mixed solvent of acetonitrile, and fixed phase stuffing is silica gel or aluminum oxide, and flow velocity is 3.5ml/min, column temperature 35 DEG C.
As preferably, in described step (4), the concentration of concentrated solution 60 DEG C time is 35 degree Beaume.
As preferably, in described step (4), spray-dired condition is: spray-drier inlet temperature 100 ~ 140 DEG C, temperature out 60 ~ 100 DEG C, centrifugal head operating pressure 1.6 ~ 3.0kgf/cm
2.
The present invention also provides a kind of containing described cefepime hydrochloride compound prepared pharmaceutical composition, and described pharmaceutical composition is injectable sterile powder; By weight, described injectable sterile powder comprises described cefepime hydrochloride compound prepared 100 parts, L-arginine 55-65 part.
Compared with prior art, the present invention has following beneficial effect:
Provided by the invention cefepime hydrochloride compound prepared, by the absorption and purification of membrane separation, charcoal absorption and chromatographic column, substantially increase cefepime hydrochloride compound prepared purity and content, and then improve the quality product of its pharmaceutical composition, decrease toxic side effect, drastically increase the safety of patient medication; And present method technique is simple, cost is low, and yield is high, is suitable for suitability for industrialized production.
Embodiment
Below by way of specific embodiment, the application is further elaborated.
In following examples, the raw material used is commercially available.
Embodiment 1
A kind of cefepime hydrochloride compound prepared, this is cefepime hydrochloride compound prepared standby in order to below legal system:
(1), by 100g cefepime Hydrochloride crude product (purity 83.2%) be dissolved in 1500ml water, select molecular weight cut-off be 500 ~ 3000 separatory membrane, aromatic polyamides membrane separation for removing impurities under 0.3MPa working pressure condition;
(2), the cefepime Hydrochloride solution of step (1) being added to 1000ml volume ratio is in the hexanaphthene of 1:2 and the mixed solvent of acetonitrile, the gac of 7.5g is added in gained solution, be incubated 45 DEG C and stir 30min, filtering decarbonization, collect filtrate;
(3), the filtrate of step (2) is carried out chromatographic column separation and purification; The condition of described chromatographic column separation and purification is: moving phase is the Virahol of volume ratio 1: 3 and the mixed solvent of acetonitrile, and fixed phase stuffing is silica gel, and flow velocity is 3.5ml/min, column temperature 35 DEG C;
(4), the filtrate after separation and purification is condensed into the concentrated solution of 35 degree Beaume (60 DEG C), spraying dry, spray-dired condition is: spray-drier inlet temperature 100 ~ 140 DEG C, temperature out 60 ~ 100 DEG C, centrifugal head operating pressure 1.6 ~ 3.0kgf/cm
2, to obtain final product.
Be cefepime hydrochloride compound prepared by the compound of infrared spectra and nuclear magnetic resonance spectrum determination gained.
IRυKBrmax cm
-13440，1775，1515，1248，1175。
1H-NMR，δ2.15～2.4，3.13，3.58～3.62，3.70，3.79，3.80，4.2，4.57，5.12，5.15，5.41，6.88，7.21～7.32，7.84。
13C-NMR，δ20.82，21.34，22.07，23.59，25.30，42.70，48.06，51.88，53.91，55.30，61.20，64.35，65.13，68.49，96.06，112.80，114.20，126.39，127.10，129.51，130.47，131.25，134.68，134.93，160.06，165.59，166.23，171.86。
Can determine that a part cefepime Hydrochloride contains 2 molecule hydrochloric acid and 1 molecular crystal water through ultimate analysis and differential thermal analysis.
Structural formula is:
Detecting cefepime hydrochloride compound prepared purity through HPLC is 99.9%.
Embodiment 2
A kind of cefepime hydrochloride compound prepared, this is cefepime hydrochloride compound prepared standby in order to below legal system:
(1), by 100g cefepime Hydrochloride crude product (purity 82.4%) be dissolved in 1500ml water, select molecular weight cut-off be 500 ~ 3000 separatory membrane, SPSF membrane separation for removing impurities under 0.1MPa working pressure condition;
(2), the cefepime Hydrochloride solution of step (1) being added to 1000ml volume ratio is in the hexanaphthene of 1:2 and the mixed solvent of acetonitrile, the gac of 2.5g is added in gained solution, be incubated 40 DEG C and stir 20min, filtering decarbonization, collect filtrate;
(3), the filtrate of step (2) is carried out chromatographic column separation and purification; The condition of described chromatographic column separation and purification is: moving phase is the Virahol of volume ratio 2: 5 and the mixed solvent of acetonitrile, and fixed phase stuffing is silica gel, and flow velocity is 4.5ml/min, column temperature 35 DEG C;
(4), the filtrate after separation and purification is condensed into the concentrated solution of 20 degree Beaume (60 DEG C), spraying dry, spray-dired condition is: spray-drier inlet temperature 100 ~ 140 DEG C, temperature out 60 ~ 100 DEG C, centrifugal head operating pressure 1.6 ~ 3.0kgf/cm
2, to obtain final product.
Be cefepime hydrochloride compound prepared by the compound of infrared spectra and nuclear magnetic resonance spectrum determination gained.
IRυKBrmax cm
-13440，1775，1515，1248，1175。
1H-NMR，δ2.15～2.4，3.13，3.58～3.62，3.70，3.79，3.80，4.2，4.57，5.12，5.15，5.41，6.88，7.21～7.32，7.84。
13C-NMR，δ20.82，21.34，22.07，23.59，25.30，42.70，48.06，51.88，53.91，55.30，61.20，64.35，65.13，68.49，96.06，112.80，114.20，126.39，127.10，129.51，130.47，131.25，134.68，134.93，160.06，165.59，166.23，171.86。
Can determine that a part cefepime Hydrochloride contains 2 molecule hydrochloric acid and 1 molecular crystal water through ultimate analysis and differential thermal analysis.
Structural formula is:
Detecting cefepime hydrochloride compound prepared purity through HPLC is 99.8%.
Embodiment 3
A kind of cefepime hydrochloride compound prepared, this is cefepime hydrochloride compound prepared standby in order to below legal system:
(1), by 100g cefepime Hydrochloride crude product (purity 81.7%) be dissolved in 1500ml water, select molecular weight cut-off be 500 ~ 3000 separatory membrane, polysulfone membrane separation, impurity removal under 0.5MPa working pressure condition;
(2), the cefepime Hydrochloride solution of step (1) being added to 1000ml volume ratio is in the hexanaphthene of 1:2 and the mixed solvent of acetonitrile, the gac of 10g is added in gained solution, be incubated 50 DEG C and stir 25min, filtering decarbonization, collect filtrate;
(3), the filtrate of step (2) is carried out chromatographic column separation and purification; The condition of described chromatographic column separation and purification is: moving phase is the Virahol of volume ratio 1: 4 and the mixed solvent of acetonitrile, and fixed phase stuffing is aluminum oxide, and flow velocity is 3ml/min, column temperature 40 DEG C;
(4), the filtrate after separation and purification is condensed into the concentrated solution of 40 degree Beaume (60 DEG C), spraying dry, spray-dired condition is: spray-drier inlet temperature 100 ~ 140 DEG C, temperature out 60 ~ 100 DEG C, centrifugal head operating pressure 1.6 ~ 3.0kgf/cm
2, to obtain final product.
Be cefepime hydrochloride compound prepared by the compound of infrared spectra and nuclear magnetic resonance spectrum determination gained.
IRυKBrmax cm
-13440，1775，1515，1248，1175。
1H-NMR，δ2.15～2.4，3.13，3.58～3.62，3.70，3.79，3.80，4.2，4.57，5.12，5.15，5.41，6.88，7.21～7.32，7.84。
13C-NMR，δ20.82，21.34，22.07，23.59，25.30，42.70，48.06，51.88，53.91，55.30，61.20，64.35，65.13，68.49，96.06，112.80，114.20，126.39，127.10，129.51，130.47，131.25，134.68，134.93，160.06，165.59，166.23，171.86。
Can determine that a part cefepime Hydrochloride contains 2 molecule hydrochloric acid and 1 molecular crystal water through ultimate analysis and differential thermal analysis.
Structural formula is:
Cefepime hydrochloride compound prepared purity 99.5% is detected through HPLC.
Embodiment 4
Prepared by cefepime dihydrochloride for injection sterilized powder:
Aseptically, take cefepime hydrochloride compound prepared 100g prepared by embodiment 1, L-arginine 55g, is placed in solid powder mixer Homogeneous phase mixing, is sub-packed in cillin bottle after the assay was approved, jumps a queue, Zha Gai, packaging, censorship.
Embodiment 5
Prepared by cefepime dihydrochloride for injection sterilized powder:
Aseptically, take cefepime hydrochloride compound prepared 100g prepared by embodiment 1, L-arginine 60g, is placed in solid powder mixer Homogeneous phase mixing, is sub-packed in cillin bottle after the assay was approved, jumps a queue, Zha Gai, packaging, censorship.
Experimental example 1
Product of the present invention compares with the accelerated test related substance data of reference examples, the results are shown in Table 1.
Table 1
| 0 month | 1 month | 2 months | 3 months | 6 months | |
| Embodiment 4 | 0.37％ | 0.37％ | 0.39％ | 0.39％ | 0.40％ |
| Embodiment 5 | 0.39％ | 0.36％ | 0.38％ | 0.38％ | 0.40％ |
| Commercially available prod | 0.61％ | 0.64％ | 0.65％ | 0.64％ | 0.67％ |
Product of the present invention compares with the test of long duration related substance data of reference examples, the results are shown in Table 2.
Table 2
| 0 month | 3 months | 6 months | 9 months | 12 months | 15 months | |
| Embodiment 4 | 0.37％ | 0.38％ | 0.38％ | 0.38％ | 0.40％ | 0.41％ |
| Embodiment 5 | 0.39％ | 0.38％ | 0.40％ | 0.42％ | 0.41％ | 0.42％ |
| Commercially available prod | 0.61％ | 0.61％ | 0.63％ | 0.65％ | 0.67％ | 0.68％ |
The above results shows, product cefepime dihydrochloride for injection sterilized powder of the present invention is compared to commercially available prod, and its related substances is low, good stability.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (10)
1. one kind cefepime hydrochloride compound prepared, it is characterized in that, described cefepime hydrochloride compound prepared structural formula is:
Described cefepime hydrochloride compound prepared standby in order to below legal system: (1), by soluble in water for cefepime Hydrochloride crude product, select molecular weight cut-off be 500 ~ 3000 separatory membrane, under 0.1 ~ 0.5MPa working pressure condition, carry out membrane separation for removing impurities;
(2), be added in organic solvent by the cefepime Hydrochloride solution of step (1), in gained solution, add gac, 40 ~ 50 DEG C are stirred 20 ~ 30min, filtering decarbonization, collect filtrate;
(3), the filtrate of step (2) is carried out chromatographic column separation and purification; The condition of described chromatographic column separation and purification is: moving phase is the Virahol of volume ratio 1: 2.5 ~ 4 and the mixed solvent of acetonitrile, and fixed phase stuffing is silica gel or aluminum oxide, and flow velocity is 3 ~ 4.5ml/min, column temperature 30 ~ 40 DEG C;
(4), the filtrate after separation and purification is condensed into the concentrated solution of 20 ~ 40 degree Beaume 60 DEG C time, spray-dried, to obtain final product.
2. according to claim 1 cefepime hydrochloride compound prepared, it is characterized in that, the film that separation, impurity removal uses in described step (1) is aromatic polyamide membrane, sulfonated polysulfone membrane or polysulfone membrane.
3. according to claim 1 cefepime hydrochloride compound prepared, it is characterized in that, in described step (1), the working pressure of membrane separation for removing impurities is 0.3MPa.
4. according to claim 1 cefepime hydrochloride compound prepared, it is characterized in that, in described step (2), organic solvent is volume ratio is the hexanaphthene of 1:2 and the mixed solvent of acetonitrile.
5. according to claim 1 cefepime hydrochloride compound prepared, it is characterized in that, in described step (2), the add-on of gac is 2.5 ~ 10% of cefepime Hydrochloride crude product.
6. according to claim 5 cefepime hydrochloride compound prepared, it is characterized in that, in described step (2), the add-on of gac is 7.5% of cefepime Hydrochloride crude product.
7. according to claim 1 cefepime hydrochloride compound prepared, it is characterized in that, in described step (3), the condition of chromatographic column separation and purification is: moving phase is the Virahol of volume ratio 1: 3 and the mixed solvent of acetonitrile, fixed phase stuffing is silica gel or aluminum oxide, flow velocity is 3.5ml/min, column temperature 35 DEG C.
8. according to claim 1 cefepime hydrochloride compound prepared, it is characterized in that, in described step (4), the concentration of concentrated solution 60 DEG C time is 35 degree Beaume.
9. according to claim 1 cefepime hydrochloride compound prepared, it is characterized in that, in described step (4), spray-dired condition is: spray-drier inlet temperature 100 ~ 140 DEG C, temperature out 60 ~ 100 DEG C, centrifugal head operating pressure 1.6 ~ 3.0kgf/cm
2.
10., containing the cefepime hydrochloride compound prepared pharmaceutical composition described in any one of claim 1 ~ 9, it is characterized in that, described pharmaceutical composition is injectable sterile powder, comprises described cefepime hydrochloride compound prepared and L-arginine; By weight, described cefepime hydrochloride compound prepared be 100 parts, L-arginine is 55-60 part.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111560028A (en) * | 2020-04-25 | 2020-08-21 | 广东赛法洛药业有限公司 | New indication of cefepime hydrochloride medicinal preparation for treating otitis media |
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Address after: 100176 No. 6, Hongda Middle Road, Beijing economic and Technological Development Zone, Beijing, Daxing District Patentee after: Yuekang Pharmaceutical Group Co., Ltd. Address before: 100176 No. 6, Hongda Middle Road, Beijing economic and Technological Development Zone, Beijing, Daxing District Patentee before: YOUCARE PHARMACEUTICAL GROUP CO., LTD. |