CN103304580B - Cefepime dihydrochloride compound as well as preparation method and medicine composition thereof - Google Patents
Cefepime dihydrochloride compound as well as preparation method and medicine composition thereof Download PDFInfo
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- CN103304580B CN103304580B CN201310229537.0A CN201310229537A CN103304580B CN 103304580 B CN103304580 B CN 103304580B CN 201310229537 A CN201310229537 A CN 201310229537A CN 103304580 B CN103304580 B CN 103304580B
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to a cefepime dihydrochloride compound. The structural formula of the cefepime dihydrochloride compound is as shown in the specification; and the X-ray powder diffraction spectrogram obtained through measurement by using Cu-Kalpha rays, of the cefepime dihydrochloride compound is as shown in figure 1. The invention further provides a preparation method of the cefepime dihydrochloride compound, a medicine composition containing the cefepime dihydrochloride compound and the preparation method of the medicine composition. The cefepime dihydrochloride compound is prepared into the dosage form of sterility powder-injection. Compared with the prior art, the cefepime dihydrochloride compound and the medicine composition thereof have better storage stability, and the medication safety of patients is greatly improved.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of cefepime hydrochloride compound prepared, preparation method that this is cefepime hydrochloride compound prepared, preparation method containing this cefepime hydrochloride compound prepared pharmaceutical composition and this pharmaceutical composition.
Background technology
In prior art, there are two kinds of forms in cefepime Hydrochloride, and one is cefepime Hydrochloride monohydrate, molecular formula C
19h
24n
6o
5s
22HClH
2o, CAS 123171-59-5, a kind of is the cefepime Hydrochloride of not being with crystal water, molecular formula C
19h
24n
6o
5s
22HCl, CAS 107648-80-6.
Cefepime Hydrochloride be the 4th generation semi-synthetic cynnematin.Antimicrobial spectrum is similar to third generation cephalosporin to anti-microbial activity, but antimicrobial spectrum has had further expansion.Gram positive organism, negative bacterium are comprised to enterobacter, Pseudomonas aeruginosa, hemophilus, Neisseria gonorrhoeae genus, staphylococcus and suis (except faecalis) have stronger anti-microbial activity.Stable to beta lactamase, be clinically mainly used in various severe infections as respiratory tract infection, urinary system infection, biliary tract infection, septicemia etc.
CN 101935325A discloses a kind of cefepime Hydrochloride preparation method, comprising: oxalyl chloride and 2-methoxyimino-2-(thiazolamine-4-yl) acetic acid hydrochloride reactant salt are obtained to intermediate compound I 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride; Silanization 7-amino-cephalosporanic acid is mixed with silanization N-crassitude; reaction under Iodotrimethylsilane, Virahol, aqueous solution of hydrogen iodide exist; obtain intermediate II hydroiodic acid HI (6R, 7R)-7-amino-3-[(1-methyl isophthalic acid-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic acid betaine; Intermediate II is dissolved in to methylene dichloride, adds successively trimethylchlorosilane and hexamethyldisilazane reaction, then add intermediate compound I and triethylamine reaction to make cefepime Hydrochloride.
CN 102408440A discloses a kind of synthetic method of cefepime Hydrochloride, its step is as follows: by (6R, 7R)-7-amino-3-[(1-methyl isophthalic acid-tetramethyleneimine) methyl] cephalo-3-alkene-4-carboxylic acid hydrochloride and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester join in the mixed solvent of water and water-miscible organic solvent; After regulating pH value to be 5.5～7.5, under heat-retaining condition, carry out acylation reaction; After reaction finishes, extract, organic phase reclaims by underpressure distillation; Regulate with hydrochloric acid after the pH value of water, crystallization, makes cefepime Hydrochloride.The present invention's reaction is gentleer, for acid and partial neutral environment, impact on cefepime is less, more easy to control, reduce the probability of its degraded and open loop, increased the purity of the finished product, improved the productive rate of cefepime, the quality of cefepime is improved, and HPLC detects purity higher than 99.5%.
CN 101638412A discloses the cefepime hydrochloride compound prepared of a kind of novel synthesis, first by ainothiazoly loximate and formic acid reaction, generate 2-(2-formamido group thiazole-4-yl)-2-methoxyimino Acetic Acid, add again 7-MPYCA and triethylamine, with DIPEA and N, dinethylformamide is solvent, taking Tosyl chloride as catalyzer, stirring reaction, makes cefepime Hydrochloride.
CN 102675345A discloses a kind of preparation method of cefepime Hydrochloride, the method is in 7-ACA, to add hmds and Iodotrimethylsilane vacuum back-flow 12h at 55 DEG C, cooling dilution, add N-Methyl pyrrolidone and Iodotrimethylsilane to react 23h at 40 DEG C, aftertreatment recrystallization obtains 7-ACMPHCl, at 0-5 DEG C, 7-ACMPHCl is dissolved in solvent, repeatedly adds on a small quantity 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester and triethylamine, and reaction finishes aftertreatment and obtains cefepime Hydrochloride.By the way, the preparation method of a kind of cefepime Hydrochloride provided by the invention, the method speed of response is fast, and production cost is low, and product purity is high, good fluidity.
The less stable of this cefepime Hydrochloride of two types of the prior art, all needs lucifuge under 0-5 DEG C of condition to store, better cefepime hydrochloride compound prepared in order to obtain a kind of stability, special proposition the present invention.
Summary of the invention
It is a kind of cefepime hydrochloride compound prepared that the first object of the present invention is to provide, and this is cefepime hydrochloride compound prepared has better stability in storage.
The present invention's the second object is to provide a kind of above-mentioned cefepime hydrochloride compound prepared preparation method.
The 3rd object of the present invention is to provide a kind of above-mentioned cefepime hydrochloride compound prepared pharmaceutical composition that contains.
The 4th object of the present invention is to provide a kind of preparation method of described pharmaceutical composition.
In order to realize foregoing invention object, the present invention takes following technical scheme:
A kind of cefepime hydrochloride compound prepared, described cefepime hydrochloride compound prepared structural formula is:
The X-ray powder diffraction spectrogram that described cefepime hydrochloride compound prepared use Cu-K alpha-ray measures as shown in Figure 1.
The inside solid-state structure of compound has very large impact to its physicochemical property, same compound, its intramolecule arrangement mode difference, cause its lattice energy difference, thereby the difference of the binding force size of lattice to molecule causes its physicals also different, for example stability, dissolution rate, solubleness, water absorbability etc.
Cefepime hydrochloride compound prepared X-RD provided by the invention is different from the cefepime hydrochloride compound prepared X-RD in existing, shows cefepime hydrochloride compound prepared solid interior molecular arrangement mode provided by the invention unlike the prior art.Compared with the cefepime Hydrochloride of cefepime hydrochloride compound prepared and prior art provided by the invention, have higher lattice energy, its lattice is bound stronger to cefepime Hydrochloride molecule, thereby has improved cefepime hydrochloride compound prepared stability.Contriver is by stability experiment, and result shows, compared with the cefepime Hydrochloride of cefepime hydrochloride compound prepared and prior art provided by the present invention, to have stronger stability in storage, and this has greatly improved patient's drug safety.
Described cefepime hydrochloride compound prepared preparation method comprises: get hydrochloric acid cefepime raw material medicine, add DMF, the ratio of the weight of described cefepime Hydrochloride and the volume of DMF is 1g:8～10ml, be stirred to whole dissolvings, regulate pH to 1.5-2.0, be heated to 40～60 DEG C, under agitation condition, slowly add again ether, the volume of the ether adding and the volume ratio of DMF are 2-3:5, continue to stir 20-30min, add again gac, whip attachment, filter decarburization degerming, obtain settled solution, settled solution is moved in reactor, at 130～150 DEG C, place after 24～36h, leave standstill, naturally be cooled to 55～75 DEG C, open reactor, slowly drip acetone and be cooled to 0～5 DEG C, the consumption of acetone is 5-8 times of DMF, filter, washing, drying under reduced pressure, obtain white micro-crystals powder.
In order to obtain a kind of cefepime Hydrochloride of the solid form that is different from cefepime Hydrochloride of the prior art, contriver has done a large amount of experiments, comprise continuous change crystallization method and comprise the crystallization conditions such as pressure, temperature, solvent, pH, anti-solvent, finally obtain a kind of the solid-state cefepime hydrochloride compound prepared of brand-new molecular arrangement mode that have, its X-RD spectrogram shows, cefepime hydrochloride compound prepared solid interior molecular structure provided by the invention is different from cefepime Hydrochloride of the prior art.
In described cefepime hydrochloride compound prepared preparation method, the mixing speed while dripping acetone is 15～25rmp.
The described decolorizing with activated carbon that adds is this area common technology means, can be referring to any decolouring processing, those skilled in the art are without paying any creative work, and the prior art that can grasp according to himself is carried out appropriate selection, and realizes the object of the invention.
In described cefepime hydrochloride compound prepared preparation method, preferred, the amount that adds gac is the 0.2-0.3%g/ml of liquid cumulative volume.
In described cefepime hydrochloride compound prepared preparation method, the particle diameter of the white micro-crystals powder obtaining is 75～150 μ m.
The present invention also provides a kind of described cefepime hydrochloride compound prepared pharmaceutical composition that contains.
The present invention is by changing cefepime hydrochloride compound prepared solid interior structure, what obtain cefepime hydrochloride compound preparedly has a higher stability in storage, and then improve the stability in storage that contains cefepime hydrochloride compound prepared pharmaceutical composition, compared with the cefepime Hydrochloride pharmaceutical composition of prior art, the pharmaceutical composition that contains cefepime Hydrochloride provided by the invention has better stability in storage, has greatly improved patient's drug safety.
Pharmaceutical composition of the present invention can be prepared into various formulations, as liquid preparation, solid preparation.
Preferably, described pharmaceutical composition is sterile powder injection.
Preferably, by weight, described sterile powder injection comprises cefepime Hydrochloride 80-95 part, arginine 5-20 part.
Preferred, by weight, described sterile powder injection comprises cefepime Hydrochloride 80-90 part, arginine 10-20 part.
In the present invention, because the solvability of cefepime Hydrochloride in water for injection is very little, therefore in the time preparing cefepime dihydrochloride for injection composition, need to add arginine as solubility promoter and stablizer, said composition can be dissolved in water for injection in use in specific time.In addition, in sterile powder injection provided by the invention, add arginic consumption, can regulate the pH value of aseptic cefepime Hydrochloride, make its pH value in Human Tolerance scope, and clarity and the stability of prepared cefepime hydrochloride powder injection after redissolution be better.
The present invention also provides a kind of preparation method of described pharmaceutical composition, comprises the following steps:
(1) get hydrochloric acid cefepime raw material medicine, add DMF, the ratio of the weight of described cefepime Hydrochloride and the volume of DMF is 1g:8～10ml, be stirred to whole dissolvings, regulate pH to 1.5-2.0, be heated to 40～60 DEG C, under agitation condition, slowly add again ether, the volume of the ether adding and the volume ratio of DMF are 2-3:5, continue to stir 20-30min, add again gac, whip attachment, filter decarburization degerming, obtain settled solution, settled solution is moved in reactor, at 130～150 DEG C, place after 24～36h, leave standstill, naturally be cooled to 55～75 DEG C, open reactor, slowly drip acetone and be cooled to 0～5 DEG C, the consumption of acetone is 5-8 times of DMF, filter, washing, drying under reduced pressure, obtain white micro-crystals powder,
(2) the white micro-crystals powder and the pharmaceutically acceptable carrier that step (1) are obtained are made pharmaceutical composition.
In the preparation method of described pharmaceutical composition, in described step (1), the particle diameter of the white micro-crystals powder obtaining is 75～150 μ m.
In the preparation method of described pharmaceutical composition, in described step (2), after white micro-crystals powder is mixed with pharmaceutically acceptable carrier by the aseptic subpackaged sterile powder injection of making.
In the present invention, described sterile powder injection can adopt the preparation method of prior art, and those skilled in the art are without paying any creative work, and the prior art that can grasp according to himself is carried out appropriate selection, and realizes the object of the invention.
Compared with prior art, cefepime hydrochloride compound prepared and pharmaceutical composition tool provided by the invention has the following advantages:
(1) cefepime hydrochloride compound prepared long-time storage foreign matter content of the present invention is few, and stability in storage is good;
(2) the pharmaceutical composition stability in storage that contains cefepime Hydrochloride of the present invention is good, and safety performance is higher.
Brief description of the drawings
Fig. 1 is cefepime hydrochloride compound prepared X-powdery diffractometry spectrogram prepared by the embodiment of the present invention 1.
Embodiment
With embodiment, technical scheme of the present invention is further described below; by the advantage contributing to technical scheme of the present invention; effect has further to be understood, and embodiment does not limit protection scope of the present invention, and protection scope of the present invention is decided by claim.
Embodiment 1
Described cefepime hydrochloride compound prepared preparation method:
Get hydrochloric acid cefepime raw material medicine, add DMF, the ratio of the weight of described cefepime Hydrochloride and the volume of DMF is 1g:8ml, be stirred to whole dissolvings, regulate pH to 1.5, be heated to 40 DEG C, under agitation condition, slowly add again ether, the volume of the ether adding and the volume ratio of DMF are 2:5, continue to stir 20min, add again gac, the amount that adds gac is the 0.2%g/ml of liquid cumulative volume, stir 30min, filter decarburization degerming, obtain settled solution, settled solution is moved in reactor, at 130 DEG C, place after 36h, leave standstill, naturally be cooled to 55 DEG C, open reactor, slowly drip acetone and be cooled to 5 DEG C, the consumption of acetone is 8 times of DMF, mixing speed while dripping acetone is 25rmp, filter, with washing with acetone 3 times, drying under reduced pressure, obtain white micro-crystals powder.Yield 72.2%, HPLC content 99.88%.Particle diameter is 75～150 μ m.
Use X-ray powder diffraction spectrogram that Cu-K alpha-ray measures for Fig. 1 shown.
Embodiment 2
Described cefepime hydrochloride compound prepared preparation method:
Get hydrochloric acid cefepime raw material medicine, add DMF, the ratio of the weight of described cefepime Hydrochloride and the volume of DMF is 1g:10ml, be stirred to whole dissolvings, regulate pH to 2.0, be heated to 60 DEG C, under agitation condition, slowly add again ether, the volume of the ether adding and the volume ratio of DMF are 3:5, continue to stir 30min, add again gac, the amount that adds gac is the 0.3%g/ml of liquid cumulative volume, whip attachment 30min, filter decarburization degerming, obtain settled solution, settled solution is moved in reactor, at 150 DEG C, place after 24h, leave standstill, naturally be cooled to 75 DEG C, open reactor, slowly drip acetone and be cooled to 0 DEG C, the consumption of acetone is 5 times of DMF, mixing speed while dripping acetone is 15rmp, filter, with washing with acetone 3 times, drying under reduced pressure, obtain white micro-crystals powder.Yield 71.5%, HPLC content 99.91%.Particle diameter is 75～150 μ m.
The X-ray powder diffraction figure that uses Cu-K alpha-ray to measure is consistent with the result of embodiment 1.
Embodiment 3
The preparation of cefepime Hydrochloride sterile powder injection:
Under aseptic condition, take cefepime Hydrochloride 80g, arginase 12 0g prepared by embodiment 1, be placed in solid powder mixer and evenly mix, gained raw material proceeds to sterile preparation workshop, delicate metering packing, every bottle of hydrochloric cefepime 0.25g, jumps a queue, rolls lid, finished product packing warehouse-in censorship.
Embodiment 4
The preparation of cefepime Hydrochloride sterile powder injection:
Under aseptic condition, take cefepime Hydrochloride 90g, arginine 10g prepared by embodiment 1, be placed in solid powder mixer and evenly mix, gained raw material proceeds to sterile preparation workshop, delicate metering packing, every bottle of hydrochloric cefepime 0.5g, jumps a queue, rolls lid, finished product packing warehouse-in censorship.
Embodiment 5
The preparation of cefepime Hydrochloride sterile powder injection:
Under aseptic condition, take cefepime Hydrochloride 95g, arginine 5g prepared by embodiment 1, be placed in solid powder mixer and evenly mix, gained raw material proceeds to sterile preparation workshop, delicate metering packing, every bottle of hydrochloric cefepime 0.75g, jumps a queue, rolls lid, finished product packing warehouse-in censorship.
Experimental example 1
This test example detects related substance in the prepared cefepime Hydrochloride of embodiment 1～2, this test is carried out according to 2010 editions second annex VIII P residual solvent assay method of Chinese Pharmacopoeia, annex XIX F medicine impurity analysis governing principle, and it the results are shown in Table 1:
The assay of table 1 related substance
| Preparation | Ether | DMF | Acetone | Other related substance |
| Embodiment 1 product | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Embodiment 2 products | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
Experimental example 2
This experimental example has been investigated the stability of cefepime Hydrochloride provided by the invention
This test is carried out according to 2005 editions second annex XIX C medicine stability test governing principle of Chinese Pharmacopoeia, and result is as follows:
Table 2, accelerated test assay result
| ? | 0 month | 1 month | 3 months | 6 months | 9 months | 12 months |
| 1 | 99.70％ | 99.68％ | 99.63％ | 99.53％ | 99.45％ | 99.29％ |
| 2 | 99.76％ | 99.74％ | 99.68％ | 99.59％ | 99.51％ | 99.31％ |
| 3 | 99.79％ | 99.75％ | 99.67％ | 99.28％ | 98.23％ | 97.58％ |
| 4 | 99.65％ | 99.61％ | 99.54％ | 99.16％ | 98.08％ | 97.16％ |
Table 3, test of long duration assay result
| ? | 0 month | 3 months | 6 months | 9 months | 15 months | 24 months |
| 1 | 99.70％ | 99.70％ | 99.65％ | 99.61％ | 99.57％ | 99.25％ |
| 2 | 99.76％ | 99.76％ | 99.74％ | 99.70％ | 99.63％ | 99.21％ |
| 3 | 99.79％ | 99.75％ | 99.66％ | 99.31％ | 98.77％ | 97.89％ |
| 4 | 99.65％ | 99.61％ | 99.50％ | 99.25％ | 98.54％ | 97.81％ |
Sample 1 is the product of the embodiment of the present invention 1;
Sample 2 is the product of the embodiment of the present invention 2;
The cefepime Hydrochloride of sample 3 for preparing with reference to CN 102675345A embodiment 1, HPLC is 99.78%;
Sample 4 is the commercially available not cefepime Hydrochloride with crystal water, originates from Bai Li bio tech ltd, Shanghai, and HPLC is 99.95%;
Accelerated test and test of long duration by this experimental example are known, and compared with prior art, the stability of cefepime Hydrochloride provided by the invention is better.
Claims (8)
- One kind cefepime hydrochloride compound prepared, it is characterized in that, described cefepime hydrochloride compound prepared structural formula is:The X-ray powder diffraction spectrogram that described cefepime hydrochloride compound prepared use Cu-K alpha-ray measures as shown in Figure 1.
- 2. a cefepime hydrochloride compound prepared preparation method claimed in claim 1, it is characterized in that, described preparation method comprises: get hydrochloric acid cefepime raw material medicine, add DMF, the ratio of the weight of described cefepime Hydrochloride and the volume of DMF is 1g:8～10ml, be stirred to whole dissolvings, regulate pH to 1.5-2.0, be heated to 40～60 DEG C, under agitation condition, slowly add again ether, the volume of the ether adding and the volume ratio of DMF are 2-3:5, continue to stir 20-30min, add again gac, whip attachment, filter decarburization degerming, obtain settled solution, settled solution is moved in reactor, at 130～150 DEG C, place after 24～36h, leave standstill, naturally be cooled to 55～75 DEG C, open reactor, slowly drip acetone and be cooled to 0～5 DEG C, the consumption of acetone is 5-8 times of DMF, filter, washing, drying under reduced pressure, obtain white micro-crystals powder.
- 3. one kind contains cefepime hydrochloride compound prepared pharmaceutical composition claimed in claim 1.
- 4. pharmaceutical composition according to claim 3, is characterized in that, described pharmaceutical composition is sterile powder injection.
- 5. pharmaceutical composition according to claim 4, is characterized in that, by weight, described sterile powder injection comprises cefepime Hydrochloride 80-95 part, arginine 5-20 part.
- 6. pharmaceutical composition according to claim 5, is characterized in that, by weight, described sterile powder injection comprises cefepime Hydrochloride 80-90 part, arginine 10-20 part.
- 7. a preparation method for composition claimed in claim 3, is characterized in that, comprises the following steps:(1) get hydrochloric acid cefepime raw material medicine, add DMF, the ratio of the weight of described cefepime Hydrochloride and the volume of DMF is 1g:8～10ml, be stirred to whole dissolvings, regulate pH to 1.5-2.0, be heated to 40～60 DEG C, under agitation condition, slowly add again ether, the volume of the ether adding and the volume ratio of DMF are 2-3:5, continue to stir 20-30min, add again gac, whip attachment, filter decarburization degerming, obtain settled solution, settled solution is moved in reactor, at 130～150 DEG C, place after 24～36h, leave standstill, naturally be cooled to 55～75 DEG C, open reactor, slowly drip acetone and be cooled to 0～5 DEG C, the consumption of acetone is 5-8 times of DMF, filter, washing, drying under reduced pressure, obtain white micro-crystals powder,(2) the white micro-crystals powder and the pharmaceutically acceptable carrier that step (1) are obtained are made pharmaceutical composition.
- 8. preparation method according to claim 7, is characterized in that, in described step (2), after white micro-crystals powder is mixed with pharmaceutically acceptable carrier by the aseptic subpackaged sterile powder injection of making.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4910301A (en) * | 1985-08-05 | 1990-03-20 | Bristol-Myers Company | Cefepime cephalosporin salts |
| US5095011A (en) * | 1989-03-06 | 1992-03-10 | Bristol-Myers Company | Lyophilized cefepime dihydrochloride for parenteral use |
| WO2006109324A3 (en) * | 2005-04-13 | 2007-04-05 | Lupin Ltd | Processes for preparation of amorphous cefepime acid addition salts |
| CN101200473A (en) * | 2007-06-07 | 2008-06-18 | 深圳信立泰药业股份有限公司 | Method for preparing cefepime dihydrochloride monohydrate crystal |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4910301A (en) * | 1985-08-05 | 1990-03-20 | Bristol-Myers Company | Cefepime cephalosporin salts |
| US5095011A (en) * | 1989-03-06 | 1992-03-10 | Bristol-Myers Company | Lyophilized cefepime dihydrochloride for parenteral use |
| WO2006109324A3 (en) * | 2005-04-13 | 2007-04-05 | Lupin Ltd | Processes for preparation of amorphous cefepime acid addition salts |
| CN101200473A (en) * | 2007-06-07 | 2008-06-18 | 深圳信立泰药业股份有限公司 | Method for preparing cefepime dihydrochloride monohydrate crystal |
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