CN103304580A - 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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- -1 Cefepime dihydrochloride compound Chemical class 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 239000000203 mixture Substances 0.000 title claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 16
- 239000007924 injection Substances 0.000 claims abstract description 16
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 5
- 229960000927 cefepime hydrochloride Drugs 0.000 claims description 84
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 34
- 239000000843 powder Substances 0.000 claims description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 229960002100 cefepime Drugs 0.000 claims description 12
- 239000013081 microcrystal Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 239000004475 Arginine Substances 0.000 claims description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 7
- 238000013019 agitation Methods 0.000 claims description 6
- 238000005261 decarburization Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 229910017488 Cu K Inorganic materials 0.000 claims description 4
- 229910017541 Cu-K Inorganic materials 0.000 claims description 4
- 230000005260 alpha ray Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000003860 storage Methods 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000002552 dosage form Substances 0.000 abstract 1
- 230000036512 infertility Effects 0.000 abstract 1
- 238000005259 measurement Methods 0.000 abstract 1
- LRAJHPGSGBRUJN-OMIVUECESA-N cefepime hydrochloride Chemical compound O.Cl.[Cl-].S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 LRAJHPGSGBRUJN-OMIVUECESA-N 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000012856 packing Methods 0.000 description 6
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
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- 238000000034 method Methods 0.000 description 3
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- 239000002904 solvent Substances 0.000 description 3
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- 238000005303 weighing Methods 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- COFDRZLHVALCDU-LICLKQGHSA-N s-(1,3-benzothiazol-2-yl) (2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoethanethioate Chemical compound N=1C2=CC=CC=C2SC=1SC(=O)/C(=N/OC)C1=CSC(N)=N1 COFDRZLHVALCDU-LICLKQGHSA-N 0.000 description 2
- 238000002444 silanisation Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- XQQAUWFZBOTKFQ-MHRNPJSASA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;dihydrochloride Chemical compound Cl.[Cl-].S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 XQQAUWFZBOTKFQ-MHRNPJSASA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 102000004452 Arginase Human genes 0.000 description 1
- 108700024123 Arginases Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- IIPCKBQYWCDXLT-UHFFFAOYSA-N C=N.C=N.C=N.C=N.CC1(C(=O)O)CC(C(=O)O)=CC=C1 Chemical compound C=N.C=N.C=N.C=N.CC1(C(=O)O)CC(C(=O)O)=CC=C1 IIPCKBQYWCDXLT-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- BQCLJECBJVWSES-UHFFFAOYSA-N acetyl chloride;hydrochloride Chemical compound Cl.CC(Cl)=O BQCLJECBJVWSES-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- HNPPKZRZKDKXDO-UHFFFAOYSA-N n,n-dimethylformamide;propan-2-one Chemical compound CC(C)=O.CN(C)C=O HNPPKZRZKDKXDO-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Images
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- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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, contain the preparation method of this cefepime hydrochloride compound prepared pharmaceutical composition and this pharmaceutical composition.
Background technology
In the prior art, there are two kinds of forms in cefepime Hydrochloride, and a kind of is the 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 is semi-synthetic cynnematin of the 4th generation.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 that enterobacter, Pseudomonas aeruginosa, hemophilus, Neisseria gonorrhoeae genus, staphylococcus and suis (except faecalis) have stronger anti-microbial activity.Stable to beta lactamase, clinical various severe infections such as respiratory tract infection, urinary system infection, biliary tract infection, the septicemia etc. of being mainly used in.
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 intermediate compound I 2-methoxyimino-2-(thiazolamine-4-yl) acetyl chloride hydrochloride; The silanization 7-amino-cephalosporanic acid is mixed with silanization N-crassitude, reaction in the presence of Iodotrimethylsilane, Virahol, aqueous solution of hydrogen iodide, 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 methylene dichloride, adds successively the reaction of trimethylchlorosilane and hexamethyldisilazane, add again the reaction of intermediate compound I and triethylamine and make cefepime Hydrochloride.
CN 102408440A discloses a kind of synthetic method of cefepime Hydrochloride, its step is as follows: with (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 adjusting pH value is 5.5～7.5, under heat-retaining condition, carry out acylation reaction; Reaction extracts after finishing, and organic phase reclaims by underpressure distillation; Regulate the pH value of water with hydrochloric acid after, crystallization makes cefepime Hydrochloride.The present invention's reaction is gentle, be 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 and is higher than 99.5%.
CN 101638412A discloses the cefepime hydrochloride compound prepared of a kind of novel synthesis, first with 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, take Tosyl chloride as catalyzer, stirring reaction makes cefepime Hydrochloride.
CN 102675345A discloses a kind of preparation method of cefepime Hydrochloride, the method is to add hmds and Iodotrimethylsilane among the 7-ACA at 55 ℃ of lower vacuum back-flow 12h, the cooling dilution, add N-Methyl pyrrolidone and Iodotrimethylsilane at 40 ℃ of lower reaction 23h, the aftertreatment recrystallization obtains 7-ACMPHCl, be dissolved in the solvent at 0-5 ℃ of lower 7-ACMPHCl, repeatedly add on a small quantity 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester and triethylamine, 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 storage under the 0-5 ℃ of condition, and is better cefepime hydrochloride compound prepared in order to obtain a kind of stability, special proposition the present invention.
Summary of the invention
The first purpose of the present invention is to provide a kind of cefepime hydrochloride compound prepared, and this is cefepime hydrochloride compound prepared to have better stability in storage.
The present invention's the second purpose is to provide a kind of above-mentioned cefepime hydrochloride compound prepared preparation method.
The 3rd purpose of the present invention is to provide a kind of above-mentioned cefepime hydrochloride compound prepared pharmaceutical composition that contains.
The 4th purpose of the present invention is to provide a kind of preparation method of described pharmaceutical composition.
In order to realize the foregoing invention purpose, 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, the same compound, its intramolecule arrangement mode is different, cause its lattice energy different, thereby lattice causes its physicals also different to the difference of the binding force size of molecule, for example stability, dissolution rate, solubleness, water absorbability etc.
Cefepime hydrochloride compound prepared X-RD provided by the invention is different from 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.Cefepime hydrochloride compound prepared comparing with the cefepime Hydrochloride of prior art provided by the invention has higher lattice energy, and its lattice is bound stronger to the cefepime Hydrochloride molecule, thereby has improved cefepime hydrochloride compound prepared stability.The contriver is by stability experiment, and the result shows provided by the present invention cefepime hydrochloride compound preparedly compare with the cefepime Hydrochloride of prior art, has stronger stability in storage, and this has greatly improved patient's drug safety.
Described cefepime hydrochloride compound prepared preparation method comprises: get the 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, is stirred to whole dissolvings, regulate pH to 1.5-2.0, be heated to 40～60 ℃, slowly add ether again under agitation condition, the volume of the ether of adding and the volume ratio of DMF are 2-3:5, continue to stir 20-30min, add gac, whip attachment is filtered the decarburization degerming again, obtain settled solution, settled solution is moved in the reactor, behind 130～150 ℃ of lower placement 24～36h, leave standstill, naturally be cooled to 55～75 ℃, open reactor, slowly drip acetone and be cooled to 0～5 ℃, the consumption of acetone is 5-8 times of DMF, filter, washing, drying under reduced pressure namely gets the white micro-crystals powder.
In order to obtain a kind of cefepime Hydrochloride that is different from the solid form of cefepime Hydrochloride of the prior art, the 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 obtained 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.
Among the described cefepime hydrochloride compound prepared preparation method, the mixing speed when dripping acetone is 15～25rmp.
Described adding decolorizing with activated carbon is this area common technology means, can process referring to any decolouring, those skilled in the art need not to pay any creative work, can carry out appropriate selection according to the prior art of himself grasping, and realize the object of the invention.
Among the 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.
Among the described cefepime hydrochloride compound prepared preparation method, the particle diameter of the white micro-crystals powder that obtains 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 improved the stability in storage that contains cefepime hydrochloride compound prepared pharmaceutical composition, compare 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, such 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 when preparation cefepime dihydrochloride for injection composition, need to add arginine as solubility promoter and stablizer, so that said composition can be dissolved in the water for injection in setting time in use.In addition, add arginic consumption in the sterile powder injection provided by the invention, can regulate the pH value of aseptic cefepime Hydrochloride, make its pH value be in the Human Tolerance scope, and the clarity of prepared cefepime hydrochloride powder injection after redissolution and stable better.
The present invention also provides a kind of preparation method of described pharmaceutical composition, may further comprise the steps:
(1) gets the 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, is stirred to whole dissolvings, regulate pH to 1.5-2.0, be heated to 40～60 ℃, slowly add ether again under agitation condition, the volume of the ether of adding and the volume ratio of DMF are 2-3:5, continue to stir 20-30min, add gac, whip attachment is filtered the decarburization degerming again, obtain settled solution, settled solution is moved in the reactor, behind 130～150 ℃ of lower placement 24～36h, leave standstill, naturally be cooled to 55～75 ℃, open reactor, slowly drip acetone and be cooled to 0～5 ℃, the consumption of acetone is 5-8 times of DMF, filter, washing, drying under reduced pressure namely gets the white micro-crystals powder;
(2) the white micro-crystals powder and the pharmaceutically acceptable carrier that step (1) are obtained are made pharmaceutical composition.
Among the preparation method of described pharmaceutical composition, in the described step (1), the particle diameter of the white micro-crystals powder that obtains is 75～150 μ m.
Among the preparation method of described pharmaceutical composition, in the described step (2), mix white micro-crystals powder and pharmaceutically acceptable carrier rear by the aseptic subpackaged sterile powder injection of making.
Among the present invention, described sterile powder injection can adopt the preparation method of prior art, and those skilled in the art need not to pay any creative work, can carry out appropriate selection according to the prior art of himself grasping, and realizes the object of the invention.
Compared with prior art, cefepime hydrochloride compound prepared and pharmaceutical composition provided by the invention has following advantage:
(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.
Description of drawings
Fig. 1 is the cefepime hydrochloride compound prepared X-powdery diffractometry spectrogram of the embodiment of the invention 1 preparation.
Embodiment
Below with embodiment technical scheme of the present invention is further described; to help the advantage 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 the 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 ℃, under agitation condition, slowly add again ether, the volume of the ether that adds and the volume ratio of DMF are 2:5, continue to stir 20min, add gac again, the amount that adds gac is the 0.2%g/ml of liquid cumulative volume, stir 30min, filter the decarburization degerming, obtain settled solution, settled solution is moved in the reactor, behind 130 ℃ of lower placement 36h, leave standstill, naturally be cooled to 55 ℃, open reactor, slowly drip acetone and be cooled to 5 ℃, the consumption of acetone is 8 times of DMF, and the mixing speed when dripping acetone is 25rmp, filter, with washing with acetone 3 times, drying under reduced pressure namely gets the white micro-crystals powder.Yield 72.2%, HPLC content 99.88%.Particle diameter is 75～150 μ m.
The X-ray powder diffraction spectrogram that uses the Cu-K alpha-ray to measure is shown as Fig. 1.
Embodiment 2
Described cefepime hydrochloride compound prepared preparation method:
Get the 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 ℃, under agitation condition, slowly add again ether, the volume of the ether that adds and the volume ratio of DMF are 3:5, continue to stir 30min, add gac again, the amount that adds gac is the 0.3%g/ml of liquid cumulative volume, whip attachment 30min filters the decarburization degerming, obtains settled solution, settled solution is moved in the reactor, behind 150 ℃ of lower placement 24h, leave standstill, naturally be cooled to 75 ℃, open reactor, slowly drip acetone and be cooled to 0 ℃, the consumption of acetone is 5 times of DMF, and the mixing speed when dripping acetone is 15rmp, filter, with washing with acetone 3 times, drying under reduced pressure namely gets the 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 the Cu-K alpha-ray to measure is consistent with the result of embodiment 1.
Embodiment 3
The preparation of cefepime Hydrochloride sterile powder injection:
Take by weighing cefepime Hydrochloride 80g, the arginase 12 0g of embodiment 1 preparation under aseptic condition, place solid powder mixer evenly to mix, the gained raw material changes the sterile preparation workshop over to, the delicate metering packing, every bottle of hydrochloric cefepime 0.25g jumps a queue, rolls lid, finished product packing warehouse-in and censorship.
Embodiment 4
The preparation of cefepime Hydrochloride sterile powder injection:
Take by weighing cefepime Hydrochloride 90g, the arginine 10g of embodiment 1 preparation under aseptic condition, place solid powder mixer evenly to mix, the gained raw material changes the sterile preparation workshop over to, the delicate metering packing, every bottle of hydrochloric cefepime 0.5g jumps a queue, rolls lid, finished product packing warehouse-in and censorship.
Embodiment 5
The preparation of cefepime Hydrochloride sterile powder injection:
Take by weighing cefepime Hydrochloride 95g, the arginine 5g of embodiment 1 preparation under aseptic condition, place solid powder mixer evenly to mix, the gained raw material changes the sterile preparation workshop over to, the delicate metering packing, every bottle of hydrochloric cefepime 0.75g jumps a queue, rolls lid, finished product packing warehouse-in and 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 appendix VIII P of Chinese Pharmacopoeia residual solvent assay method, appendix 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 | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 2 products | Up to specification | Up to specification | Up to specification | Up to specification |
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 appendix XIX C of Chinese Pharmacopoeia medicine stability test governing principle, and the 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 invention 1;
Sample 2 is the product of the embodiment of the invention 2;
Sample 3 is that HPLC is 99.78% with reference to the cefepime Hydrochloride of CN 102675345A embodiment 1 preparation;
Sample 4, originates from Shanghai to visit Lik-Sang thing Science and Technology Ltd. not with the cefepime Hydrochloride of crystal water for commercially available, and HPLC is 99.95%;
Accelerated test by this experimental example and test of long duration as can be known, 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. cefepime hydrochloride compound prepared preparation method claimed in claim 1, it is characterized in that, described preparation method comprises: get the 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, is stirred to whole dissolvings, regulate pH to 1.5-2.0, be heated to 40～60 ℃, slowly add ether again under agitation condition, the volume of the ether of adding and the volume ratio of DMF are 2-3:5, continue to stir 20-30min, add gac, whip attachment is filtered the decarburization degerming again, obtain settled solution, settled solution is moved in the reactor, behind 130～150 ℃ of lower placement 24～36h, leave standstill, naturally be cooled to 55～75 ℃, open reactor, slowly drip acetone and be cooled to 0～5 ℃, the consumption of acetone is 5-8 times of DMF, filter, washing, drying under reduced pressure namely gets the 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. the preparation method of a composition claimed in claim 3 is characterized in that, may further comprise the steps:(1) gets the 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, is stirred to whole dissolvings, regulate pH to 1.5-2.0, be heated to 40～60 ℃, slowly add ether again under agitation condition, the volume of the ether of adding and the volume ratio of DMF are 2-3:5, continue to stir 20-30min, add gac, whip attachment is filtered the decarburization degerming again, obtain settled solution, settled solution is moved in the reactor, behind 130～150 ℃ of lower placement 24～36h, leave standstill, naturally be cooled to 55～75 ℃, open reactor, slowly drip acetone and be cooled to 0～5 ℃, the consumption of acetone is 5-8 times of DMF, filter, washing, drying under reduced pressure namely gets the 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 the described step (2), mixes white micro-crystals powder and pharmaceutically acceptable carrier rear by the aseptic subpackaged sterile powder injection of making.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804396A (en) * | 2013-12-20 | 2014-05-21 | 悦康药业集团有限公司 | Cefepime dihydrochloride compound |
| CN108165511A (en) * | 2018-01-22 | 2018-06-15 | 四川农业大学 | A kind of screening and culturing medium and preparation method and application and the screening and culturing method of microorganism |
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| 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 |
| WO2006109324A2 (en) * | 2005-04-13 | 2006-10-19 | Lupin Limited | 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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2013
- 2013-06-09 CN CN201310229537.0A patent/CN103304580B/en not_active Expired - Fee Related
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 |
| WO2006109324A2 (en) * | 2005-04-13 | 2006-10-19 | Lupin Limited | 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804396A (en) * | 2013-12-20 | 2014-05-21 | 悦康药业集团有限公司 | Cefepime dihydrochloride compound |
| CN103804396B (en) * | 2013-12-20 | 2016-01-27 | 悦康药业集团有限公司 | A kind of cefepime hydrochloride compound prepared |
| CN108165511A (en) * | 2018-01-22 | 2018-06-15 | 四川农业大学 | A kind of screening and culturing medium and preparation method and application and the screening and culturing method of microorganism |
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