CN103265561A - Azlocillin sodium compound, preparation method and medicine composition thereof - Google Patents
Azlocillin sodium compound, preparation method and medicine composition thereof Download PDFInfo
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- CN103265561A CN103265561A CN2013102293996A CN201310229399A CN103265561A CN 103265561 A CN103265561 A CN 103265561A CN 2013102293996 A CN2013102293996 A CN 2013102293996A CN 201310229399 A CN201310229399 A CN 201310229399A CN 103265561 A CN103265561 A CN 103265561A
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- azlocillin
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- azlocillin sodium
- sodium compound
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- NRSJYUSYBNFGAK-UHFFFAOYSA-N 3-bromo-4-propan-2-yloxybenzoic acid Chemical compound CC(C)OC1=CC=C(C(O)=O)C=C1Br NRSJYUSYBNFGAK-UHFFFAOYSA-N 0.000 title claims abstract description 87
- 229960003200 azlocillin sodium Drugs 0.000 title claims abstract description 87
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 239000003814 drug Substances 0.000 title claims abstract description 17
- 239000000203 mixture Substances 0.000 title claims abstract description 5
- 239000000843 powder Substances 0.000 claims abstract description 42
- 238000002347 injection Methods 0.000 claims abstract description 20
- 239000007924 injection Substances 0.000 claims abstract description 20
- 229940079593 drug Drugs 0.000 claims abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 6
- 229910017488 Cu K Inorganic materials 0.000 claims abstract description 5
- 229910017541 Cu-K Inorganic materials 0.000 claims abstract description 5
- 230000005260 alpha ray Effects 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 239000000243 solution Substances 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- 239000012046 mixed solvent Substances 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 16
- 238000004108 freeze drying Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000013081 microcrystal Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
- 229960003623 azlocillin Drugs 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 238000009413 insulation Methods 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 7
- 230000003647 oxidation Effects 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 150000003388 sodium compounds Chemical class 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 229920002307 Dextran Polymers 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 235000015424 sodium Nutrition 0.000 claims description 2
- 238000003860 storage Methods 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 4
- 239000002552 dosage form Substances 0.000 abstract 1
- 238000005259 measurement Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 235000014347 soups Nutrition 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 8
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 7
- 235000010234 sodium benzoate Nutrition 0.000 description 7
- 239000004299 sodium benzoate Substances 0.000 description 7
- 230000001186 cumulative effect Effects 0.000 description 6
- 239000000890 drug combination Substances 0.000 description 6
- 238000012856 packing Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
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- 239000008215 water for injection Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 229960003311 ampicillin trihydrate Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
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- 238000005516 engineering process Methods 0.000 description 2
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- 239000012074 organic phase Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- -1 2-oxo-1-imidazolidyl Chemical group 0.000 description 1
- 206010051548 Burn infection Diseases 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010067268 Post procedural infection Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
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- 239000012296 anti-solvent Substances 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
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- 206010014665 endocarditis Diseases 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
- 206010033072 otitis externa Diseases 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- BNRLJJXPMKKGJR-UHFFFAOYSA-M sodium;2-methylheptanoate Chemical compound [Na+].CCCCCC(C)C([O-])=O BNRLJJXPMKKGJR-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to an azlocillin sodium compound. The structural formula of the azlocillin sodium compound is defined in the specification, and the X-ray powder diffraction spectrogram of the azlocillin sodium compound, which is obtained by measurement by using Cu-K alpha ray, is shown in the figure 1. The invention further provides a preparation method of the azlocillin sodium compound, a medicine composition containing the azlocillin sodium compound, and a preparation method of the medicine composition. The dosage forms of the azlocillin sodium compound are sterile powder injection and freeze-dried powder injection. The azlocillin sodium compound provided by the invention almost does not absorb moisture, is easy to store and has good storage stability and low impurity content; and therefore, medication safety is greatly improved.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to a kind of azlocillin sodium compound, its preparation method, contain pharmaceutical composition and this preparation of drug combination method of this azlocillin sodium compound.
Background technology
Azlocillin sodium, English name: Azlocillin Sodium, CAS:37091-65-9, molecular formula: C
20H
22N
5NaO
6S, chemical name (2S, 5R, 6R)-3, and 3-dimethyl-6-[[[[(2-oxo-1-imidazolidyl) carbonyl] amino] phenyl acetyl] amino]-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium salt.
Azlocillin sodium is Penicillin antibiotics, third generation wide spectrum semisynthetic penicillin, be applicable to the gram-negative bacteria for the treatment of sensitivity and the various infection due to the positive bacteria, and charrin's disease, comprise septicemia, meningitis, endocarditis, purulent pleurisy, peritonitis and lower respiratory tract, gi tract, biliary tract, kidney and ureter, bone and soft tissue and reproductive organ infection, gynaecology, obstetrics' infection, external otitis, burn, skin and postoperative infection.
CN101265265A discloses a kind of method for preparing the high purity azlocillin sodium, and the method for preparing the azlocillin sodium injection.Method comprises the steps: that (1) dissolve the azlocillin sodium crude product with purified water, adds the PH conditioning agent solution pH value is transferred to acidity; (2) extract with organic solvent, separate organic phase, reclaim under reduced pressure after the organic phase usefulness siccative drying is got the upper prop product to doing; (3) with the filler of aluminum oxide as the medium pressure chromatography post, be eluent with the mixed solution of hydrocarbon solvent and chlorinated solvents, the upper prop product are with eluent dissolving back feed liquor, the flow point Fractional Collections behind the wash-out; (4) merge the azlocillin acid content more than or equal to 80% flow point, add dissolve with ethanol behind the concentrating under reduced pressure, separate out precipitation after adding the alkali alkalization; (5) precipitation is used ethyl alcohol recrystallization, and crystallisate namely gets the high purity azlocillin sodium through lyophilize.
CN1778804A discloses a kind of crystalline azlocillin sodium and preparation method thereof, this crystallization is on differential scanning calorimeter and X-ray powder diffraction pattern, show the characteristic described in specification sheets, the easy easy control of this preparation method, preparation cost are cheap, production cycle is shorter, the crystalline azlocillin sodium that obtains is more stable than the amorphous powder that lyophilization obtains, and purity is good.
CN102311450A discloses a kind of Preparation of Azlocillin sodium method, belongs to the antibiotics synthesis technical field.The step that comprises: preparation condensation reaction solution, earlier with in the methylene dichloride suction retort, under agitation in retort, drop into the Ampicillin Trihydrate again, the weight ratio of control methylene dichloride and Ampicillin Trihydrate, lower the temperature then and control cooling temperature, then regulate pH to weakly alkaline with pH value conditioning agent, obtain condensation reaction solution; Condensation reaction; Extracting and separating; Crystallization; Dry; Salt-forming reaction; Decolouring; Lyophilize; Pulverize.Advantage: both simplified operations and reduce the use of chemical solvents, can reduce the risk of environmental pollution again; Not only easy and simple to handle, and can avoid effectively because chromatography causes loss, the yield of azlocillin sodium improved; The salt-forming reaction mild condition has reduced the risk that azlocillin sodium is met alkaline degradation, and single impurity＜0.6% of the azlocillin dry product that obtains, and total impurities＜1% significantly is better than standards of pharmacopoeia.
Azlocillin sodium of the prior art have draw moist, the long-time storage, the outward appearance of azlocillin sodium gradually becomes flaxen bulk by the white loose powder, related substance increases, and in order to obtain a kind of azlocillin sodium of more excellent performance, specially proposes the present invention.
Summary of the invention
First purpose of the present invention is to provide a kind of azlocillin sodium compound, and described azlocillin sodium compound is difficult for moisture absorption, is easy to store, and has better stability in storage, and foreign matter content is few, has improved drug safety greatly.
The preparation method of the azlocillin sodium compound that second purpose of the present invention is to provide above-mentioned.
The 3rd purpose of the present invention is to provide a kind of pharmaceutical composition that contains above-mentioned azlocillin sodium compound.
The 4th purpose of the present invention is to provide the preparation method of aforementioned pharmaceutical compositions.
To achieve these goals, the spy is by the following technical solutions:
A kind of azlocillin sodium compound, the structural formula of described azlocillin sodium compound is:
The X-ray powder diffraction spectrogram that described azlocillin sodium compound use Cu-K alpha-ray measures as shown in Figure 1.
The solid inner molecular arrangement mode that compound is different, cause its lattice energy difference, the difference in size of lattice energy has reflected lattice varying in size to the binding force of molecule, this means that the physicals when compound is in different crystal forms is also different, the dissolution rate when being in different crystal forms as compound, stability, solubleness, draw that moist also each is variant.According in this, the contriver attempts the structure by the solid interior molecular arrangement that changes the azlocillin sodium compound, thereby improves the physicochemical property of azlocillin sodium compound, in the hope of obtaining the better azlocillin of a kind of physicochemical property sodium compound.
Drawing of the azlocillin sodium of contriver by water absorbability experiment azlocillin sodium more provided by the invention and prior art is moist, the result shows that azlocillin provided by the present invention sodium compound compares with the azlocillin sodium of prior art, be difficult for moisture absorption, be easy to store, has better stability in storage, improve patient's drug safety greatly, also solved the moist problem of drawing of azlocillin sodium product in the market.
The preparation method of a kind of described azlocillin sodium compound, described preparation method comprises: with N, dinethylformamide and ethanol are mixed with mixed solvent with the volume ratio of 3-5:1, get the azlocillin sodium bulk drug, add N, dinethylformamide and ethanol mixed solvent are heated to 50-65 ℃, be stirred to whole dissolvings, the pH of solution is transferred to 6.0～7.0, and insulation is carried out magnetic treatment with solution, add decolorizing with activated carbon in the solution of handling, filter, obtain settled solution, slowly in settled solution, adding ethyl acetate under the stirring condition, ethyl acetate and volume ratio mixed solvent are 4-6:1, filter, obtain filter cake, use the washing with acetone filter cake, drying under reduced pressure 2～4h namely gets the white micro-crystals powder again.
Among the preparation method of described azlocillin sodium compound, described magnetic treatment is: solution is flowed through the direct magnetic field of 0.5T with the speed of 7～15m/s, and field direction is vertical with the flow of solution direction.
Among the preparation method of described azlocillin sodium compound, the stir speed (S.S.) when dripping ethyl acetate is 8-15rpm.
Among the preparation method of described azlocillin sodium compound, the particle diameter of the white micro-crystals powder that obtains is 75～150 μ m.
The present inventor is through repeatedly experiment, be raw material with commercially available azlocillin sodium crude product, constantly change crystallization method and comprise crystallization conditions such as pressure, temperature, solvent, pH, anti-solvent, finally obtained a kind of brand-new azlocillin sodium compound by recrystallization, its X-RD spectrogram shows that the solid interior molecule arranging structure of azlocillin provided by the invention sodium compound is different with azlocillin sodium of the prior art.
Described adding decolorizing with activated carbon is this area common technology means, can handle 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 present invention, preferred, the amount that adds gac is the 0.2-0.3%g/ml of soup cumulative volume.
The present invention also provides a kind of pharmaceutical composition that contains described azlocillin sodium compound.
The present invention is by changing the solid structure of azlocillin sodium compound, the azlocillin sodium compound that obtains is difficult for moisture absorption, be easy to store, has better stability in storage, be difficult for moisture absorption with this azlocillin sodium at the pharmaceutical composition that is mixed and made into other medicines activeconstituents or pharmaceutically acceptable carrier, stability in storage is good, has greatly improved patient's drug safety.
Pharmaceutical composition of the present invention can be prepared into various formulations, and as liquid preparation, solid preparation, preferred, described pharmaceutical composition is sterile powder injection and lyophilized injectable powder.
Preferably, by weight, described sterile powder injection comprises azlocillin sodium 99.5-99.9 part, oxidation inhibitor 0.5-0.1 part.
Preferred, by weight, described sterile powder injection comprises azlocillin sodium 99.8-99.9 part, oxidation inhibitor 0.2-0.1 part.
Preferably, described oxidation inhibitor comprises one or more in Sodium Benzoate, xitix, the S-WAT, is preferably Sodium Benzoate.
Preferably, by weight, described lyophilized injectable powder comprises 100 parts of azlocillin sodiums, freeze-drying propping agent 5-15 part.
Preferably, described freeze-drying propping agent comprises one or more in N.F,USP MANNITOL, sorbyl alcohol, glucose, the dextran.
The present invention also provides a kind of described preparation of drug combination method, may further comprise the steps:
(1) described preparation method comprises: with N, dinethylformamide and ethanol are mixed with mixed solvent with the volume ratio of 3-5:1, get the azlocillin sodium bulk drug, add N, dinethylformamide and ethanol mixed solvent, be heated to 50-65 ℃, be stirred to whole dissolvings, the pH of solution is transferred to 6.0～7.0, insulation, solution is carried out magnetic treatment, add decolorizing with activated carbon in the solution of handling, filter, obtain settled solution, slowly adding ethyl acetate under the stirring condition in settled solution, ethyl acetate and volume ratio mixed solvent are 4-6:1, filter, obtain filter cake, use the washing with acetone filter cake, drying under reduced pressure 2～4h namely gets the white micro-crystals powder again;
(2) white micro-crystals powder and the pharmaceutically acceptable carrier that step (1) is obtained made pharmaceutical composition.
In the described preparation of drug combination method, in the described step (1), described magnetic treatment is: solution is flowed through the direct magnetic field of 0.5T with the speed of 7～15m/s, and field direction is vertical with the flow of solution direction.
In the described preparation of drug combination method, in the described step (1), the stir speed (S.S.) when dripping ethyl acetate is 8-15rpm.
In the described preparation of drug combination method, in the described step (1), the particle diameter of the white micro-crystals powder that obtains is 75～150 μ m.
In the described preparation of drug combination method, in the described step (2), white micro-crystals powder and oxidation inhibitor are mixed the back by the aseptic subpackaged sterile powder injection of making, or white micro-crystals powder and freeze-drying propping agent are made lyophilized injectable powder by lyophilize.
Described oxidation inhibitor comprises one or more in Sodium Benzoate, xitix, the S-WAT, is preferably Sodium Benzoate; Described freeze-drying propping agent comprises one or more in N.F,USP MANNITOL, sorbyl alcohol, glucose, the dextran.
Among the present invention, described sterile powder injection and lyophilized injectable powder all can adopt the preparation method of prior art, 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.
Compared with prior art, azlocillin sodium compound provided by the invention and pharmaceutical composition thereof have following advantage:
(1) azlocillin of the present invention sodium compound is difficult for moisture absorption, is easy to store, and has better stability in storage;
(2) pharmaceutical composition that contains azlocillin sodium of the present invention is difficult for moisture absorption, and stability in storage is good, has greatly improved patient's drug safety.
Description of drawings
Fig. 1 is the X-powdery diffractometry spectrogram of the azlocillin sodium compound 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
The preparation method of azlocillin sodium compound:
With N, dinethylformamide and ethanol are mixed with mixed solvent with the volume ratio of 5:1, get the azlocillin sodium bulk drug, add N, dinethylformamide and ethanol mixed solvent, be heated to 50 ℃, be stirred to whole dissolvings, the pH of solution is transferred to 6.0, insulation, solution is carried out magnetic treatment, and described magnetic treatment is: solution is flowed through the direct magnetic field of 0.5T with the speed of 7m/s, and field direction is vertical with the flow of solution direction.Add decolorizing with activated carbon in the solution of handling, the amount that adds gac is the 0.2%g/ml of soup cumulative volume, stirs 30min, filter, obtain settled solution, slowly adding ethyl acetate under the stirring condition in settled solution, ethyl acetate and volume ratio mixed solvent are 4:1, stir speed (S.S.) when dripping ethyl acetate is 8rpm, filter, obtain filter cake, use washing with acetone filter cake 3 times, drying under reduced pressure 4h namely gets the white micro-crystals powder again.Yield 77.1%, HPLC content 99.93%.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
The preparation method of azlocillin sodium compound:
With N, dinethylformamide and ethanol are mixed with mixed solvent with the volume ratio of 3:1, get the azlocillin sodium bulk drug, add N, dinethylformamide and ethanol mixed solvent, be heated to 65 ℃, be stirred to whole dissolvings, the pH of solution is transferred to 7.0, insulation, solution is carried out magnetic treatment, and described magnetic treatment is: solution is flowed through the direct magnetic field of 0.5T with the speed of 15m/s, and field direction is vertical with the flow of solution direction.Add decolorizing with activated carbon in the solution of handling, the amount that adds gac is the 0.3%g/ml of soup cumulative volume, stirs 30min, filter, obtain settled solution, slowly adding ethyl acetate under the stirring condition in settled solution, ethyl acetate and volume ratio mixed solvent are 6:1, stir speed (S.S.) when dripping ethyl acetate is 15rpm, filter, obtain filter cake, use washing with acetone filter cake 3 times, drying under reduced pressure 2h namely gets the white micro-crystals powder again.Yield 76.3%, HPLC content 99.89%.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 azlocillin sodium sterile powder injection:
Take by weighing azlocillin sodium 99.5g, the Sodium Benzoate 0.5g of embodiment 1 preparation under aseptic condition, place the pressed powder mixing machine evenly to mix, the gained raw material changes the sterile preparation workshop over to, the delicate metering packing, every bottle contains azlocillin sodium 0.5g, jumps a queue, rolls lid, finished product packing warehouse-in and censorship.
Embodiment 4
The preparation of azlocillin sodium sterile powder injection:
Take by weighing azlocillin sodium 99.8g, the Sodium Benzoate 0.2g of embodiment 1 preparation under aseptic condition, place the pressed powder mixing machine evenly to mix, the gained raw material changes the sterile preparation workshop over to, the delicate metering packing, every bottle contains azlocillin sodium 2.0g, jumps a queue, rolls lid, finished product packing warehouse-in and censorship.
Embodiment 5
The preparation of azlocillin sodium sterile powder injection:
Take by weighing azlocillin sodium 99.9g, the Sodium Benzoate 0.1g of embodiment 1 preparation under aseptic condition, place the pressed powder mixing machine evenly to mix, the gained raw material changes the sterile preparation workshop over to, the delicate metering packing, every bottle contains azlocillin sodium 1.0g, jumps a queue, rolls lid, finished product packing warehouse-in and censorship.
Embodiment 6
The azlocillin sodium freeze-dried powder injection
Earlier 85% water for injection that adds the dosing total amount adds azlocillin sodium again in Agitation Tank, be stirred to dissolving fully after.The sorbyl alcohol that adds recipe quantity continues to stir to make to be dissolved into clear and bright solution.Regulate soup pH value to 6.0 with the sodium hydroxide solution of 1mol/L, replenish water for injection to full dose, evenly mixed.Add medicinal carbon, the amount of gac is the 0.3%g/ml of soup cumulative volume, and whip attachment 30min takes off charcoal, after the intermediate detection is qualified, and Sterile Filtration, be filled in the injection cillin bottle gained filtrate branch, and the false add plug is put into Freeze Drying Equipment and is carried out lyophilize.Lyophilize is divided into pre-freeze, primary drying and redrying three phases.Pre-freeze: shelf temperature was down to about-45 ℃ in about 1.5 hours, when treating that sample temperature reaches-35 ℃, is incubated 3 hours, insulation arranges shelf temperature and is-2 ℃ after finishing.Primary drying: condenser temperature is down to below-50 ℃, opens case trap valve, be evacuated to below the 10pa, heating shelf (about 1.5 hours) is warming up to-2 ± 1 ℃, is incubated to the ice crystal disappearance, is incubated 3 hours again.Redrying: shelf temperature was risen to 15 ± 1 ℃ fast in about 0.5 hour, and be incubated 1 hour; Shelf continues to be warming up to about 40 ℃, treats that sample temperature rises to 35 ℃ and plays timing, is incubated about 5 hours again.Check the vacuum tightness changing conditions, finish whole freeze-drying process, total head plug, outlet.
Embodiment 7
The azlocillin sodium freeze-dried powder injection
Earlier 85% water for injection that adds the dosing total amount adds azlocillin sodium again in Agitation Tank, be stirred to dissolving fully after.The N.F,USP MANNITOL that adds recipe quantity continues to stir to make to be dissolved into clear and bright solution.Regulate soup pH value to 6.0 with the sodium hydroxide solution of 1mol/L, replenish water for injection to full dose, evenly mixed.Add medicinal carbon, the amount of gac is the 0.2%g/ml of soup cumulative volume, and whip attachment 30min takes off charcoal, after the intermediate detection is qualified, and Sterile Filtration, be filled in the injection cillin bottle gained filtrate branch, and the false add plug is put into Freeze Drying Equipment and is carried out lyophilize.Lyophilize is divided into pre-freeze, primary drying and redrying three phases.Pre-freeze: shelf temperature was down to about-45 ℃ in about 1.5 hours, when treating that sample temperature reaches-35 ℃, is incubated 3 hours, insulation arranges shelf temperature and is-2 ℃ after finishing.Primary drying: condenser temperature is down to below-50 ℃, opens case trap valve, be evacuated to below the 10pa, heating shelf (about 1.5 hours) is warming up to-2 ± 1 ℃, is incubated to the ice crystal disappearance, is incubated 3 hours again.Redrying: shelf temperature was risen to 15 ± 1 ℃ fast in about 0.5 hour, and be incubated 1 hour; Shelf continues to be warming up to about 40 ℃, treats that sample temperature rises to 35 ℃ and plays timing, is incubated about 5 hours again.Check the vacuum tightness changing conditions, finish whole freeze-drying process, total head plug, outlet.
Embodiment 8
The azlocillin sodium freeze-dried powder injection
Earlier 85% water for injection that adds the dosing total amount adds azlocillin sodium again in Agitation Tank, be stirred to dissolving fully after.The glucose that adds recipe quantity continues to stir to make to be dissolved into clear and bright solution.Regulate soup pH value to 7.0 with the sodium hydroxide solution of 1mol/L, replenish water for injection to full dose, evenly mixed.Add medicinal carbon, the amount of gac is the 0.3%g/ml of soup cumulative volume, and whip attachment 30min takes off charcoal, after the intermediate detection is qualified, and Sterile Filtration, be filled in the injection cillin bottle gained filtrate branch, and the false add plug is put into Freeze Drying Equipment and is carried out lyophilize.Lyophilize is divided into pre-freeze, primary drying and redrying three phases.Pre-freeze: shelf temperature was down to about-45 ℃ in about 1.5 hours, when treating that sample temperature reaches-35 ℃, is incubated 3 hours, insulation arranges shelf temperature and is-2 ℃ after finishing.Primary drying: condenser temperature is down to below-50 ℃, opens case trap valve, be evacuated to below the 10pa, heating shelf (about 1.5 hours) is warming up to-2 ± 1 ℃, is incubated to the ice crystal disappearance, is incubated 3 hours again.Redrying: shelf temperature was risen to 15 ± 1 ℃ fast in about 0.5 hour, and be incubated 1 hour; Shelf continues to be warming up to about 40 ℃, treats that sample temperature rises to 35 ℃ and plays timing, is incubated about 5 hours again.Check the vacuum tightness changing conditions, finish whole freeze-drying process, total head plug, outlet.
Experimental example 1
This test example detects related substance in the prepared azlocillin sodium of embodiment 1～2, and 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 2 related substance
| Preparation | N, dinethylformamide | Ethanol | Ethyl acetate | 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
Draw moist test: this test example has been investigated the water absorbability of azlocillin sodium provided by the invention.
Under the condition of humidity 80% and 90%, each sample thief 1g places on the electronic balance this test example respectively, and time recording weight is to detect the moisture absorption degree.
Table 2 draws moist test-results
Wherein: sample 1 is embodiment 1 product;
Sample 2 is embodiment 2 products;
Sample 3 is that HPLC content is 99.89% with reference to the azlocillin sodium of CN101265265A embodiment 1 preparation;
Sample 4 is commercially available azlocillin sodium, originates from Shanghai Ya Ji bio tech ltd, and HPLC content is 98.65%.
Above-mentionedly draw moist test and show that the prepared azlocillin sodium of the present invention is difficult for moisture absorption, good stability.
Claims (10)
1. an azlocillin sodium compound is characterized in that, the structural formula of described azlocillin sodium compound is:
The X-ray powder diffraction spectrogram that described azlocillin sodium compound use Cu-K alpha-ray measures as shown in Figure 1.
2. the preparation method of the described azlocillin of claim 1 sodium compound, it is characterized in that, described preparation method comprises: with N, dinethylformamide and ethanol are mixed with mixed solvent with the volume ratio of 3-5:1, get the azlocillin sodium bulk drug, add N, dinethylformamide and ethanol mixed solvent, be heated to 50-65 ℃, be stirred to whole dissolvings, the pH of solution is transferred to 6.0～7.0, insulation, solution is carried out magnetic treatment, add decolorizing with activated carbon in the solution of handling, filter, obtain settled solution, slowly adding ethyl acetate under the stirring condition in settled solution, ethyl acetate and volume ratio mixed solvent are 4-6:1, filter, obtain filter cake, use the washing with acetone filter cake, drying under reduced pressure 2～4h namely gets the white micro-crystals powder again.
3. preparation method according to claim 2 is characterized in that, described magnetic treatment is: solution is flowed through the direct magnetic field of 0.5T with the speed of 7～15m/s, and field direction is vertical with the flow of solution direction.
4. the preparation method of azlocillin according to claim 2 sodium compound is characterized in that, the stir speed (S.S.) when dripping ethyl acetate is 8-15rpm.
5. pharmaceutical composition that contains the described azlocillin of claim 1 sodium compound.
6. pharmaceutical composition according to claim 5 is characterized in that, described pharmaceutical composition is sterile powder injection and lyophilized injectable powder.
7. pharmaceutical composition according to claim 6 is characterized in that, by weight, described sterile powder injection comprises azlocillin sodium 99.5-99.9 part, oxidation inhibitor 0.5-0.1 part.
8. pharmaceutical composition according to claim 6 is characterized in that, by weight, described lyophilized injectable powder comprises 100 parts of azlocillin sodiums, freeze-drying propping agent 5-15 part; Described freeze-drying propping agent comprises one or more in N.F,USP MANNITOL, sorbyl alcohol, glucose, the dextran.
9. the described preparation of compositions method of claim 5 is characterized in that, may further comprise the steps:
(1) described preparation method comprises: with N, dinethylformamide and ethanol are mixed with mixed solvent with the volume ratio of 3-5:1, get the azlocillin sodium bulk drug, add N, dinethylformamide and ethanol mixed solvent, be heated to 50-65 ℃, be stirred to whole dissolvings, the pH of solution is transferred to 6.0～7.0, insulation, solution is carried out magnetic treatment, add decolorizing with activated carbon in the solution of handling, filter, obtain settled solution, slowly adding ethyl acetate under the stirring condition in settled solution, ethyl acetate and volume ratio mixed solvent are 4-6:1, filter, obtain filter cake, use the washing with acetone filter cake, drying under reduced pressure 2～4h namely gets the white micro-crystals powder again;
(2) white micro-crystals powder and the pharmaceutically acceptable carrier that step (1) is obtained made pharmaceutical composition.
10. preparation method according to claim 9, it is characterized in that, in the described step (2), white micro-crystals powder and oxidation inhibitor are mixed the back by the aseptic subpackaged sterile powder injection of making, or white micro-crystals powder and freeze-drying propping agent are made lyophilized injectable powder by lyophilize.
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