CN102766148A - Cefamandole nafate compound and composite thereof - Google Patents
Cefamandole nafate compound and composite thereof Download PDFInfo
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- CN102766148A CN102766148A CN2012102846006A CN201210284600A CN102766148A CN 102766148 A CN102766148 A CN 102766148A CN 2012102846006 A CN2012102846006 A CN 2012102846006A CN 201210284600 A CN201210284600 A CN 201210284600A CN 102766148 A CN102766148 A CN 102766148A
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- cefamandole nafate
- sodium
- ether
- nafate compounds
- solution
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- 229960002440 cefamandole nafate Drugs 0.000 title abstract description 19
- -1 Cefamandole nafate compound Chemical class 0.000 title abstract description 8
- 239000002131 composite material Substances 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 13
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 75
- 229910052708 sodium Inorganic materials 0.000 claims description 75
- 239000011734 sodium Substances 0.000 claims description 75
- 239000000243 solution Substances 0.000 claims description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 50
- RRJHESVQVSRQEX-SUYBPPKGSA-N O-formylcefamandole Chemical class CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](OC=O)C=3C=CC=CC=3)[C@H]2SC1 RRJHESVQVSRQEX-SUYBPPKGSA-N 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- ICZOIXFFVKYXOM-YCLOEFEOSA-M cefamandole nafate Chemical compound [Na+].CN1N=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)[C@H](OC=O)C=3C=CC=CC=3)[C@H]2SC1 ICZOIXFFVKYXOM-YCLOEFEOSA-M 0.000 claims description 32
- 238000002156 mixing Methods 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 32
- 239000000843 powder Substances 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 15
- 238000002347 injection Methods 0.000 claims description 14
- 239000007924 injection Substances 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 230000001133 acceleration Effects 0.000 claims description 7
- 230000002045 lasting effect Effects 0.000 claims description 7
- 238000003556 assay Methods 0.000 claims description 5
- 238000013019 agitation Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 239000013078 crystal Substances 0.000 description 17
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000004108 freeze drying Methods 0.000 description 9
- 108010024636 Glutathione Proteins 0.000 description 8
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 8
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 8
- 229960003180 glutathione Drugs 0.000 description 8
- 229960004194 lidocaine Drugs 0.000 description 8
- 235000013923 monosodium glutamate Nutrition 0.000 description 8
- 229940073490 sodium glutamate Drugs 0.000 description 8
- 239000000203 mixture Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 239000000470 constituent Substances 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000014347 soups Nutrition 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 210000004907 gland Anatomy 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 3
- 235000010234 sodium benzoate Nutrition 0.000 description 3
- 239000004299 sodium benzoate Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- JFPVXVDWJQMJEE-QMTHXVAHSA-N Cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)C(=NOC)C1=CC=CO1 JFPVXVDWJQMJEE-QMTHXVAHSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 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
- 230000002950 deficient Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 150000004686 pentahydrates Chemical class 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Images
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- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a cefamandole nafate compound and a composite thereof. The cefamandole nafate compound is detected by using a powder X-ray diffraction method, and an X-ray powder diffraction pattern indicated by a diffraction angle at 2 theta +-0.2 degrees shows characteristic diffraction peaks at 11.45 degrees, 13.63 degrees, 14.68 degrees, 15.69 degrees, 18.39 degrees, 20.30 degrees, 26.09 degrees, 27.11 degrees, 28.74 degrees, 30.27 degrees, 31.90 degrees, 34.01 degrees and 35.88 degrees. The cefamandole nafate compound and a preparation of the cefamandole nafate compound have good stability, and therefore curative effect of the preparation is improved, and effectiveness and safety of drugs are guaranteed.
Description
Technical field
The present invention relates to field of medicaments, specifically, relate to a kind of Cefamandole nafate compounds and compsn thereof.
Background technology
Mol is succeeded in developing by U.S. E.Lilly company at first, for one of representative drugs of second generation cephalosporin, except that tool Kefzol same function, also some gram positive organisms is had anti-microbial effect.Have characteristics such as few side effects, safe, determined curative effect.Be mainly used in the various infection due to the sensitive organism clinically, like infection such as respiratory tract infection, biliary tract infection, pyelonephritis, urinary tract infections, peritonitis, septicemia and skin soft tissue, bone, joints.Because urine drug level is high, and urinary tract infections is had efficiently.Sodium O-formylcefamole is the prodrug of Mol, and its anti-microbial activity is merely the 1/5-1/10 of Mol, and Sodium O-formylcefamole gets in the body and is hydrolyzed to Mol rapidly, so the two anti-microbial effect in vivo is basic identical.At present, how to process powder injection with Sodium O-formylcefamole with yellow soda ash clinically, because sodium carbonates' presence can discharge CO2 in the use, effective constituent is decomposed easily, and injection is unstable, influences result of use.
China application 201010257886.x discloses a kind of hydrate of Sodium O-formylcefamole, and the preparation method of this Cefamandole nafate hydrate may further comprise the steps: Sodium O-formylcefamole is used water dissolution, put into mold; Add the dissolved agent of 5～15 parts of weight, be cooled to 2～8 ℃, treat that solid separates out; Filter, solids is with dissolved agent rinse, and is dry under ventilation or vacuum condition; 3～5 hours time of drying, 10～50 ℃ of drying temperatures get said Cefamandole nafate hydrate.The Cefamandole nafate hydrate that the present invention obtains has specific crystal formation, contains 5 crystal water; The Cefamandole nafate hydrate good stability; Be prone to dissolving, and be dissolved in after the water, its mechanism of action is the same with the Sodium O-formylcefamole that existing technology makes with clinical efficacy.
Chinese patent ZL201010199235.x discloses a kind of Mandokef composition of sodium, and said composition comprises that mass percent is the Sodium Benzoate of 99.00%-99.90% Cefamandole nafate hydrate crystal and 0.1-1.00%, wherein; Described Cefamandole nafate hydrate crystalline molecular formula is C19H17N6NaO6S22.5H2O, and has main peaks at 6.9 °, 10.0 ° in the Cefamandole nafate hydrate crystalline X-ray powder diffraction; 11.3 °, 16.9 °, 17.2 °; 17.9 °, 19.0 °, 21.6 °; 22.0 °, 22.8 ° and 25.5 ° of diffraction angle demonstrations.
Though the Cefamandole nafate hydrate crystal that technique scheme provided has higher stability than the Sodium O-formylcefamole of prior art; But find in the actual production process; The unsettled defective of crystal water appears in crystal easily that have crystal water in follow-up preparation process; Because the crystal water in the raw material in case not exclusively lose or lose fully after influence the aspects such as dissulution, disintegration of product probably; In addition, if the Mandokef preparation of sodium has adopted the auxiliary material to water sensitive, also can form the microenvironment of drug reaction degraded; So the more commercially available Sodium O-formylcefamole of Cefamandole nafate hydrate itself or its crystal has better stability in earlier stage; As the China application Cefamandole nafate hydrate that 201010257886.x protected only in 10 days stability test stability be superior to prior art, but its stability significantly descends in test of long duration and accelerated test, possibly be to have grown easy appearance the time partly or completely to lose the phenomenon influence of crystal water stable.Therefore, but there is potential safety hazard all the time in the preparation that contains above-claimed cpd, unsuitable applying.
In sum, urgently be necessary to provide higher Sodium O-formylcefamole of a kind of stability and pharmaceutical prepn thereof, to satisfy demand at present.
Summary of the invention
It is a kind of not with the Cefamandole nafate compounds of crystal water that first purpose of the present invention is to provide, and makes this compound itself and preparation thereof have better stability, with the curative effect of further raising preparation, thus the validity and the security of assurance medicine.
In order to realize the foregoing invention purpose, the present invention takes following technical scheme:
The Cefamandole nafate compounds of a kind of formula (I); It is characterized in that; Described Cefamandole nafate compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle is represented at 11.45 °, 13.63 °, 14.68 °, 15.69 °, 18.39 °, 20.30 °, 26.09 °, 27.11 °, 28.74 °, 30.27 °, 31.90 °, 34.01 °, 35.88 °
Formula (I).
The present invention obtains a kind of brand-new Cefamandole nafate compounds through commercially available Mandokef sodium raw materials is carried out recrystallization, and this compound stability is significantly improved.
Said Cefamandole nafate compounds adopts following method to be prepared from:
(1) it is soluble in water to get the Sodium O-formylcefamole bullion, obtains the Mandokef sodium water solution;
(2) under agitation in the Mandokef sodium water solution, drip Virahol, occur muddy to solution;
(3) under ultrasonic field, in step 2 gained solution, flow the organic mixing solutions that adds ethanol and ether, continue to stir;
(4) under stirring at low speed, continued ultrasonic 5-15 minute, stop to stir, and in 20-35min, make solution be cooled to 0-5 ℃, leave standstill growing the grain more than 16 hours, filter, wash filter residue with ether, drying gets described Cefamandole nafate compounds.
Among the above-mentioned preparation method, in the said step 1, the concentration of Mandokef sodium water solution is 0.08-0.45g/ml.Preferred 0.25g/ml, the Mandokef sodium water solution of this concentration helps follow-up crystalline and separates out.
In the wherein said step 2, mixing speed is 15-35rmp.
Dropping in the step 2 can be at room temperature to carry out.
The Virahol that drips in the step 2 adds to solution and muddy getting final product occur.
In the wherein said step 3; At power is under the ultrasonic field of 0.4～0.6KW; Flow acceleration with 5-15ml/min in step 2 gained solution flows the organic mixing solutions that adds ethanol and ether; The volume ratio of ethanol and ether is 1:3-5:3 in said organic mixing solutions, and the weightmeasurement ratio of said Sodium O-formylcefamole and organic mixing solutions is 3:4-5:18; Stream adds in the process with the lasting stirring of the speed of 10-20rmp.
Wherein said step 4 is: under the stirring at low speed of 2-6rmp, continued ultrasonic 5-15 minute, ultrasonic power is 0.05-0.1KW, stops to stir; And in 20-35min, make solution at the uniform velocity be cooled to 0-5 ℃; Left standstill growing the grain 18-32 hour, and filtered, the ether of doubly measuring with 1-2 washs filter residue 2 times; Drying gets described Cefamandole nafate compounds.
Only, Cefamandole nafate compounds of the present invention adopts following method to be prepared from:
Said Cefamandole nafate compounds adopts following method to be prepared from:
(1) it is soluble in water to get the Sodium O-formylcefamole bullion, obtains 0.20g/ml Mandokef sodium water solution;
(2) in the Mandokef sodium water solution, dripping Virahol under the stirring velocity of 20rmp, occurring muddy to solution;
(3) be under the ultrasonic field of 0.5KW at power; Flow acceleration with 10ml/min in step 2 gained solution flows the organic mixing solutions that adds ethanol and ether; The volume ratio of ethanol and ether is 4:3 in said organic mixing solutions, and the weightmeasurement ratio of said Sodium O-formylcefamole and organic mixing solutions is 4:9; Stream adds in the process with the lasting stirring of the speed of 15rmp;
(4) under the stirring at low speed of 4rmp, continued ultrasonic 10 minutes, ultrasonic power is 0.08KW, stops to stir; And in 30min, make solution at the uniform velocity be cooled to 2 ℃, and left standstill growing the grain 24 hours, filter; Ether with 2 times of amounts washs filter residue 2 times, and drying gets described Cefamandole nafate compounds.
In addition, the present invention's second purpose is to provide a kind of compsn that contains above-mentioned Cefamandole nafate compounds, and described compsn is powder injection or lyophilized injectable powder.
When described compsn was powder injection, the present invention can adopt Mandokef sodium crystal and Sodium Benzoate are carried out preparing behind the thorough mixing, and wherein the weight percent of Sodium Benzoate is 0.05-0.2%.The preparation method of powder injection can adopt those skilled in the art to commonly use; The present invention preferably accurately takes by weighing the Mandokef sodium crystal and pulverizes under aseptic condition, granularity is 75～90 μ m, sieves; Sodium O-formylcefamole after taking by weighing the sterile sodium carbonate powder then and sieving places pressed powder mixing machine uniform mixing; By every bottle of 1g or the packing of 0.5g effective constituent delicate metering, gland promptly gets the Sodium O-formylcefamole aseptic powder injection.
The preferred Mandokef sodium freeze-dried powder injection of the present invention comprises the Sodium O-formylcefamole crystalline compounds of 500-1000 part, the lignocaine of 100-200 part, the reductive glutathione of 50-80 part and the Sodium Glutamate of 300-400 part; During preparation; Get the Sodium O-formylcefamole crystalline compounds of recipe quantity; Add an amount of water for injection dissolving, more successively dissolving lignocaine, reductive glutathione and Sodium Glutamate respectively; The resulting composition soup is through the membrane ultrafiltration of molecular weight cut-off 3000D, and getting the filtrating adjust pH is 8.5-9.5, filters, and freeze-drying gets the Mandokef sodium freeze-dried powder injection.
Above-mentioned lyophilized injectable powder can adopt the disclosed freeze drying technology scheme commonly used of prior art, but higher in order to obtain stability, the freeze-dried prepn that solubility and outward appearance are better, and the present invention preferably adopts following freeze-drying way:
The pre-freeze stage: shelf temperature is reduced to about-40～-50 ℃, be incubated 3～5 hours, be evacuated to 10Pa;
The primary drying stage: shelf temperature is slowly risen to-20～-30 ℃ with 1～4 ℃ heat-up rate per hour; At the uniform velocity be warming up to-20～0 ℃ with 1～4 ℃ heat-up rate per hour again, be incubated 1～3 hour;
The redrying stage: with 3-5 ℃ heat-up rate per hour shelf temperature is risen to 30～40 ℃, continue insulation 3-6 hour.
It is simple that above-mentioned freeze-dried powder preparation prepares process, and Sodium O-formylcefamole crystalline stability all is significantly improved than its hydrate crystal or commercially available coarse raw materials, thereby guaranteed patient's drug safety conscientiously.In addition, as a kind of new Cefamandole nafate compounds, suit in various Mandokef preparation of sodium, to apply.
Description of drawings
Fig. 1 is a Sodium O-formylcefamole X diffractogram of the present invention.
Embodiment
Below with embodiment technical scheme of the present invention is explained in more detail, but it is not to be limitation of the present invention.
The preparation of embodiment 1 Cefamandole nafate compounds
(1) it is soluble in water to get the Sodium O-formylcefamole bullion, obtains 0.20g/ml Mandokef sodium water solution;
(2) in the Mandokef sodium water solution, dripping Virahol under the stirring velocity of 20rmp, occurring muddy to solution;
(3) be under the ultrasonic field of 0.5KW at power; Flow acceleration with 10ml/min in step 2 gained solution flows the organic mixing solutions that adds ethanol and ether; The volume ratio of ethanol and ether is 4:3 in said organic mixing solutions, and the weightmeasurement ratio of said Sodium O-formylcefamole and organic mixing solutions is 4:9; Stream adds in the process with the lasting stirring of the speed of 15rmp;
(4) under the stirring at low speed of 4rmp, continued ultrasonic 10 minutes, ultrasonic power is 0.08KW, stops to stir; And in 30min, make solution at the uniform velocity be cooled to 2 ℃, and left standstill growing the grain 24 hours, filter; Ether with 2 times of amounts washs filter residue 2 times, and drying gets described Cefamandole nafate compounds.
Described Cefamandole nafate compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle is represented at 11.45 °, 13.63 °, 14.68 °, 15.69 °, 18.39 °, 20.30 °, 26.09 °, 27.11 °, 28.74 °, 30.27 °, 31.90 °, 34.01 °, 35.88 °.
The preparation of embodiment 2 Cefamandole nafate compounds
(1) it is soluble in water to get the Sodium O-formylcefamole bullion, obtains 0.08g/ml Mandokef sodium water solution;
(2) in the Mandokef sodium water solution, dripping Virahol under the stirring velocity of 15rmp, occurring muddy to solution;
(3) be under the ultrasonic field of 0.4KW at power; Flow acceleration with 5ml/min in step 2 gained solution flows the organic mixing solutions that adds ethanol and ether; The volume ratio of ethanol and ether is 1:3 in said organic mixing solutions, and the weightmeasurement ratio of said Sodium O-formylcefamole and organic mixing solutions is 3:4; Stream adds in the process with the lasting stirring of the speed of 10rmp;
(4) under the stirring at low speed of 2rmp, continued ultrasonic 5 minutes, ultrasonic power is 0.05KW, stops to stir; And in 20min, make solution at the uniform velocity be cooled to 0 ℃, and left standstill growing the grain 18 hours, filter; Ether with 1 times of amount washs filter residue 2 times, and drying gets described Cefamandole nafate compounds.
Described Cefamandole nafate compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle is represented at 11.45 °, 13.63 °, 14.68 °, 15.69 °, 18.39 °, 20.30 °, 26.09 °, 27.11 °, 28.74 °, 30.27 °, 31.90 °, 34.01 °, 35.88 °.
The preparation of embodiment 3 Cefamandole nafate compounds
(1) it is soluble in water to get the Sodium O-formylcefamole bullion, obtains 0.45g/ml Mandokef sodium water solution;
(2) in the Mandokef sodium water solution, dripping Virahol under the stirring velocity of 35rmp, occurring muddy to solution;
(3) be under the ultrasonic field of 0.6KW at power; Flow acceleration with 15ml/min in step 2 gained solution flows the organic mixing solutions that adds ethanol and ether; The volume ratio of ethanol and ether is 5:3 in said organic mixing solutions, and the weightmeasurement ratio of said Sodium O-formylcefamole and organic mixing solutions is 5:18; Stream adds in the process with the lasting stirring of the speed of 20rmp;
(4) under the stirring at low speed of 6rmp, continued ultrasonic 15 minutes, ultrasonic power is 0.1KW, stops to stir; And in 35min, make solution at the uniform velocity be cooled to 5 ℃, and left standstill growing the grain 32 hours, filter; Ether with 2 times of amounts washs filter residue 2 times, and drying gets described Cefamandole nafate compounds.
Described Cefamandole nafate compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle is represented at 11.45 °, 13.63 °, 14.68 °, 15.69 °, 18.39 °, 20.30 °, 26.09 °, 27.11 °, 28.74 °, 30.27 °, 31.90 °, 34.01 °, 35.88 °.
Embodiment 4 Sodium O-formylcefamole powder pins
Under aseptic condition, accurately taking by weighing 100g Mandokef sodium crystal (embodiment 1 prepares) pulverizes; Granularity is 80 μ m; Sieve, the Sodium O-formylcefamole after taking by weighing 20g sterile sodium carbonate powder then and sieving places pressed powder mixing machine uniform mixing, by the packing of every bottle of 1g effective constituent delicate metering; Gland promptly gets the Sodium O-formylcefamole aseptic powder injection.
Embodiment 5 Sodium O-formylcefamole powder pins
Under aseptic condition, accurately taking by weighing 100g Mandokef sodium crystal (embodiment 2 prepares) pulverizes; Granularity is 75 μ m; Sieve, the Sodium O-formylcefamole after taking by weighing 18g sterile sodium carbonate powder then and sieving places pressed powder mixing machine uniform mixing, by the packing of every bottle of 0.5g effective constituent delicate metering; Gland promptly gets the Sodium O-formylcefamole aseptic powder injection.
Embodiment 6
Prescription: the lignocaine of the Sodium O-formylcefamole crystalline compounds of 800g (embodiment 1 prepares), 150g, the reductive glutathione of 60g and the Sodium Glutamate of 350g.
Preparing method: get the Sodium O-formylcefamole crystalline compounds of recipe quantity, add an amount of water for injection dissolving, more successively dissolving lignocaine, reductive glutathione and Sodium Glutamate respectively; The resulting composition soup is through the membrane ultrafiltration of molecular weight cut-off 3000D, and getting the filtrating adjust pH is 9.0, filters, and freeze-drying gets the Mandokef sodium freeze-dried powder injection.
Above-mentioned freeze-drying process comprises the steps:
The pre-freeze stage: shelf temperature is reduced to about-45 ℃, be incubated 4 hours, be evacuated to 10Pa;
The primary drying stage: shelf temperature is slowly risen to-25 ℃ with 3 ℃ heat-up rate per hour; At the uniform velocity be warming up to-10 ℃ with 2 ℃ heat-up rate per hour again, be incubated 2 hours;
The redrying stage: with 4 ℃ heat-up rate per hour shelf temperature is risen to 35 ℃, continue insulation 4 hours.
Embodiment 7
Prescription: the lignocaine of the Sodium O-formylcefamole crystalline compounds of 1000g (embodiment 2 prepares), 200g, the reductive glutathione of 80g and the Sodium Glutamate of 400g.
Preparing method: get the Sodium O-formylcefamole crystalline compounds of recipe quantity, add an amount of water for injection dissolving, more successively dissolving lignocaine, reductive glutathione and Sodium Glutamate respectively; The resulting composition soup is through the membrane ultrafiltration of molecular weight cut-off 3000D, and getting the filtrating adjust pH is 9.5, filters, and freeze-drying gets the Mandokef sodium freeze-dried powder injection.
Above-mentioned freeze-drying process comprises the steps:
The pre-freeze stage: shelf temperature is reduced to about-50 ℃, be incubated 5 hours, be evacuated to 10Pa;
The primary drying stage: shelf temperature is slowly risen to-30 ℃ with 4 ℃ heat-up rate per hour; At the uniform velocity be warming up to 0 ℃ with 4 ℃ heat-up rate per hour again, be incubated 3 hours;
The redrying stage: with 5 ℃ heat-up rate per hour shelf temperature is risen to 40 ℃, continue insulation 6 hours.
Embodiment 8
Prescription: the lignocaine of the Sodium O-formylcefamole crystalline compounds of 500g (embodiment 3 prepares), 100g, the reductive glutathione of 50g and the Sodium Glutamate of 300g.
Preparing method: get the Sodium O-formylcefamole crystalline compounds of recipe quantity, add an amount of water for injection dissolving, more successively dissolving lignocaine, reductive glutathione and Sodium Glutamate respectively; The resulting composition soup is through the membrane ultrafiltration of molecular weight cut-off 3000D, and getting the filtrating adjust pH is 8.5, filters, and freeze-drying gets the Mandokef sodium freeze-dried powder injection.
Above-mentioned freeze-drying process comprises the steps:
The pre-freeze stage: shelf temperature is reduced to about-40 ℃, be incubated 3 hours, be evacuated to 10Pa;
The primary drying stage: shelf temperature is slowly risen to-20 ℃ with 1 ℃ heat-up rate per hour; At the uniform velocity be warming up to-20 ℃ with 1 ℃ heat-up rate per hour again, be incubated 1 hour;
The redrying stage: with 3 ℃ heat-up rate per hour shelf temperature is risen to 30 ℃, continue insulation 3 hours.
The present invention also further provides following Test Example, further technical scheme of the present invention is described.
Test Example 1 stability test
This Test Example has detected the stability of Cefamandole nafate compounds provided by the present 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 following:
Table 1, accelerated test result
| 1 month | 2 months | 3 months | 6 months | 12 months | |
| 1 | 99.89％ | 99.68％ | 99.27％ | 98.89％ | 96.54％ |
| 2 | 99.83％ | 99.65％ | 99.25％ | 98.80％ | 96.28％ |
| 3 | 99.75％ | 99.13％ | 96.54％ | 92.82％ | 86.88％ |
| 4 | 99.79％ | 99.53％ | 98.94％ | 98.78％ | 94.80％ |
| 5 | 99.72％ | 99.02％ | 94.50％ | 91.49％ | 85.12％ |
Table 2, long-term test results
| 3 months | 6 months | 9 months | 12 months | 18 months | |
| 1 | 99.83％ | 99.72％ | 99.52％ | 99.05％ | 98.12％ |
| 2 | 99.76％ | 99.68％ | 99.40％ | 98.88％ | 97.93％ |
| 3 | 99.71％ | 99.03％ | 97.20％ | 95.35％ | 88.27％ |
| 4 | 99.75％ | 99.59％ | 98.89％ | 96.30％ | 92.86％ |
| 5 | 99.69％ | 98.03％ | 95.79％ | 92.21％ | 86.21％ |
Wherein sample 1 is embodiment 1 product, and sample 2 is embodiment 2 products;
Sample 3 is China application CN201010257886.x embodiment 1 a gained Sodium O-formylcefamole pentahydrate;
Sample 4 is Chinese patent ZL201010199235.x embodiment 1 a gained Cefamandole nafate hydrate crystal;
Sample 5 is commercially available Mandokef sodium raw materials, and HPLC pure 99.83%;
This description of test, Sodium O-formylcefamole crystallization-stable property provided by the invention is good, quickens, test of long duration purity content is little.Wherein with the best stability of embodiment 1.And commercially available Mandokef sodium raw materials and sample 3 stability are the poorest.
Other embodiment products of the present invention have also carried out identical experiment, and obtain the experimental result of same trend, but length limits, and the present invention enumerates no longer one by one.
Claims (9)
1. the Cefamandole nafate compounds of a formula (I); It is characterized in that; Described Cefamandole nafate compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle is represented at 11.45 °, 13.63 °, 14.68 °, 15.69 °, 18.39 °, 20.30 °, 26.09 °, 27.11 °, 28.74 °, 30.27 °, 31.90 °, 34.01 °, 35.88 °
Formula (I).
2. Cefamandole nafate compounds according to claim 1 is characterized in that, said Cefamandole nafate compounds adopts following method to be prepared from:
(1) it is soluble in water to get the Sodium O-formylcefamole bullion, obtains the Mandokef sodium water solution;
(2) under agitation in the Mandokef sodium water solution, drip Virahol, occur muddy to solution;
(3) under ultrasonic field, in step 2 gained solution, flow the organic mixing solutions that adds ethanol and ether, continue to stir;
(4) under stirring at low speed, continued ultrasonic 5-15 minute, stop to stir, and in 20-35min, make solution be cooled to 0-5 ℃, leave standstill growing the grain more than 16 hours, filter, wash filter residue with ether, drying gets described Cefamandole nafate compounds.
3. Cefamandole nafate compounds according to claim 2 is characterized in that, in the said step 1, the concentration of Mandokef sodium water solution is 0.08-0.45g/ml.
4. Cefamandole nafate compounds according to claim 2 is characterized in that, in the said step 2, mixing speed is 15-35rmp.
5. Cefamandole nafate compounds according to claim 2; It is characterized in that; In the said step 3, be under the ultrasonic field of 0.4～0.6KW at power, the flow acceleration with 5-15ml/min in step 2 gained solution flows the organic mixing solutions that adds ethanol and ether; The volume ratio of ethanol and ether is 1:3-5:3 in said organic mixing solutions, and the weightmeasurement ratio of said Sodium O-formylcefamole and organic mixing solutions is 3:4-5:18; Stream adds in the process with the lasting stirring of the speed of 10-20rmp.
6. Cefamandole nafate compounds according to claim 2 is characterized in that, said step 4 is: under the stirring at low speed of 2-6rmp, continued ultrasonic 5-15 minute; Ultrasonic power is 0.05-0.1KW, stops to stir, and in 20-35min, makes solution at the uniform velocity be cooled to 0-5 ℃; Left standstill growing the grain 18-32 hour, and filtered, the ether of doubly measuring with 1-2 washs filter residue 2 times; Drying gets described Cefamandole nafate compounds.
7. Cefamandole nafate compounds according to claim 2 is characterized in that, said Cefamandole nafate compounds adopts following method to be prepared from:
(1) it is soluble in water to get the Sodium O-formylcefamole bullion, obtains 0.20g/ml Mandokef sodium water solution;
(2) in the Mandokef sodium water solution, dripping Virahol under the stirring velocity of 20rmp, occurring muddy to solution;
(3) be under the ultrasonic field of 0.5KW at power; Flow acceleration with 10ml/min in step 2 gained solution flows the organic mixing solutions that adds ethanol and ether; The volume ratio of ethanol and ether is 4:3 in said organic mixing solutions, and the weightmeasurement ratio of said Sodium O-formylcefamole and organic mixing solutions is 4:9; Stream adds in the process with the lasting stirring of the speed of 15rmp;
(4) under the stirring at low speed of 4rmp, continued ultrasonic 10 minutes, ultrasonic power is 0.08KW, stops to stir; And in 30min, make solution at the uniform velocity be cooled to 2 ℃, and left standstill growing the grain 24 hours, filter; Ether with 2 times of amounts washs filter residue 2 times, and drying gets described Cefamandole nafate compounds.
8. the compsn that contains any described Cefamandole nafate compounds of claim 1-7.
9. compsn according to claim 8 is characterized in that: described compsn is powder injection or lyophilized injectable powder.
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| CN103145736A (en) * | 2013-03-29 | 2013-06-12 | 四川省惠达药业有限公司 | Medicine composite containing cefamandole nafate compound |
| CN104829631A (en) * | 2015-05-08 | 2015-08-12 | 天津大学 | New crystal form of cefamandole nafate and crystallization and preparation methods thereof |
| CN104844625A (en) * | 2015-05-08 | 2015-08-19 | 天津大学 | Cefamandole nafate new crystal form and crystallization preparing method thereof |
| CN104844626A (en) * | 2015-05-08 | 2015-08-19 | 天津大学 | Cefamandole nafate new crystal form and crystallization preparing method thereof |
| CN105037391A (en) * | 2015-07-07 | 2015-11-11 | 山东罗欣药业集团股份有限公司 | Cefamandole nafate compound and preparation thereof |
| CN105566351A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefamandole nafate compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
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| CN105566351A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefamandole nafate compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
| CN110734455A (en) * | 2018-07-20 | 2020-01-31 | 罗欣药业(上海)有限公司 | novel crystal form of cefamandole nafate and preparation method thereof |
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Application publication date: 20121107 Assignee: HAINAN GOURD DOLL PHARMACEUTICAL Co.,Ltd. Assignor: Xia Zhihong|Zhou Xiaodong Contract record no.: 2014360000027 Denomination of invention: Cefamandole nafate compound and composite thereof Granted publication date: 20130717 License type: Common License Record date: 20140128 |
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