CN1462751A - Method for preparing crystalline cefathiamidine and its usage - Google Patents
Method for preparing crystalline cefathiamidine and its usage Download PDFInfo
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- CN1462751A CN1462751A CN 03136191 CN03136191A CN1462751A CN 1462751 A CN1462751 A CN 1462751A CN 03136191 CN03136191 CN 03136191 CN 03136191 A CN03136191 A CN 03136191A CN 1462751 A CN1462751 A CN 1462751A
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Abstract
A crystallized cefathiamidine is prepared from the cefathiamidine solution through controlling pH to 3.5-6.5, adding proper solvent until the solution becomes cloudy, controlling saturation procedure and crystal growth speed while adding said solvent, separating and drying. Its advantage is uniform granularity. It can be used to prepare the medicines for treating the infection of staphylococcus aureus, pneumoccus, enterococcus, streptococcus, etc.
Description
Technical field
The present invention relates to chemical pharmacy field, particularly, the present invention relates to crystalline cephem sulphur amidine and its production and use.
Background technology
The chemistry of cefathiamidine by name (6R, 7R)-3[(ethanoyl) methyl]-7-[α-(N, N '-diisopropylamidinateand sulfenyl)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-formic acid betaine, molecular formula is C
19H
28N
4O
6S
2, structural formula is:
Cefathiamidine is a β-Nei Xiananleikangshengsu, antimicrobial spectrum is similar to cefoxitin, stronger to golden Portugal bacterium, Streptococcus viridans, pneumococcal effect, faecalis there is unique anti-microbial activity, in addition to Hemolytic streptococcus, hemophilus influenzae, viridans streptococci, streptococcus pneumoniae, diphtheria corynebacterium, tetanus bacillus, intestinal bacteria, Proteus mirabilis etc. also have certain effect, orally do not absorb.The serum protein combination rate is low, and it is the highest with bile to distribute in the body, and concentration is lower in the cerebral tissue.Not metabolism in the body is mainly discharged by urine.Cefathiamidine is mainly used in the infection such as respiratory tract infection, biliary tract infection, urinary tract infections, wound and surgical infection, skin and soft tissue infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, pneumonia or meningitis due to golden Portugal bacterium, staphylococcus epidermidis, streptococcus pneumoniae, faecalis and the suis.
Cefathiamidine has the unique molecular structure of zwitter-ion inner salt, case of thermal instability, and easily molten in water, form amorphous powder easily.Adopt crystallization method commonly used on the pharmaceutical manufacturing, as changing the temperature crystallization, utilizing production operation inconvenience such as isoelectric point crystallizing, additive salt agent crystallization, component distillation crystallization, cost is higher, and non-conformity of quality closes the cefathiamidine of medicinal standard.
Summary of the invention
The purpose of this invention is to provide a kind of crystalline cephem sulphur amidine;
Another object of the present invention has provided a kind of method for preparing crystalline cephem sulphur amidine;
Another object of the present invention has provided crystalline cephem sulphur amidine and has been used to prepare the purposes of treatment by the medicine of respiratory tract infection, biliary tract infection, urinary tract infections, wound and surgical infection, skin and soft tissue infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, pneumonia or meningitis etc. due to golden Portugal bacterium, staphylococcus epidermidis, streptococcus pneumoniae, faecalis and the suis;
Another object of the present invention has provided a kind of pharmaceutical composition, especially injection that contains crystalline cephem sulphur amidine as activeconstituents.
Technical scheme of the present invention is the pH value by adjusting cefathiamidine solution, and adds appropriate solvent, and control solution saturation history obtains the well-crystallized that the cefathiamidine uniform particle size distributes.
The characteristic present of crystalline cephem sulphur amidine of the present invention is to use by 2 θ, d-interplanar distance and the X-ray powder diffraction pattern represented more than or equal to 5% relative intensity, this diffractogram uses Cu, and the K alpha-ray is measured: 2 θ d relative intensity I/I.(＞＝5％)7.54??????????????????????11.71????????????????????58.34??????????????????????10.59????????????????????10010.92?????????????????????8.09?????????????????????513.24?????????????????????6.68?????????????????????514.88?????????????????????5.94?????????????????????916.94?????????????????????5.22?????????????????????517.78?????????????????????4.98?????????????????????518.5??????????????????????4.79?????????????????????1319.72?????????????????????4.49?????????????????????520.52?????????????????????4.32?????????????????????521.54?????????????????????4.12?????????????????????1022.44?????????????????????3.95?????????????????????623.28?????????????????????3.82?????????????????????523.52?????????????????????3.78?????????????????????926.48?????????????????????3.36?????????????????????630.6??????????????????????2.91?????????????????????532.18?????????????????????2.78?????????????????????5
The feature of crystalline cephem sulphur amidine of the present invention is that also the infared spectrum of its KBr compressing tablet has following charateristic avsorption band: 1770～1782cm
-1(carbonyl of beta-lactam) 1730～1743cm
-1, 1227～1235cm
-1(C
3-acetic ester); 1602～1608cm
-1(C
4-COO
-); 1388～1395cm
-11333～1343cm
-1(CH (CH
3)
2).
Technical solution of the present invention is to be 3.5-6.5 by control cefathiamidine pH value of solution, add with the sl. sol. at the most solvent of cefathiamidine to solution and muddiness occurs, control saturation history and crystalline growth velocity continue to add solvent crystallization, separation, drying get crystalline cephem sulphur amidine.
The sl. sol. at the most solvent of the above and cefathiamidine is lower alcohol (as Virahol, ethanol, n-propyl alcohol, propyl carbinol, 2-butanols), lower ketones (as acetone, methylethylketone, pentanone), nitrile (as acetonitrile), ethers (as dioxan, tetrahydrofuran (THF)), or above-mentioned solvent binary, ternary or multicomponent mixture.These mixtures and water soluble and with the cefathiamidine slightly soluble.
Preferred solvent is ethanol, Virahol, acetone, acetonitrile or their binary, ternary or multicomponent mixture.
The solvability (25 ℃) of cefathiamidine in several solvents
| The solvent title | Solvability |
| Virahol | Soluble,very slightly |
| Dehydrated alcohol | Soluble,very slightly |
| Butanols | Soluble,very slightly |
| Acetone | Soluble,very slightly |
| Tetrahydrofuran (THF) | Soluble,very slightly |
| Acetonitrile | Soluble,very slightly |
What above the present invention controlled the pH value of solution employing is mineral acid, alkali or organic acid, alkali.Mineral acid, alkali are hydrochloric acid, sulfuric acid, sodium hydroxide, yellow soda ash, ammoniacal liquor, sodium bicarbonate, and organic acid, alkali are formic acid, acetate, triethylamine.
PH value of solution directly influences cefathiamidine quality and yield, and general regulator solution pH is controlled between the 3.5-6.5, preferred 4.0-5.5.
In the cefathiamidine crystal process, adding and the sl. sol. at the most solvent of cefathiamidine such as ethanol, Virahol, acetone, acetonitrile etc. progressively reach capacity or hypersaturated state cefathiamidine in cefathiamidine solution, can progressively separate out crystal; By continuous adding solvent, the control supersaturation concentration is constant or stable, makes the brilliant habit of the crystal of separating out good, avoids supersaturation concentration instantaneous too high, and the crystal crystallization is too fast, produces sticking group.And after supersaturated solution is separated out crystal, be not higher than under 150 stirrings of changeing at per minute, preferred per minute stirring velocity is that 20-80 changes, and micro crystal is progressively grown up, form the crystal of uniform particle size size, make simultaneously to be adsorbed in crystalline impurity and progressively to break away from crystal and reach purifying.
This crystallization method regardless of batch crystallization, continuous crystallisation, stirred crystallization, leave standstill crystallization operations such as crystallization, can implement.
The present invention also comprises crystalline cephem sulphur amidine is used to prepare the purposes of treatment by respiratory tract infection, biliary tract infection, urinary tract infections, gynecological infection, septicemia, pneumonia or meningitic medicine due to golden Portugal bacterium, streptococcus pneumoniae and the suis.
The present invention also comprises a kind of pharmaceutical composition, especially injection that contains crystalline cephem sulphur amidine as activeconstituents.
Therefore the present invention also provides a kind of injectable drug that contains crystalline cephem sulphur amidine as activeconstituents.Promptly under the sterile production envrionment conditions, by mechanical packing, preparation 0.5 gram, 1 gram, 2 grams or 5 gram dress powder injection add injection water dissolved dilution during clinical use and get final product.
Above-mentioned injection cefathiamidine is the antibiotic medicine of treatment by respiratory tract infection, biliary tract infection, urinary tract infections, wound and surgical infection, skin and soft tissue infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, pneumonia or meningitis etc. due to golden Portugal bacterium, staphylococcus epidermidis, streptococcus pneumoniae, faecalis and the suis.
Advantage of the present invention is that gained crystalline cephem sulphur amidine is a kind of well-crystallized that distributes than uniform particle size, and it is more stable than amorphous powder; Crystalline cephem sulphur amidine is placed for a long time, and product color is constant substantially.The easy easy control of production process helps operations such as filtration and drying, helps reducing production costs.Crystalline cephem sulphur amidine of the present invention has and infects due to the anti-gram positive organism, and clinical application effect is good.
Description of drawings
Accompanying drawing 1 is the X-ray powder diffraction pattern of crystalline cephem sulphur amidine of the present invention, its condition determination is to use D/max-IIIA DIFFRATOMETER (RIGAKUCORPORATION, JANPAN) X-diffractometer, with Cu, K α 1, λ=1.54056A radionetric survey cefathiamidine crystalline X-ray powder diffraction pattern.
Accompanying drawing 2 is infared spectrums of the KBr compressing tablet of crystalline cephem sulphur amidine of the present invention, and its condition determination is to adopt German BRUKER EQUINOX-55 Fourier transformation infrared spectrometer to measure, and uses the KBr compressing tablet.
Embodiment
Embodiment one
Under the normal temperature, drop into 5 kilograms of cefathiamidines, add 49 liters water dissolution to reactor, stirred 30 minutes, and filtered, regulating filtrate pH with hydrochloric acid is 4.5, add 200 liters of acetone to the filtrate muddiness, under the stirring that per minute 60 changes, control solution supersaturation concentration, continue to add slowly 200 liters of acetone (weight ratio 10: 1), growing the grain, suction filtration, with 50 liters of washing with acetones 2 times, drain, drying under reduced pressure gets 4.6 kilograms of crystalline cephem sulphur amidines.
Use D/max-IIIA DIFFRATOMETER (RIGAKU CORPORATION, JANPAN) X-diffractometer, with Cu, K α 1, λ=1.54056A radionetric survey, the X-ray powder diffraction pattern of crystalline cephem sulphur amidine (seeing accompanying drawing 1) is expressed as follows by 2 θ, d-interplanar distance with greater than 5% relative intensity: 2 θ d relative intensity I/I.(＞5％)7.540??????????????????????11.7146????????????????????58.340??????????????????????10.5926????????????????????10010.920?????????????????????8.0951?????????????????????513.24??????????????????????6.6814?????????????????????514.88??????????????????????5.9485?????????????????????916.94??????????????????????5.2295?????????????????????517.78??????????????????????4.9842?????????????????????518.5???????????????????????4.7919?????????????????????1319.72??????????????????????4.4981?????????????????????520.52??????????????????????4.3203?????????????????????521.54??????????????????????4.1219?????????????????????1022.44??????????????????????3.9586?????????????????????623.28??????????????????????3.8209?????????????????????523.52??????????????????????3.7824?????????????????????926.48??????????????????????3.3631?????????????????????630.6???????????????????????2.9190?????????????????????532.18??????????????????????2.7792?????????????????????5
Adopt German BRUKER EQUINOX-55 Fourier transformation infrared spectrometer to measure, use the KBr compressing tablet, crystalline cephem sulphur amidine IR (KBr cm
-1) following charateristic avsorption band (seeing accompanying drawing 2) arranged: 1774.6 (carbonyls of beta-lactam); 1739.0,1230.9 (C
3-acetic ester); 1605.9 (C
4-COO
-); 1391.7,1340.6 (CH (CH
3)
2).Embodiment two
Under 0 ℃, dropping into pH to reactor is 50 liters of 14% (w/w) cefathiamidine aqueous solution of 5.5, sterile filtration.Under the sterile production envrionment conditions of GMP compatible, stirring with per minute 70 commentaries on classics, add 300 liters of acetone to the filtrate muddiness in bacteria-free filtrate, control solution supersaturation concentration continues to add slowly 350 liters of acetone, growing the grain, suction filtration with 50 liters of washing with acetones 2 times, is drained, drying under reduced pressure gets 7.3 kilograms of crystalline cephem sulphur amidine aseptic powder.
Gained crystalline X-ray and infared spectrum are consistent with embodiment's one.Stability test: according to Pharmacopoeia of the People's Republic of China appendix medicine stability test governing principle, the crystalline cephem sulphur amidine sample (lot number 010210020) of selecting unformed cefathiamidine sample (lot number 8801) and preparing by present embodiment carries out 2-8 ℃ of reserved sample observing, cefathiamidine kept sample test, the result shows (seeing Table 1):
Unformed cefathiamidine was placed 6 months, the solution color and luster is by rising to for No. 4 less than yellow-green colour less than No. 6, yellow-green colour, the solution color and luster changes very obvious, place after 12 months, the solution color and luster has been upgraded to less than No. 7, yellow-green colour, and clarity is greater than 1, and content reduces to 94.8%, outward appearance is a milk yellow, and quality has not met national drug standards WS-10001-(HD-0607)-2002.
Crystalline cephem sulphur amidine was placed 24 months, and the solution color and luster is constant substantially, and product is stable, places 24 months, and drug quality still meets the national drug standards.
This shows that crystalline cephem sulphur amidine is more stable than unformed cefathiamidine.
Table 1 cefathiamidine reserved sample observing result
Embodiment three
| Lot number | Keep sample the time (moon) | Outward appearance | The solution color and luster | Clarity | Content | Crystal formation |
| ????8801 | ????0 | White powder | No. 4,＜yellow-green colour | ????＜0.5 | ????97.7 | Unformed |
| ????6 | Off-white powder | No. 6,＜yellow-green colour | ????＜1 | ????97.2 | ||
| ????12 | The milk yellow powder | No. 7,＜yellow-green colour | ????＞1 | ????94.85 | ||
| ????010210020 | ????0 | White crystalline powder | No. 5,＜yellow-green colour | ????＜0.5 | ????98.2 | Crystallization |
| ????6 | White crystalline powder | No. 5,＜yellow-green colour | ????＜0.5 | ????98.2 | ||
| ????12 | White crystalline powder | No. 5,＜yellow-green colour | ????＜0.5 | ????97.9 | ||
| ????18 | White crystalline powder | No. 5,＜yellow-green colour | ????＜0.5 | ????97.6 | ||
| ????24 | The off-white color crystalline powder | No. 5,＜yellow-green colour | ????＜0.5 | ????97.5 |
Under-8 ℃, drop into 5 kilograms of cefathiamidines, add 170 liter 85% isopropanol water solution dissolving to reactor, stirred 30 minutes, press filtration, regulating filtrate pH with hydrochloric acid is 5.0, add 300 liters of Virahols to the solution muddiness, under the stirring that per minute 80 changes, control solution supersaturation concentration continues to add slowly 330 liters of Virahols, growing the grain, suction filtration with 60 liters of washings of acetone 2 times, is drained, drying under reduced pressure under the normal temperature gets 4.63 kilograms of crystalline cephem sulphur amidines.
Gained crystallization infared spectrum is consistent with embodiment's one.
Embodiment four
Under the normal temperature, drop into 5 kilograms of cefathiamidine crude products, add 49 liters water dissolution to reactor, add 0.1 kilogram of gac, stirred press filtration 30 minutes, regulating filtrate pH with triethylamine is 5.5, under the stirring that per minute 70 changes, adds 300 liters of ethanol to the solution muddiness, control solution supersaturation concentration continues to add 330 liters of Virahols, growing the grain, suction filtration with 60 liters of washings of acetone 2 times, is drained, drying under reduced pressure gets 4.4 kilograms of crystalline cephem sulphur amidines.
Gained crystallization infared spectrum is consistent with embodiment's one.
Embodiment five
30 ℃, (acetone: water=7.5: 1) 50 restrain, regulating filtrate pH with ammoniacal liquor is 5.5, adds 300 milliliters of tetrahydrofuran (THF)/acetone (1: 1) to the solution muddiness to drop into 15.8% cefathiamidine aqueous acetone solution to reaction flask, under the stirring that per minute 70 changes, control solution supersaturation concentration continues to add slowly 230 milliliters of tetrahydrofuran (THF)/acetone (1: 1), suction filtration, with 60 milliliters of washings of acetone 2 times, drain, drying under reduced pressure under the normal temperature gets crystalline cephem sulphur amidine 46.3 grams.
Gained crystalline X-ray and infared spectrum are consistent with embodiment's one.
Embodiment six
Drop into 50 gram cefathiamidine crude products to reaction flask, add 170 milliliter 80% acetonitrile solution dissolving, normal temperature stirred 30 minutes down, filter, regulating filtrate pH with acetate is 4.1, adds 300 milliliters of acetonitriles to the solution muddiness, under the stirring that per minute 60 changes, control solution supersaturation concentration continues to add slowly 230 milliliters of acetonitriles, filter,, drain with 60 milliliters of washings of acetone 2 times, drying under reduced pressure under the normal temperature gets crystalline cephem sulphur amidine 44.1 grams.
Gained crystallization infared spectrum is consistent with embodiment's one.Embodiment seven
Under the normal temperature, drop into 50 gram cefathiamidine crude products, add 180 milliliter 75% dioxan aqueous solution dissolving to reaction flask, stirred 30 minutes, and filtered, regulating filtrate pH with sodium hydroxide is 6.0, add 300 milliliters of dioxan to the solution muddiness, under the stirring that per minute 50 changes, control solution supersaturation concentration, continue to add slowly 250 milliliters of dioxan, suction filtration with 60 milliliters of washings of acetone 2 times, is drained, drying under reduced pressure under the normal temperature gets crystalline cephem sulphur amidine 45.3 grams.
Gained crystallization infared spectrum is consistent with embodiment's one.
Embodiment eight
Under the ice bath, drop into 5 kilograms of cefathiamidines, add 170 liter of 95% aqueous ethanolic solution dissolving to reactor, stirred 30 minutes, press filtration, regulating filtrate pH with hydrochloric acid is 5.0, add 10 liters of Virahols, 5 liters of acetonitriles and 100 liters of acetone respectively to the solution muddiness, under the stirring that per minute 60 changes, control solution supersaturation concentration, continue to add slowly 200 liters of acetone, growing the grain, suction filtration, with 60 liters of washings of acetone 2 times, drain, drying under reduced pressure under the normal temperature gets 4.5 kilograms of crystalline cephem sulphur amidines.
Gained crystallization infared spectrum is consistent with embodiment's one.
Embodiment nine
Adopt embodiment two to make crystalline cephem sulphur amidine aseptic powder, under the sterile production envrionment conditions of GMP compatible, with the pure 10000 gram crystalline cephem sulphur amidine aseptic powder of the giving money as a gift calculating that feeds intake, be distributed into about 19600 of 0.5g specification injection cefathiamidine with eight screw type sub packaging machines of KFG300 type.
Above-mentioned injection cefathiamidine is the antibiotic medicine of treatment by respiratory tract infection, biliary tract infection, urinary tract infections, wound and surgical infection, skin and soft tissue infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, pneumonia or meningitis etc. due to golden Portugal bacterium, staphylococcus epidermidis, streptococcus pneumoniae, faecalis and the suis.
Embodiment ten
The test of pesticide effectiveness of crystalline cephem sulphur amidine
Bacterial strain: experiment is intestinal bacteria 13 strains (all being the beta-lactamase-producing strain), hemophilus influenzae 30 strains with bacterial strain, streptococcus aureus 15 strains (all being MSSA and all beta-lactamase-producing strains), staphylococcus epidermidis 15 strains (all being the beta-lactamase-producing strain), streptococcus pneumoniae 15 strains, micrococcus scarlatinae 15 strains, enterococcus faecalis 15 strains, moraxelle catarrhalis 15 strains.The evaluation of bacterial strain is carried out with the VITEK-AMS system, and identification of strains is to planting.
Experimental technique: carry out MIC with broth dilution method (MIC) and measure, test operation is by accurate operation of the stdn council of U.S. clinical labororatory (NCCLS) nineteen ninety-five scale and interpretation as a result.
The result: crystalline cephem sulphur amidine is to hemophilus influenzae, the MIC of streptococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, micrococcus scarlatinae, enterococcus faecalis, moraxelle catarrhalis
50, MIC
90Detected result shows that crystalline cephem sulphur amidine has shown good antimicrobial effect (table 2).
Table 2 crystalline cephem sulphur amidine antibacterial activity in vitro
| Bacteria name | ????MIC 50 | ????MIC 90 | Scope |
| Intestinal bacteria (13 strain) | ????32 | ????512 | ????8-512 |
| Hemophilus influenzae (30 strain) | ????4 | ????8 | ????2-16 |
| Streptococcus aureus (15 strain) | ????0.5 | ????2 | ????0.5-2 |
| Staphylococcus epidermidis (15 strain) | ????0.125 | ????0.25 | ????0.016-0.25 |
| Streptococcus pneumoniae (15 strain) | ????0.016 | ????0.062 | ????0.008-0.125 |
| Micrococcus scarlatinae (15 strain) | ????0.004 | ????0.008 | ????0.004-0.008 |
| Enterococcus faecalis (15 strain) | ????2 | ????16 | ????1-16 |
| Moraxelle catarrhalis (15 strain) | ????0.5 | ????1 | ????0.5-1 |
Claims (16)
1. crystalline cephem sulphur amidine is characterized in that this crystallization uses 2 θ, d-interplanar distance and relative intensity in the X-ray powder diffraction pattern that the Cu-K alpha-ray measures to have following numerical value: 2 θ d I/I.8.34??????????????????10.59??????????????????????10014.88?????????????????5.94???????????????????????918.5??????????????????4.79???????????????????????1321.54?????????????????4.12???????????????????????1022.44?????????????????3.95???????????????????????623.52?????????????????3.78???????????????????????926.48?????????????????3.36???????????????????????6
2. according to the crystalline cephem sulphur amidine of claim 1, it is characterized in that the infared spectrum of its KBr compressing tablet has following charateristic avsorption band: 1770～1782cm
-11730～1743cm
-11602～1608cm
-11388～1395cm
-11333～1343cm
-11227～1235cm
-1
3. method for preparing crystalline cephem sulphur amidine, it is characterized in that the pH by control cefathiamidine solution is 3.5-6.5, add and occur muddy with the sl. sol. at the most solvent of cefathiamidine to solution, control solution saturation history and crystalline growth velocity, continue to add solvent crystallization, separation, drying get crystalline cephem sulphur amidine.
4. the preparation method of crystalline cephem sulphur amidine according to claim 3, it is characterized in that with the sl. sol. at the most solvent of cefathiamidine be lower ketones, lower alcohol, nitrile, ethers, or the mixture of described solvent.
5. the preparation method of crystalline cephem sulphur amidine according to claim 4 is characterized in that lower ketones is acetone, methylethylketone, pentanone.
6. the preparation method of crystalline cephem sulphur amidine according to claim 4 is characterized in that lower alcohol is ethanol, Virahol, n-propyl alcohol, propyl carbinol, 2-butanols.
7. the preparation method of crystalline cephem sulphur amidine according to claim 4 is characterized in that nitrile is an acetonitrile.
8. the preparation method of crystalline cephem sulphur amidine according to claim 4 is characterized in that ethers is dioxan, tetrahydrofuran (THF).
9. the preparation method of crystalline cephem sulphur amidine according to claim 4, it is characterized in that with the sl. sol. at the most solvent of cefathiamidine be acetone, methylethylketone, pentanone, ethanol, Virahol, n-propyl alcohol, propyl carbinol, 2-butanols, acetonitrile, dioxan, tetrahydrofuran (THF) or their binary, ternary or multicomponent mixture.
10. the preparation method of crystalline cephem sulphur amidine according to claim 9, it is characterized in that with the sl. sol. at the most solvent of cefathiamidine be ethanol, Virahol, acetone, acetonitrile or their mixture.
11. the preparation method of crystalline cephem sulphur amidine according to claim 4, it is characterized in that controlling saturation history is to continue to add solvent, and the control supersaturation concentration is stable, makes its stable crystalline.
12. preparation method according to the described crystalline cephem sulphur of one of claim 3-11 amidine, it is characterized in that controlling the crystalline growth, be after saturated solution is separated out crystal, 150 stirring velocitys of changeing that are lower than per minute stir down, continuing to add solvent progressively grows up micro crystal, form the crystal of uniform particle size size, make simultaneously to be adsorbed in crystalline impurity and progressively to break away from crystal and reach purifying.
13. the preparation method of crystalline cephem sulphur amidine according to claim 12 is characterized in that stirring velocity is per minute 20-80 commentaries on classics.
14. the crystalline cephem sulphur amidine of one of claim 1-2 is used to prepare the purposes of treatment by respiratory tract infection, biliary tract infection, urinary tract infections, wound and surgical infection, skin and soft tissue infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, pneumonia or meningitic medicine due to golden Portugal bacterium, staphylococcus epidermidis, streptococcus pneumoniae, faecalis and the suis.
15. a treatment is by respiratory tract infection, biliary tract infection, urinary tract infections, wound and surgical infection, skin and soft tissue infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, pneumonia or meningitic pharmaceutical composition due to golden Portugal bacterium, staphylococcus epidermidis, streptococcus pneumoniae, faecalis and the suis, its crystalline cephem sulphur amidine that contains one of claim 1-2 is or/and pharmaceutically acceptable carrier.
16., it is characterized in that it being injection according to the pharmaceutical composition of claim 15.
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|---|---|---|---|
| CN 03136191 CN1212324C (en) | 2002-06-10 | 2003-05-19 | Method for preparing crystalline cefathiamidine and its usage |
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|---|---|---|---|
| CN02115356.6 | 2002-06-10 | ||
| CN 02115356 CN1385434A (en) | 2002-06-10 | 2002-06-10 | Method for making cefathiamidine crystal |
| CN021153566 | 2002-06-10 | ||
| CN 03136191 CN1212324C (en) | 2002-06-10 | 2003-05-19 | Method for preparing crystalline cefathiamidine and its usage |
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| EP1759749A1 (en) * | 2005-08-30 | 2007-03-07 | F.Hoffmann-La Roche Ag | Method for crystallization of a weakly acidic and/or weakly basic compound |
| EP1759750A1 (en) * | 2005-08-30 | 2007-03-07 | F.Hoffmann-La Roche Ag | Method for crystallization of a weakly acidic and/or weakly basic compound |
| CN103012434A (en) * | 2012-12-14 | 2013-04-03 | 海南合瑞制药股份有限公司 | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
| WO2016107331A1 (en) * | 2014-12-31 | 2016-07-07 | 天津大学 | New crystal form of cefathiamidine compound and preparation method therefor |
| CN109810122A (en) * | 2019-01-30 | 2019-05-28 | 山东省分析测试中心 | A method of by control solution degree of supersaturation than preparing cefathiamidine crystal |
-
2003
- 2003-05-19 CN CN 03136191 patent/CN1212324C/en not_active Ceased
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298723C (en) * | 2004-06-18 | 2007-02-07 | 广州白云山制药股份有限公司 | Amorphous cephalosporin |
| EP1759749A1 (en) * | 2005-08-30 | 2007-03-07 | F.Hoffmann-La Roche Ag | Method for crystallization of a weakly acidic and/or weakly basic compound |
| EP1759750A1 (en) * | 2005-08-30 | 2007-03-07 | F.Hoffmann-La Roche Ag | Method for crystallization of a weakly acidic and/or weakly basic compound |
| US7381265B2 (en) | 2005-08-30 | 2008-06-03 | Hoffmann-La Roche Inc. | Method for crystallization of a weakly acidic and/or weakly basic compound |
| CN1923328B (en) * | 2005-08-30 | 2010-09-01 | F·霍夫曼-拉·罗奇股份有限公司 | Method for crystallization of a weakly acidic and/or weakly basic compound |
| CN103012434A (en) * | 2012-12-14 | 2013-04-03 | 海南合瑞制药股份有限公司 | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof |
| CN103012434B (en) * | 2012-12-14 | 2014-11-05 | 海南合瑞制药股份有限公司 | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof |
| WO2016107331A1 (en) * | 2014-12-31 | 2016-07-07 | 天津大学 | New crystal form of cefathiamidine compound and preparation method therefor |
| US20170044184A1 (en) * | 2014-12-31 | 2017-02-16 | Tianjin University | New crystal form of cefathiamidine compound and preparation method therefor |
| US9637502B2 (en) * | 2014-12-31 | 2017-05-02 | Tianjin University | Crystal form of Cefathiamidine compound and preparation method therefor |
| CN105646534A (en) * | 2016-02-18 | 2016-06-08 | 海南灵康制药有限公司 | Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation |
| CN109810122A (en) * | 2019-01-30 | 2019-05-28 | 山东省分析测试中心 | A method of by control solution degree of supersaturation than preparing cefathiamidine crystal |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1212324C (en) | 2005-07-27 |
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