CN103556226B - Cefathiamidine monocrystal - Google Patents
Cefathiamidine monocrystal Download PDFInfo
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Abstract
The present invention relates to Cefathiamidine monocrystal, its preparation method, purposes and combinations thereof thing, ethanol, water, three kinds of solvents of acetone are added in clean conical flask with ratio in any order, ethanol: water: the volume ratio of acetone three is 4～10:1:0.05～3.67, during adding each solvent or front and back, add cefathiamidine, dissolve under room temperature, be made into the cefathiamidine solution of 0.05g/ml～0.5g/ml concentration；With plastic film sealing, and prick some apertures on a plastic film；At a temperature of depositing in 0 DEG C～15 DEG C；Within about 48 hours, begin with tiny crystals to generate, to more than 96 hours, to obtain final product.The preparation method of the present invention is easy and simple to handle, and equipment is simple, the monocrystalline good stability obtained.The Cefathiamidine monocrystal compositions of the present invention is the compositions of monocrystalline and pharmaceutically acceptable carrier composition, preferably injection.The Cefathiamidine monocrystal of the present invention can be used for preparation treatment respiratory tract infection, biliary tract infection, urinary tract infection, wound and surgical infection, skin and soft tissue infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, pneumonia, the purposes of meningitis medicine.
Description
[technical field]
The present invention relates to chemical pharmacy field, specifically, the present invention relates to Cefathiamidine monocrystal, it prepares
Method, a combination thereof thing and the application in pharmaceutical field thereof.
[background technology]
Cefathiamidine, chemical name be (6R, 7R)-3-[(acetyl group) methyl]-7-[α-(N, N '-diisopropylamidinateand sulfur
Base)-acetylamino]-8-oxo-5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-formic acid betaine, molecular formula is
C19H28N4O6S2, its structural formula is as follows:
Cefathiamidine belongs to first generation beta-lactam antibiotic, and antimicrobial spectrum is similar to cefalotin.Sun blue to leather
Property bacterium and part negative bacterium have antibacterial activity, and the effect to gram positive coccus is the strongest.To Streptococcus viridans,
Hemolytic streptococcus, anhemolytic streptococcus, diphtheria corynebacterium, bacillus perfringens, clostridium tetani and charcoal
Cellulitis bacillus all has good antibacterial action.
Cefathiamidine has the unique molecular structure of amphion inner salt, case of thermal instability, is preparing cephalo sulfur
The process of amidine crystal and during it deposits, easily degrades, storage instability；And in a solvent easily with
Solvent forms hydrogen bond, and product easily forms amorphous powder when separating out and causes at the bottom of product purity, and quality does not meets
Medicinal standard；Therefore, its crystal formation is developed the focus of always this area.
The cefathiamidine crystal formation reported at present has: number of patent application 03136191.9,03142622.0,
200410027695.9 individually disclose two kinds of crystal formations of cefathiamidine and a kind of amorphous state；It addition, also head
The crystal formation patent 200610011896.9 of spore sulfur amidine alcohol hydrate, cefathiamidine hydrate patent
201110068052.9 the most all disclose the relevant crystal formation of cefathiamidine solvate or hydrate.
But so far, still not about the report of Cefathiamidine monocrystal.
[summary of the invention]
Therefore, it is an object of the invention to provide a kind of purity height, stability more preferable cefathiamidine novel crystal forms head
Spore sulfur amidine monocrystalline.
It is a further object to provide the preparation method of Cefathiamidine monocrystal.
The present invention also provides for the purposes of Cefathiamidine monocrystal.
The present invention also provides for the compositions containing Cefathiamidine monocrystal.
The Cefathiamidine monocrystal physicochemical characteristics of the present invention is as follows:
(1) outward appearance: water white transparency flat crystal,
(2) molecular formula: C19H28N4O6S2,
(3) molecular structural formula:
(4) Cefathiamidine monocrystal of the present invention, in Japan, Rigaku company R-AXIS-RAPID X-ray monocrystalline spreads out
Penetrate on instrument, use through graphite monochromatised Mo K alpha ray0.997 °≤θ≤
25.20 ° of scopes collect 10484 point diffractions with ω/2 θ scan mode, wherein 6508 be independent diffraction I >=
2σ(I).Non-hydrogen atom coordinate direct method solves, and method of least square carries out anisotropy temperature to non-hydrogen atom
Factor correction, minimum deflection factor R=0.0721, Rw=0.1873.Cefathiamidine of the present invention is monocrystalline, brilliant
Body belongs to rhombic system, space group P212121, cell parameter Unit cell volumeIn brilliant bag, molecular number is 8, has 4 asymmetric cell,
Each asymmetric cell is contained within two cefathiamidine molecules.Calculate crystalline density d=1.076g/cm3.Specifically
Data see attached list 1～5.
(5) two cefathiamidine molecular structures of the interior each asymmetric cell of brilliant bag in Cefathiamidine monocrystal structure
Figure: see Figure of description 1.
The preparation method of Cefathiamidine monocrystal of the present invention is: by ethanol, water, three kinds of solvents of acetone by the most suitable
Sequence and ratio add in clean conical flask, ethanol: water: the volume ratio of acetone three is 4～10:1:
0.05～3.67, during adding each solvent or front and back, add cefathiamidine, dissolve under room temperature, be made into 0.05g/ml～
The cefathiamidine solution of 0.5g/ml concentration.With plastic film sealing, and prick some apertures on a plastic film.
Deposit under uniform temperature.Within about 48 hours, begin with tiny crystals to generate, to more than 96 hours, to obtain final product.
Solvent burden ratio directly affects the dissolubility of cefathiamidine, affects the growth of monocrystalline.Thus solvent burden ratio is non-
The normally off key.In the ethanol/water/acetone mixed solvent of certain proportioning of the present invention, solvent adds order and does not limits,
Final proportioning meets and specifies.
Why ethanol, water, three kinds of solvents of acetone select arbitrary proportions, are because cefathiamidine molten at three kinds
Dissolubility in agent is different with dissolution velocity, but the equal energy of mixed solvent of the aforementioned proportion of final three kinds of solvents
Effectively it is dissolved into the cefathiamidine solution of 0.05g/ml～0.5g/ml concentration.
The ethanol of this ratio can be made into water with 95% ethanol with water mixed liquid, or mixes with water with dehydrated alcohol
Conjunction forms.
Preferably, ethanol of the present invention: water: propanol solvent mixture volume ratio is 6.5～8.5:1:0.39～2.23.
The concentration of cefathiamidine directly affects the degree of saturation of crystal, directly affects the speed of separating out of crystal.Cause
This, we are different from common single crystal cultivation technology, are not to be configured to saturated solution or supersaturated solution,
But control the concentration of cefathiamidine, control rate of crystalline growth.Wherein said is made into cefathiamidine solution
Concentration is 0.05g/ml～0.5g/ml.
Preferably, cefathiamidine solution concentration of the present invention is 0.10g/ml～0.25g/ml.
Wherein said storage temperature is 0 DEG C～15 DEG C.
Preferably, the preferred storage temperature of the present invention is 2 DEG C～8 DEG C.
The Cefathiamidine monocrystal that the present invention relates to, is that the one of cefathiamidine is from undocumented novel crystal forms, preparation
Easy and simple to handle, equipment is simple.
The Cefathiamidine monocrystal of the present invention is to staphylococcus aureus, streptococcus pneumoniae, Hai Shi enterococcus, excrement
Enterococcus etc. have obvious antibacterial effect.The invention still further relates to Cefathiamidine monocrystal above-mentioned for preparing treatment
Bacterial respiratory tract infection, biliary tract infection, urinary tract infection, wound and surgical infection, skin and soft group
Knit infection, gynecological infection, otorhinolaryngology infection, endocarditis, septicemia, the purposes of pneumonia meningitis medicine.
The present invention further provides the compositions containing Cefathiamidine monocrystal, the compositions of the present invention is cephalo sulfur
The compositions that amidine forms with pharmaceutically acceptable carrier.
Pharmaceutically acceptable carrier is well known in the art and is pharmaceutically acceptable material, compositions
Or carrier, such as liquid or solid filler, diluent, excipient, solvent or encapsulating material.Various carriers
Must be acceptable, i.e. compatible with cefathiamidine and harmless to patient.
The using dosage of cefathiamidine compositions of the present invention and the treatment course for the treatment of and cefathiamidine other preparations existing
Unanimously.
The Cefathiamidine monocrystal pharmaceutical composition of the present invention, is preferably made injectable powder, is using injection before use
Normal saline becomes injection.Under aseptic environment, by machinery subpackage, be prepared as 0.5 gram, 1
Gram, 2 grams or 5 grams dress injectable powder.
The cefathiamidine novel crystal forms of the present invention has preferable stability.
[accompanying drawing explanation]
The molecular structure of each asymmetric cell in Fig. 1 crystalline substance bag；
Fig. 2 is cefathiamidine crystalline substance bag figure of the present invention.
[detailed description of the invention]
Technical scheme is expanded on further by below embodiment, but following example should not be construed as
Limiting the scope of the invention.
Embodiment 1
In clean conical flask, add cefathiamidine 12g, be separately added into water 9.4ml the most in order,
Ethanol 47.6ml, dissolves under room temperature.Add ethanol 37.3ml, acetone 5.7ml.Finally it is made into 0.12g/ml
Cefathiamidine solution [being equivalent to the mixed solvent 100ml of ethanol/water/acetone (volume ratio is 9:1:0.6)].With
Plastic film sealing, and prick some apertures on a plastic film.Deposit at a temperature of certain 2～6 DEG C.Stand
96 hours, to obtain final product.
Japan's Rigaku company R-AXIS-RAPID X-ray single crystal diffractometer is used gained crystal prototype to be carried out point
Analysis, the results are shown in Table 1～5 and accompanying drawing 1～2, wherein:
Table 1 is crystal data and structure optimization result；
Table 2 is non-hydrogen atom coordinate
Table 3 bond distance
Table 4 bond angle (°)；
Table 5 hydrogen atom coordinate
Fig. 1 is the molecular structure of the interior each asymmetric cell of brilliant bag；
Fig. 2 is brilliant bag figure.
Crystal is transparent sheet-like, and 0.18 × 0.16 × 0.13mm is therefrom chosen in experiment3The monocrystal of size is used for monocrystalline
Diffraction, on R-AXIS-RAPID X-ray single crystal diffractometer, uses through graphite monochromatised Mo K α
Ray10484 are collected with ω/2 θ scan mode in 0.997 °≤θ≤25.20 ° scope
Individual point diffraction, wherein 6508 is independent diffraction I >=2 σ (I).Non-hydrogen atom coordinate direct method solves,
Little square law carries out anisotropic temperature factor correction, minimum deflection factor R=0.0721, Rw=to non-hydrogen atom
0.1873.Crystal is monocrystalline, belongs to rhombic system, space group P212121, cell parameter Unit cell volumeIn brilliant bag, molecular number is 8,
Having 4 asymmetric cell, each asymmetric cell is contained within two cefathiamidine molecules, calculates crystalline density d
=1.076g/cm3.Concrete data and matching crystalline substance bag figure see attached list 1～5, accompanying drawing 1～2.
Embodiment 2
The mixed solvent 100ml of ethanol/water/acetone (volume ratio is 4:1:0.05) is added in clean conical flask,
It is subsequently adding cefathiamidine 5g, is made into the cefathiamidine solution of 0.15g/ml.With plastic film sealing, and
Some apertures are pricked on plastic sheeting.Deposit at a temperature of certain 0～8 DEG C.Stand 96 hours, to obtain final product.
The experiment of gained cefathiamidine crystal diffraction sees attached list 1～5 and accompanying drawing 1～2.
Embodiment 3
Adding ethanol/water volume ratio in clean conical flask is 10:1 mixed solvent 75ml, is subsequently adding cephalo
Sulfur amidine 50g, dissolves under room temperature, then drips acetone 25ml, is made into the cefathiamidine solution of 0.5g/ml [quite
In the mixed solvent 100ml that ethanol/water/acetone volume ratio is 10:1:3.67].With plastic film sealing, and
Some apertures are pricked on plastic sheeting.Deposit at a temperature of certain 7～15 DEG C.Stand 96 hours, to obtain final product.
The experiment of gained cefathiamidine crystal diffraction sees attached list 1～5 and accompanying drawing 1～2.
Embodiment 4
The mixed solvent 100ml of ethanol/water/acetone (volume ratio is 6.5:1:1.5) is added in clean conical flask,
It is subsequently adding cefathiamidine 20g, dissolves under room temperature, be made into the cefathiamidine solution of 0.2g/ml.Thin with plastics
Film seals, and pricks some apertures on a plastic film.Deposit at a temperature of certain 2～5 DEG C.Stand 96 little
Time, to obtain final product.
The experiment of gained cefathiamidine crystal diffraction sees attached list 1～5 and accompanying drawing 1～2.
Embodiment 5 stability test
Monocrystalline is prepared according to embodiment 1 method；Powder crystal I is prepared according to the method for 03136191.9 patent；According to
200410027695.9 the method for patent prepares unformed cefathiamidine.By three kinds of cefathiamidine products to be investigated
It is sealed in clean cillin bottle.Stand respectively and deposit in 40 degree of calorstats, shady and cool storehouse, freezer.Cillin bottle is all the time
It is kept upright.
Test: 40 DEG C of calorstats the 10th day, shady and cool stock puts the 180th day, and freezer is deposited the 180th day to enter respectively
Row test.Respectively take 1g sample, be dissolved in 10ml respectively and boil and place the purified water to room temperature, according to China
Pharmacopeia IX solution A colour measurement method the first method measures.
Result such as table 6 below: table 6 stability test result table
Result shows, monocrystalline color stability is under three kinds of storage conditions, and all good than other two kinds (YG is i.e.
Yellow green, the yellowish green meaning).
Embodiment 6 minimal inhibitory concentration method carries out antibacterial tests
Use the compounds I of embodiment 1 preparation, apply " disinfection technology standard " 2002 editions 2.1.8.4 minimums
Mlc (MIC) method carries out antibacterial tests, with 0.1mol/L phosphate buffer (pH6.0) as solvent,
Being dissolved by test medicine, after two-fold dilution, medicinal liquid and Muller-Hinton culture medium are mixed into concentration in proportion and are
A series of pastille flat boards of 512～0.015 μ g/ml, by dilute for 6～8h bacterium culture physiological saline solution to be measured
Release and manage (10 to Maxwell 0.58CFU/ml) 10 times (10 it is diluted to again7CFU/ml), the bacterium solution prepared has been added
Sample-adding after autoclaving holds in plate, is seeded to respectively containing variable concentrations medicinal liquid with MIC inoculation instrument
In culture medium, each vaccination of final quantity of microorganism inoculated 107CFU.Put 35 DEG C to cultivate 18 hours, by NCCLS
Standard judged result.
Result is as shown in table 7 below: table 7 antibacterial activity in vitro measurement result table
Antibacterial activity in vitro measurement result shows, Cefathiamidine monocrystal has preferable bactericidal action.To golden yellow
Color staphylococcus, streptococcus pneumoniae, Hai Shi enterococcus, enterococcus faecalis etc. have obvious antibacterial effect.
Embodiment 7
The Cefathiamidine monocrystal using embodiment 3 to prepare, in GMP workshop, is distributed into 1g specification
Cefathiamidine for injection powder pin.
Table 1. crystal data and structure optimization
w=1/[σ2(Fo2)+(0.1434P)2],P=(Fo2+2Fc2)/3
Table 2 non-hydrogen atom coordinate
Continued
Table 3 bond distance
Table 4 bond angle (°)
Continued
Table 5 hydrogen atom coordinate
Continued
Claims (4)
1. ethanol, water, three kinds of solvents of acetone are added clean by the method preparing Cefathiamidine monocrystal
In conical flask, ethanol: water: the volume ratio of acetone three is 4～10:1:0.05～3.67, add each solvent
Period or front and back, add cefathiamidine, dissolve under room temperature, be made into the cephalo of 0.05g/ml～0.5g/ml concentration
Sulfur amidine solution；With plastic film sealing, and prick some apertures on a plastic film；Deposit in 0 DEG C～15 DEG C of temperature
Under degree；Within about 48 hours, begin with tiny crystals to generate, to more than 96 hours, obtain following cefathiamidine list
Brilliant:
Outward appearance: water white transparency flat crystal, crystal belongs to rhombic system, space group P212121, cell parameterUnit cell volume In brilliant bag, molecular number is 8, has 4 asymmetric cell, and each asymmetric cell is contained within two cephalo sulfur
Amidine molecule.
2. according to the method preparing Cefathiamidine monocrystal described in described in right 1, it is characterised in that ethanol: water:
Propanol solvent mixture volume ratio is 6.5～8.5:1:0.39～2.23.
3. according to the method preparing Cefathiamidine monocrystal described in described in right 1, it is characterised in that the head of preparation
Spore sulfur amidine solution concentration is 0.10g/ml～0.25g/ml.
4. according to the method preparing Cefathiamidine monocrystal described in described in right 1, it is characterised in that storage temperature
It it is 2 DEG C～8 DEG C.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102453042A (en) * | 2010-11-01 | 2012-05-16 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method of high-purity cefathiamidine |
| CN102532165A (en) * | 2010-12-20 | 2012-07-04 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method for cefathiamidine crystals |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102453042A (en) * | 2010-11-01 | 2012-05-16 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method of high-purity cefathiamidine |
| CN102532165A (en) * | 2010-12-20 | 2012-07-04 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method for cefathiamidine crystals |
| 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 |
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