CN103717607A - Cefuroxime sodium crystal compound and composition powder injection thereof - Google Patents
Cefuroxime sodium crystal compound and composition powder injection thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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Abstract
The invention provides a cefuroxime sodium crystal compound and a composition powder injection thereof, and relates to the fields of medicament and preparation method technology of medicament, and cefuroxime sodium crystal compound composition belongs to a new crystal type-amorphous. The crystal form of cefuroxime sodium is amorphous and the preparation method thereof is as follows: reacting cefuroxime acid with sodium bicarbonate to obtain a solution and adding active carbon to discolor it, and then quick-freezing for 2 hours at -40-50 DEG C after sterile filtration using a filter membrane with aperture of 0.45 mu m and 0.22 mu m, followed by vacuum drying (drying temperature below 15 DEG C, vacuum degree 10-20 Pa, time 30-35 hours). The components of the cefuroxime sodium composition powder injection are: 95-100 parts of cefuroxime sodium crystal compound and 5-10 parts of mannitol. The component is packaged into bottles of 0.25 g, 0.75 g, 1.5 g, 2.25 g or 2.5 g as power injection preparation for clinic injection. The cefuroxime sodium crystal compound has the advantages of a simple preparation method, good stability, high solubility and dissolving quickly in water, and is convenient for clinical use.
Description
Technical field:
The present invention relates to preparation method's technical field of medicine and medicine, relate in particular to a kind of cephalofruxin sodium novel crystal form compound and composition powder injection thereof.
Background technology:
Cefuroxime sodium chemical name is: (6R, 7R)-7-[2-furyl (methoxyimino) kharophen]-3-carbamyl oxygen methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid sodium salt.Molecular formula: C
16h
15n
4naO
8s, molecular weight: 446.37.Its chemical structural formula is:
Cefuroxime sodium is second generation cephalosporin, has has a broad antifungal spectrum, anti-microbial activity is strong, and gram-positive microorganism and gram-negative micro-organism are all had to good anti-microbial activity, highly stable and side effect is little to β-lactamase.The crystal formation of at present commercially available cefuroxime sodium for injection belongs to triclinic(crystalline)system, and its cell configuration master data sees the following form:
Commercially available Cefuroxime sodium cell configuration master data
Accompanying drawing 1 is shown in by commercially available cefuroxime sodium for injection powder x-ray diffraction collection of illustrative plates, and its characteristic diffraction peak d value is respectively: 25.32,8.73,7.90,6.57,4.66,4.45,4.16,3.82,3.65,3.44,3.07,2.90,2.77; Commercially available cefuroxime sodium for injection infrared spectrogram is shown in accompanying drawing 3.Commercially available cefuroxime sodium for injection water-soluble poor, in water, solubleness is little, and dissolution rate is slow, and clinical use is inconvenient.Commercially available cefuroxime sodium for injection production technique is comparatively complicated, and production cost is high.
Summary of the invention:
The object of the invention is to overcome above-mentioned defect, a kind of Cefuroxime sodium crystalline compounds is provided.
A cephalofruxin sodium novel crystal form compound, is characterized in that, this compound has new crystallized form, and new crystallized form is amorphous.
New crystal compound provided by the invention, good stability, in water, solubleness is large, dissolution rate is fast, and the medicine preparation method of this crystallized form is simple, clinical easy to use, determined curative effect.
Another object of the present invention is to overcome above-mentioned defect, and a kind of cephalofruxin sodium novel crystal form compound---the production method of amorphous sterilized powder is provided.
For realizing another object of the present invention, adopt following technical scheme:
A) Stainless Steel Disc cleans to clean by purified water, water for injection respectively, and 121 ℃ of dry sterilizations 2.5 hours are cooling standby;
B) take the cefuroxime acid being up to the standards, add in the water for injection of 1～10 times of cefuroxime acid weight part, be mixed with cephalofruxin acid solution, under whipped state, slowly drip the aqueous solution of sodium bicarbonate, after cooling, adjust pH value to 6.0～8.5, add the gac of total mass 0.1%, 2～4 ℃ are stirred 30 minutes, 5 μ m titanium rod filtering decarbonizations; Filtrate makes cephalofruxin sodium solution through 0.45 μ m, 0.22 μ m millipore filtration Sterile Filtration, standby after clarity, PH passed examination;
C) cephalofruxin sodium solution is injected in the Stainless Steel Disc of sterilizing, drying, put into vacuum freeze drier, at-40 ℃---dry through 2 hours quick-frozen final vacuums at-50 ℃ of temperature, drying temperature is below 25 ℃, vacuum tightness 10-50 handkerchief, time 30-35 hour;
D) dry product obtains the amorphous aseptic freeze-dried powder of Cefuroxime sodium, packing after pulverizing, sieving.
The amorphous aseptic freeze-dried powder, preparation method thereof of Cefuroxime sodium provided by the invention utilizes Novel freezing dry technology, and production technique is simple, and production cost is low, and steady quality is more suitable for suitability for industrialized production.
A further object of the present invention is to provide a kind of Cefuroxime sodium composition powder injection that contains cephalofruxin sodium novel crystal form compound and clinical use packing specifications.
This Cefuroxime sodium composition powder injection component is: cephalofruxin sodium novel crystal form compound 95-100 part, N.F,USP MANNITOL 5-10 part.
Described composition powder injection is distributed into every bottle of injection powder injection containing 0.25 gram, 0.75 gram, 1.5 grams, 2.25 grams or 2.5 grams for clinical application.
The usage and dosage of the cefuroxime sodium for injection of China's approval is:
1. intramuscularly: 0.25g cefuroxime sodium for injection adds 1ml water for injection or 0.75g cefuroxime sodium for injection adds 3ml water for injection, shakes up and makes to become opaque suspension gently;
2. intravenous injection: the minimum 6ml water for injection that adds of the minimum 2ml of the adding water for injection of 0.25g cefuroxime sodium for injection or 0.75g cefuroxime sodium for injection, makes to be dissolved into yellow settled solution;
3. intravenous drip: 1.5g cefuroxime sodium for injection can be dissolved in 50ml water for injection or with most of conventional intravenous fluid compatibilities (except aminoglycoside); General or grade and moderate infection a: 0.75g, 3 times on the one, intramuscular or intravenous injection; Severe infection: dosage doubles, a 1.5g, 3 times on the one.
Usage and dosage according to the rules, and from facilitating clinical application, the angle that meets clinical application needs is determined.Consider and facilitate the conformability that doctor, nurse, patient's medication and Pharmacy are convenient to the management of medicine, doctor's medication and patient uses, we provide the composition of cefuroxime sodium for injection new crystal (amorphous) compound sterilized powder to be distributed into every bottle of injection powder injection containing 0.25 gram, 0.75 gram, 2.25 grams and 2.5 grams for clinical application.Specifications design is reasonable, the convenient management to medicine, and doctor is clinical easy to use, and patient's medication conformability is good, determined curative effect.
For a kind of cefuroxime sodium for injection powder novel crystalline forms, we have formulated relevant detection method:
1. infrared spectroscopy: press two appendix IVC infrared spectrophotometrys of < < Chinese Pharmacopoeia > > version in 2010, measure recording light spectrogram in accordance with the law.The molecule of measured matter is under infrared ray radiation, only absorb the infrared spectra consistent with its molecular vibration, rotational frequency, by infared spectrum and the 2010 editions appendix standard diagrams of < < Chinese Pharmacopoeia > > that obtain, contrast, judge whether unanimously with standard diagram absorption peak feature, a kind of cefuroxime sodium for injection powder is carried out to qualitative analysis.
2.X ray powder diffraction: press two appendix IX F x-ray powder diffractions of < < Chinese Pharmacopoeia > > version in 2010, measure in accordance with the law, record diffractogram.Due to amorphous solid aperiodicity structure, can not produce diffraction effect to X ray, according to powder diagram, judge whether a kind of cefuroxime sodium for injection powder novel crystalline forms is amorphous.
3. differential scanning calorimetry: ISO11357-1 measures in accordance with the law by international standard, records DSC scanning curve.DSC measures to be input to the heat flux of sample and reference substance poor or difference power and the relation of temperature or time, and the variation of the character such as material is in temperature changing process, is often accompanied by microtexture and macroscopical physics, chemical.Physics in macroscopic view, the variation of chemical property is associated with composition and the microtexture of material conventionally.By measure and amalyzing substances heat or process of cooling in physics, the variation of chemical property, can carry out qualitative analysis to a kind of cefuroxime sodium for injection powder.
4. differential thermogravimetric analysis (TGA): utilize differential thermal analysis (DTA) and thermogravimetry (TG) technology used in conjunction under temperature programmed control condition, measure the variation that the temperature head between sample and reference substance and sample quality send in intensification, cooling or thermostatic process.By drawing TG-DTA curve, a kind of cefuroxime sodium for injection powder is carried out to qualitative analysis.
Accompanying drawing explanation:
Fig. 1 is commercially available cefuroxime sodium for injection sterilized powder X ray diffracting spectrum;
Fig. 2 is the amorphous sterilized powder X ray diffracting spectrum of cefuroxime sodium for injection;
Fig. 3 is commercially available cefuroxime sodium for injection sterilized powder infrared spectrogram;
Fig. 4 is the amorphous sterilized powder infrared spectrogram of cefuroxime sodium for injection;
Fig. 5 is the amorphous sterilized powder DSC figure of cefuroxime sodium for injection;
Fig. 6 is the amorphous sterilized powder TG-DTA figure of cefuroxime sodium for injection.
Embodiment:
For technique means, creation characteristic that the present invention is realized, reach object and effect is easy to understand, below in conjunction with specific embodiment, further set forth the present invention.
One, prescription:
(95%) 1052 gram of cefuroxime acid
(98%) 202 gram of injection sodium bicarbonate
1578 milliliters of waters for injection
Two, production technique:
By aseptic technique requirement, respectively 202g sodium bicarbonate is dissolved in 1000ml water, 1052g cefuroxime acid is dissolved in and in 578ml water, forms sodium hydrogen carbonate solution and cephalofruxin acid solution, sodium hydrogen carbonate solution is slowly added to (above-mentioned two solution water temperature controls are at 5-8 ℃) in cephalofruxin acid solution, and constantly stir 30min, after question response is complete, add 0.1% gac and stir, adjusting pH is 6.5-7.5, after 0.45 μ m and 0.22 μ m membrane filtration, pack freeze-drying deep bid (liquid level 3-4cm) into, send into immediately vacuum freezing drying oven freeze-drying, first flaggy temperature is down to below-40 ℃, send into goods, in 2 hours, make products temperature reach-41 ℃ and be incubated 2 hours, in case, vacuum tightness maintains 10-20Pa, after start to heat up, in 20 hours, products temperature rises to 0 ℃, after every two hours heat up 1.5 ℃, when 15 ℃ of products temperatures, be incubated 3 hours.Outlet crushing packing after goods (cefuroxime sodium for injection aseptic powder) moisture is lower than 1%.
Three, goods (the amorphous sterilized powder of cefuroxime sodium for injection) detect:
1, X-ray diffracting spectrum and the contrast of commercially available product X-ray diffracting spectrum, its characteristic peak disappears, and is shown as another kind of crystal formation (amorphous), and accompanying drawing 2 is shown in by collection of illustrative plates.
2,2010 editions appendix standard diagram contrasts of infared spectrum and Chinese Pharmacopoeia, its absorption peak feature is consistent, and accompanying drawing 4 is shown in by collection of illustrative plates.
3, DSC curve spectrum is shown in accompanying drawing 5,
4, TG-DTA curve spectrum is shown in accompanying drawing 6
One, prescription
(95%) 1052 gram of cefuroxime acid
(98%) 202 gram of injection sodium bicarbonate
1578 milliliters of waters for injection
Two, production technique:
By aseptic technique requirement, respectively 202g sodium bicarbonate is dissolved in 1000ml water, 1052g cefuroxime acid is dissolved in and in 578ml water, forms sodium hydrogen carbonate solution and cephalofruxin acid solution, sodium hydrogen carbonate solution is slowly added to (above-mentioned two solution water temperature controls are at 5-8 ℃) in cephalofruxin acid solution, and constantly stir 30min, after question response is complete, add 0.1% gac and stir, adjusting pH is 6.5-7.5, after 0.45 μ m and 0.22 μ m membrane filtration, pack freeze-drying deep bid (liquid level 3-4cm) into, send into immediately vacuum freezing drying oven freeze-drying, first flaggy temperature is down to below-45 ℃, send into goods, in 2 hours, make products temperature reach-50 ℃ and be incubated 2 hours, in case, vacuum tightness maintains 10-20Pa, after start to heat up, in 30 hours, products temperature rises to-1 ℃, 1 ℃ of rear intensification per hour, when 5 ℃ of products temperatures, be incubated 4 hours.Outlet crushing packing after goods (cefuroxime sodium for injection aseptic powder) moisture is lower than 1%.
The cefuroxime sodium for injection sterilized powder that above two kinds of different freeze-dry process are produced detects and proves same substance, same crystal formation (amorphous) through infrared, X-ray diffraction, differential thermal analysis (DSC), thermogravimetric analysis (TG-DTA).
Embodiment 3
The preparation of Cefuroxime sodium composition powder injection: the Cefuroxime sodium amorphous compound sterilized powder 750g that gets embodiment 1 preparation, N.F,USP MANNITOL sterilized powder 6g, mix, according to specification 2.5g/ bottle (by Cefuroxime sodium), aseptic subpackaged in antibiotic glass bottle, jump a queue, roll lid, finished product packing warehouse-in censorship.
Test example
One, solubility test
This test has illustrated that cephalofruxin sodium novel crystal form compound provided by the invention has good solvability.
Sample classification (2.5g is example):
The product of sample 1: embodiment 1 preparation
Sample 2: commercially available cefuroxime sodium for injection (crystal type) (A factory)
Sample 3: commercially available cefuroxime sodium for injection (crystal type) (B factory)
Method: in the time of 25 ℃, respectively 1ml, 3ml, 5ml, 7ml, 9ml and 11ml purified water are injected to sample, jolt 3 minutes, then filter, dry, weigh, to calculate it and dissolve per-cent, result is as follows:
As from the foregoing, the solvability of sample 1 is best, when 5ml, all dissolves, and the solvability of sample 2, sample 3 is poorer than sample 1; Result can show, cephalofruxin sodium novel crystal form compound of the present invention is better than the solvability of commercially available cefuroxime sodium for injection.
Two: dissolution rate test
This test has illustrated that cephalofruxin sodium novel crystal form compound provided by the invention has good dissolution rate.
Sample classification (2.5g is example):
The product of sample 1: embodiment 3 preparations
Sample 2: commercially available cefuroxime sodium for injection (crystal type) (A factory)
Sample 3: commercially available cefuroxime sodium for injection (crystal type) (B factory)
Method: get respectively each 25 grams, three kinds of samples, be poured in 100ml beaker, get 50ml purified water and join in beaker, utilize magnetic stirrer, record dissolution time, result is as follows:
| Sample | |
| 1 | |
| 2 | 48s |
| 3 | 50s |
As seen from the above table, the complete dissolution time of sample 1 is shorter than the dissolution time of sample 2 and sample 3, and the dissolution rate of sample 1 is better than sample 2 and sample 3, and result can show, cephalofruxin sodium novel crystal form compound of the present invention has good dissolution rate, is conducive to clinical use.
Three: stability test
This test has illustrated that cephalofruxin sodium novel crystal form compound provided by the invention has good stability.
Sample classification (2.5g is example):
The product of sample 1: embodiment 3 preparations
Sample 2: commercially available cefuroxime sodium for injection (crystal type) (A factory)
Sample 3: commercially available cefuroxime sodium for injection (crystal type) (B factory)
Method: according to < < Chinese Pharmacopoeia > > two appendix XIXC bulk drugs of version in 2010 and pharmaceutical preparation stability test governing principle, again according to cefuroxime sodium for injection quality standard and the listed investigation project of injection study on the stability repertory, primary stability to this product is investigated, and investigation project comprises proterties, pH value, related substance, content, polymkeric substance, visible foreign matters, aseptic etc.
Accelerated test: respectively at 40 ℃, place 6 months under the condition of RH=75%, the sampling respectively in 0,1,2,3,6 month, by investigating item inspection, by test-results and comparison in 0 month, the results are shown in following table:
Long-term stable experiment: respectively at 25 ℃, place under RH=60% condition, in sampling in 0,3,6,9,12 month, by investigating item inspection, by test-results and comparison in 0 month.The results are shown in following table:
From above two tables, can find out, the stability there was no significant difference of sample 1, sample 2, sample 3, all accelerating to meet quality standard in June and long-term 12 months, cephalofruxin sodium novel crystal form compound stability provided by the invention is good, and noticeable change did not all occur indices (related substance, polymkeric substance, content, pH value etc.) in 12 months.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what in above-described embodiment and specification sheets, describe is only preference of the present invention; be not used for limiting the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (3)
1. a cephalofruxin sodium novel crystal form compound, is characterized in that, this compound has new crystallized form, and new crystallized form is amorphous.
2. a preparation method for cephalofruxin sodium novel crystal form compound claimed in claim 1, is characterized in that, this preparation method's concrete steps are:
A) Stainless Steel Disc cleans to clean by purified water, water for injection respectively, and 121 ℃ of dry sterilizations 2.5 hours are cooling standby;
B) take the cefuroxime acid being up to the standards, add in the water for injection of 1～10 times of cefuroxime acid weight part, be mixed with cephalofruxin acid solution, under whipped state, slowly drip the aqueous solution of sodium bicarbonate, after cooling, adjust pH value to 6.0～8.5, add the gac of total mass 0.1%, 2～4 ℃ are stirred 30 minutes, 5 μ m titanium rod filtering decarbonizations; Filtrate makes cephalofruxin sodium solution through 0.45 μ m, 0.22 μ m millipore filtration Sterile Filtration, standby after clarity, PH passed examination;
C) cephalofruxin sodium solution is injected in the Stainless Steel Disc of sterilizing, drying, put into vacuum freeze drier, at-40 ℃---dry through 2 hours quick-frozen final vacuums at-50 ℃ of temperature, drying temperature is below 25 ℃, vacuum tightness 10-50 handkerchief, time 30-35 hour;
D) dry product obtains the amorphous aseptic freeze-dried powder of Cefuroxime sodium, packing after pulverizing, sieving.
3. a Cefuroxime sodium composition powder injection that contains cephalofruxin sodium novel crystal form compound claimed in claim 1, is characterized in that, said composition powder pin component is: cephalofruxin sodium novel crystal form compound 95-100 part, N.F,USP MANNITOL 5-10 part.
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| PCT/CN2012/081283 WO2014040239A1 (en) | 2012-09-12 | 2012-09-12 | Cefuroxime sodium crystal compound and composition powder injection thereof |
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| CN107586304A (en) * | 2017-07-14 | 2018-01-16 | 浙江永宁药业股份有限公司 | A kind of Cefuroxime Sodium crystalline compounds and preparation method thereof |
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| WO2014040239A1 (en) | 2014-03-20 |
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