CN103864819A - Ceftazidime compound and pharmaceutical composition thereof - Google Patents
Ceftazidime compound and pharmaceutical composition thereof Download PDFInfo
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- CN103864819A CN103864819A CN201410126071.6A CN201410126071A CN103864819A CN 103864819 A CN103864819 A CN 103864819A CN 201410126071 A CN201410126071 A CN 201410126071A CN 103864819 A CN103864819 A CN 103864819A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- 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
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
Abstract
The invention relates to a ceftazidime compound and a pharmaceutical composition thereof. The structural formula of the ceftazidime compound is shown in a formula (I) described in the specification. The compound is determined by a powder X-ray diffraction determination method, an X-ray powder diffraction pattern represented by a diffraction angle of 2theta+/-0.2 degrees is shown in the figure 1. The compound not only has good thermal stability, but also has excellent mobility. Pharmacokinetic study surprisingly finds out that the ceftazidime compound disclosed by the invention has good bioavailability.
Description
Technical field
The invention belongs to field of medicaments, relate in particular to a kind of ceftazime compound, its preparation method and the pharmaceutical composition without bacterium mix powder form thereof.
Background technology
Ceftazime; chemistry (6R by name; 7R)-7-[[(2-amino-4-thiazolyl)-[(1-hydroxyl-1-methyl ethoxy) imino-] ethanoyl] amino]-2-carboxyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-3-picoline inner salt pentahydrate; for applying clinically cynnematin more widely, its structural formula is:
In order to ensure human body drug safety, state-promulgated pharmacopoeia regulation, for ceftazime microbiotic, requires the content of ceftazidime pentahydrate to be not less than 95%, and the content of polymkeric substance is not higher than 0.3%, and its color and luster is not higher than No. 6 looks.Ceftazime microbiotic is depositing in process, particularly suffer in the situation of high temperature (50 DEG C of >), often there is degraded and polyreaction, generate ceftazime dipolymer, trimer and polymer etc. polymkeric substance, thereby cause active constituents of medicine content to reduce, color and luster is strengthened, and polymeric impurities content raises.In addition, expired ceftazime microbiotic, because the shelf-time is long, also usually makes active constituents of medicine content reduce, and darkens, and polymer content raises.Further, in some cases, because controlling of production process is improper, the ceftazidime pentahydrate obtaining, ceftazime dipolymer, trimer and polymer etc. polymer content is high especially.And polymer content is when high, easily make human body produce anaphylaxis.So for the high ceftazidime pentahydrate of this base polymer foreign matter content or ceftazime pharmaceutical preparation, be necessary further to carry out purifying, obtain ceftazidime pentahydrate crystal high-quality, that purity is high.
GB2063871 has disclosed the preparation method of ceftazidime pentahydrate crystal, and the method is that the pH of adjusting ceftazime hydrochlorate or the alkali salt aqueous solution is 3.3-4.0, and ceftazidime pentahydrate crystal structure is separated out.The ceftazidime pentahydrate that above-mentioned polymeric impurities content is higher or ceftazime pharmaceutical preparation, for example, polymeric impurities content is higher than 4% time, according to the method crystallization purifying of GB2063871, polymeric impurities is often accompanied by ceftazidime pentahydrate crystal and separates out together, so the content of polymeric impurities is still very high in the ceftazidime pentahydrate crystal obtaining.
GB2157682 discloses a kind of recovery method of ceftazime, the method is to adopt NOT-function large hole mesh resin, with pH be that the 2.0-5.5 ceftazime aqueous solution is removed, thereby absorb ceftazime, carry out again wash-out, isolate ceftazime or its salt or its hydrate.According to the method, final product may be ceftazime or its salt or its hydrate, and impurity polymer content reduces, product color shoals, but the method need to be used NOT-function large hole mesh resin, then carries out wash-out, separation, operation is many, complex operation, and cost is high.
US4659813 discloses a kind of preparation method of ceftazidime pentahydrate crystal, the method is, at the temperature of approximately 5～15 DEG C, pH is approximately 5.5～approximately 6.5 the ceftazime aqueous solution, regulating its pH with acid is approximately 4.0～approximately 4.7, and in crystallisation process by control acid add, make pH be maintained at about 4.0～approximately 4.7, thereby separate out ceftazidime pentahydrate crystal.Although this method is to improving product purity, reducing polymer content has certain help, and the ceftazime preparation very high for polymer content, color and luster is very poor, in this way, still can not get the ceftazidime pentahydrate crystal of high-quality.Meanwhile, this method is first dissolved in material in the system that pH is higher, causes ceftazime to be degraded to some extent, and the rate of recovery reduces like this.
CN1775784A discloses a kind of purification process of ceftazime, more particularly, relate to by impure, containing the high ceftazime of polymeric impurities by the method for the ceftazidime pentahydrate of crystalline high-quality.Ceftazidime pentahydrate impure, that polymer content is high, ceftazime hydrochloride, ceftazime ambroxol salt or ceftazime preparation expired or from retrieving on the market, be mixed with the ceftazime aqueous solution, then regulating the pH of the ceftazime aqueous solution with alkali or acid is 1.5-2.5, now impurity, ceftazime polymkeric substance follow a small amount of ceftazime to separate out together, remove by filter these precipitates, it is 3.5-4.8 that the filtrate obtaining regulates pH with alkali, and ceftazidime pentahydrate crystal structure is separated out.The method is easy and simple to handle, and cost is low, and security is good, and yield is high, and the ceftazidime pentahydrate crystal purity obtaining is high, and polymer content is low, reaches pharmacopeia specified requirement.
CN101607966A discloses a kind of preparation method of ceftazidime pentahydrate, carries out according to following step: step 1, in a dissolving vessel, inject water for injection, add ceftazime hydrochloride, after dissolving, drop into activated carbon decolorizing, filter, filtrate is stand-by; Step 2, in another dissolving vessel, inject water for injection, add ceftazime hydrochloride, after dissolving, drop into gac, decolouring, filters, and filtrate proceeds to crystallizer; Step 3 drips alkaline solution in the crystallizer in second step, regulates pH to 4.0-6.0, then the filtrate dripping in the first step makes pH value pull back to 3.6, maintenance temperature 0-10 DEG C, stirring, crystallization; After step 4, growing the grain 3-4 hour, filter, filter cake washs respectively with cold water and acetone, and vacuum-drying 2-3 hour obtains ceftazidime pentahydrate crystal.Its advantage is: economize on the use of funds, simplify technique, reduce waste gas discharge of wastewater; Easy and simple to handle, be applicable to suitability for industrialized production; Purity is high, yield is high.
Visible, the method for prior art mostly from improve stability, to reduce the quality that improves ceftazime product of polyreaction as far as possible.But ceftazime poor fluidity prepared by the method for prior art, has had a strong impact on its packing accuracy and homogeneity, is not suitable for industrial production.
In view of this, special proposition the present invention.
Summary of the invention
Primary and foremost purpose of the present invention is to provide a kind of ceftazime compound, and this not only has good thermostability, and mobility is better.
For achieving the above object, the present invention adopts following technical scheme:
A kind of ceftazime compound, is characterized in that, the structural formula of described ceftazime compound is as shown in formula I, and this compound is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle as shown in Figure 1.
The inside solid-state structure of compound has very large impact to its physicochemical property, same compound, and its crystal formation difference, causes its lattice energy difference, thereby causes its physicals also different.
The invention provides a kind of ceftazime unlike the prior art, have higher lattice energy compared with the ceftazime of prior art, lattice is stronger to the binding force of ceftazime molecule, thereby has improved the stability of ceftazime compound.Contriver is by thermally-stabilised new test, and result shows, compared with the special crystallized form of ceftazime compound provided by the present invention and the solid form of the ceftazime of prior art, to have stronger thermostability, and this has greatly improved patient's drug safety.In addition, the inventor is surprised to find that, ceftazime compound provided by the present invention has extraordinary mobility, is easy to packing.
Meanwhile, the present invention also tests by pharmacokinetics, finds that ceftazime of the present invention has better bioavailability pleasantly surprisedly.
The preparation method who the present invention also aims to provide above-mentioned ceftazime compound, the method comprises the steps:
1) prepare crude product solution: ceftazime crude product is added by methyl-sulphoxide and the formulated mixed solvent of methyl alcohol, control 20～30 DEG C of temperature, add activated carbon decolorizing, filter, obtain ceftazime crude product solution, for subsequent use;
2) nucleus generative process: control the temperature of ceftazime crude product solution within the scope of 20～30 DEG C, under agitation add deionized water to stream in this solution, have muddy appearance, obtain turbid solution;
3) crystal growing process: by step 2) turbid solution of gained is placed under ultrasonic field, controls 20～30 DEG C of solution temperatures, drips wherein trichloromethane, crystallize out; Close ultrasonic field, be cooled to 0～5 DEG C, filter, filter cake deionized water wash, vacuum-drying obtains described ceftazime compound.
In the present invention, described ceftazime crude product can be the ceftazidime pentahydrate that adopts the method for prior art to prepare as the synthetic method of the disclosed ceftazime of CN102391289A, can be also commercially available ceftazidime pentahydrate bulk drug.
Crystallization is a complicated process, and under different environment, the change of arbitrary step of crystallisation process all can form different crystallization effects.In the present invention, first for ensureing effective crystallization, step 1) by activated carbon decolorizing, filter the raw material of purifying; Step 2) and step 3) be nucleus generate and crystal growing process.Wherein step 3), after nucleus forms, has been introduced ultrasonic field, has and changes crystal morphology, regulates crystal size, improves size-grade distribution and shorten the effect of crystallization time etc. and introduce ultrasonic field in crystallisation process.In the present invention, characterize by the ceftazime compound crystal form X RD to prepared, find that prepared ceftazime compound is a kind of ceftazime that is different from prior art crystal formation.
As preferred version of the present invention, wherein, the amount ratio of the ceftazime crude product described in step 1) and described mixed solvent is 1g:5～8ml.
In described mixed solvent, the volume ratio of methyl-sulphoxide and methyl alcohol is 3～7:1.
Step 2) described in deionized water and the volume ratio of the mixed solvent described in step 1) be 5:1～10:1.
Ultrasonic field described in step 3) is that frequency is that 3.5～6.5kHz, intensity are 0.6Wcm
-2～4Wcm
-2ultrasonic field.
The volume ratio of the mixed solvent described in the trichloromethane described in step 3) and step 1) is 7:1～12:1.
Step 2) described stirring velocity is 130～200r/min.
Step 2) described in stream rate of acceleration be 10～15ml/min; Drop rate described in step 3) is 5～8ml/min.
The present invention also further provides a kind of pharmaceutical composition, and described pharmaceutical composition contains ceftazime compound provided by the present invention.
In the present invention, described pharmaceutical composition can be prepared as any applicable various formulations of prior art, described various formulations can be prepared with reference to the similar formulation of prior art, and pay more creative work without those skilled in the art, can realize object of the present invention.
The preferred injectable sterile powder of the present invention.
Preferred, injectable sterile powder of the present invention also contains anhydrous sodium carbonate.
Most preferred, in described pharmaceutical composition, the consumption of anhydrous sodium carbonate is the 11.2wt% of the consumption of ceftazime compound, and wherein the consumption of ceftazime compound is pressed ceftazime (C
22h
22n
6o
7s
2) meter.
Described pharmaceutical composition is after aseptic subpackaged, to make aseptic powder injection after ceftazime crystalline compounds mixes by described consumption with anhydrous sodium carbonate.
Sterilized powder of the present invention can carry out packing by the specification of 0.5g/ bottle, 1.0g/ bottle, 2.0g/ bottle etc.The specification is here with ceftazime (C
22h
22n
6o
7s
2) meter.
Compared with prior art, tool of the present invention has the following advantages:
(1) ceftazime compound provided by the present invention has good thermostability, and polymer content changes little;
(2) ceftazime provided by the present invention has good mobility, is conducive to improve the accuracy of packing, and is easy to mix while mixing with other composition;
(3) ceftazime provided by the present invention has good bioavailability.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of ceftazime compound of the present invention;
Fig. 2 is that 24 healthy volunteers take the average Plasma Concentration-time curve after ceftazidime for inj investigational agent and contrast medicine.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, instead of restriction the present invention.
The preparation of [embodiment 1] ceftazime compound
1) prepare crude product solution: add 110ml by methyl-sulphoxide and the formulated mixed solvent (wherein the volume ratio of methyl-sulphoxide and methyl alcohol is 6:1) of methyl alcohol 20g ceftazime crude product, control 22 DEG C of temperature, add 0.01% activated carbon decolorizing of ceftazime crude product weight, filter, obtain ceftazime crude product solution, for subsequent use;
2) nucleus generative process: control the temperature of ceftazime crude product solution within the scope of 22 DEG C, add deionized water with the data rate stream of 11ml/min under the stirring that low whipping speed is 150r/min in this solution, have muddy appearance, obtain turbid solution;
3) nucleus crystal growing process: by step 2) to be placed in frequency be that 4kHz, intensity are 3Wcm for the turbid solution of gained
-2ultrasonic field under, control 22 DEG C of solution temperatures, drip 1210ml trichloromethane, crystallize out with the speed of 8ml/min wherein; Close ultrasonic field, be cooled to 1 DEG C, filter, filter cake deionized water wash 3 times, vacuum-drying obtains described ceftazime compound.Purity 99.8%, weight loss on drying 14.1%.
The ceftazime crystalline compounds obtaining is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle as shown in Figure 1.
The preparation of [embodiment 2] ceftazime compound
1) prepare crude product solution: add 150ml by methyl-sulphoxide and the formulated mixed solvent (wherein the volume ratio of methyl-sulphoxide and methyl alcohol is 4:1) of methyl alcohol 20g ceftazime crude product, control 28 DEG C of temperature, add 0.01% activated carbon decolorizing of ceftazime crude product weight, filter, obtain ceftazime crude product solution, for subsequent use;
2) nucleus generative process: control the temperature of ceftazime crude product solution within the scope of 28 DEG C, add 1050ml deionized water with the data rate stream of 14ml/min under the stirring that low whipping speed is 180r/min in this solution, have muddy appearance, obtain turbid solution;
3) nucleus crystal growing process: by step 2) to be placed in frequency be that 4.8kHz, intensity are 1Wcm for the turbid solution of gained
-2ultrasonic field under, control 28 DEG C of solution temperatures, drip 1500ml trichloromethane, crystallize out with the speed of 7ml/min wherein; Close ultrasonic field, be cooled to 3 DEG C, filter, filter cake deionized water wash 3 times, vacuum-drying obtains described ceftazime compound.Purity 99.7%, weight loss on drying 14.0%.
The ceftazime crystalline compounds obtaining is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is consistent with embodiment 1.
The preparation of [embodiment 3] ceftazime compound
1) prepare crude product solution: add 130ml by methyl-sulphoxide and the formulated mixed solvent (wherein the volume ratio of methyl-sulphoxide and methyl alcohol is 5:1) of methyl alcohol 20g ceftazime crude product, control 25 DEG C of temperature, add 0.01% activated carbon decolorizing of ceftazime crude product weight, filter, obtain ceftazime crude product solution, for subsequent use;
2) nucleus generative process: control the temperature of ceftazime crude product solution within the scope of 25 DEG C, add 1040ml deionized water with the data rate stream of 12ml/min under the stirring that low whipping speed is 160r/min in this solution, have muddy appearance, obtain turbid solution;
3) nucleus crystal growing process: by step 2) to be placed in frequency be that 5.0kHz, intensity are 2Wcm for the turbid solution of gained
-2ultrasonic field under, control 25 DEG C of solution temperatures, drip 1170ml trichloromethane, crystallize out with the speed of 6ml/min wherein; Close ultrasonic field, be cooled to 2 DEG C, filter, filter cake deionized water wash 3 times, vacuum-drying obtains described ceftazime compound.Purity 99.8%, weight loss on drying 14.2%.
The ceftazime crystalline compounds obtaining is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is consistent with embodiment 1.
The preparation of [embodiment 4] ceftazime compound
1) prepare crude product solution: add 160ml by methyl-sulphoxide and the formulated mixed solvent (wherein the volume ratio of methyl-sulphoxide and methyl alcohol is 7:1) of methyl alcohol 20g ceftazime crude product, control 30 DEG C of temperature, add 0.01% activated carbon decolorizing of ceftazime crude product weight, filter, obtain ceftazime crude product solution, for subsequent use;
2) nucleus generative process: control the temperature of ceftazime crude product solution within the scope of 30 DEG C, add 1600ml deionized water with the data rate stream of 15ml/min under the stirring that low whipping speed is 200r/min in this solution, have muddy appearance, obtain turbid solution;
3) nucleus crystal growing process: by step 2) to be placed in frequency be that 6.5kHz, intensity are 4Wcm for the turbid solution of gained
-2ultrasonic field under, control 30 DEG C of solution temperatures, drip 1920ml trichloromethane, crystallize out with the speed of 8ml/min wherein; Close ultrasonic field, be cooled to 5 DEG C, filter, filter cake deionized water wash 3 times, vacuum-drying obtains described ceftazime compound.Purity 99.7%, weight loss on drying 14.0%.
The ceftazime crystalline compounds obtaining is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is consistent with embodiment 1.
The preparation of [embodiment 5] ceftazime compound
1) prepare crude product solution: add 100ml by methyl-sulphoxide and the formulated mixed solvent (wherein the volume ratio of methyl-sulphoxide and methyl alcohol is 3:1) of methyl alcohol 20g ceftazime crude product, control 20 DEG C of temperature, add 0.01% activated carbon decolorizing of ceftazime crude product weight, filter, obtain ceftazime crude product solution, for subsequent use;
2) nucleus generative process: control the temperature of ceftazime crude product solution within the scope of 20 DEG C, add 500ml deionized water with the data rate stream of 10ml/min under the stirring that low whipping speed is 130r/min in this solution, have muddy appearance, obtain turbid solution;
3) nucleus crystal growing process: by step 2) to be placed in frequency be that 3.5kHz, intensity are 0.6Wcm for the turbid solution of gained
-2ultrasonic field under, control 20 DEG C of solution temperatures, drip 700ml trichloromethane, crystallize out with the speed of 5ml/min wherein; Close ultrasonic field, be cooled to 0 DEG C, filter, filter cake deionized water wash 3 times, vacuum-drying obtains described ceftazime compound.Purity 99.8%, weight loss on drying 14.2%.
The ceftazime crystalline compounds obtaining is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is consistent with embodiment 1.
[example of formulations 1] ceftazidime for inj
Specification: 0.5g(presses ceftazime C
22h
22n
6o
7s
2meter)
Preparation method:
1, interior packaging material processing
The technique cleaning routinely of antibiotic glass bottle, plug, aluminium lid, oven dry, sterilizing, for subsequent use;
2, concrete steps
(1) take anhydrous sodium carbonate and the prepared ceftazime compound of embodiment 1 of recipe quantity, in sterile chamber, mix;
(2) product inspection in the middle of;
(3) undertaken aseptic subpackaged by specification;
(4) vacuumize, tamponade, roll lid;
(5) packaging, Quan Jian, warehouse-in.
[example of formulations 2] ceftazidime for inj
Specification: 1.0g(presses ceftazime C
22h
22n
6o
7s
2meter)
Preparation method: with example of formulations 1, difference is that ceftazime used is the prepared ceftazime compound of embodiment 2.
[example of formulations 3] ceftazidime for inj
Specification: 2.0g(presses ceftazime C
22h
22n
6o
7s
2meter)
Preparation method: with example of formulations 1, difference is that ceftazime used is the prepared ceftazime compound of embodiment 3.
[example of formulations 4] ceftazidime for inj
Specification: 0.5g(presses ceftazime C
22h
22n
6o
7s
2meter)
Preparation method: with example of formulations 1, difference is that ceftazime used is the prepared ceftazime compound of embodiment 4.
[example of formulations 5] ceftazidime for inj
Specification: 1.0g(presses ceftazime C
22h
22n
6o
7s
2meter)
Preparation method: with example of formulations 1, difference is that ceftazime used is the prepared ceftazime compound of embodiment 5.
[example of formulations 6] ceftazidime for inj
Specification: 2.0g(presses ceftazime C
22h
22n
6o
7s
2meter)
Preparation method: with example of formulations 1, difference is that ceftazime used is the prepared ceftazime compound of embodiment 2.
[example of formulations 7] ceftazidime for inj
Specification: 0.5g(presses ceftazime C
22h
22n
6o
7s
2meter)
Preparation method: with example of formulations 1, difference is that ceftazime used is the prepared ceftazime compound of embodiment 3.
Test example 1
Heat stability test
Depositing in process, particularly, under the condition of high temperature (50 DEG C of >), often there is degraded and polyreaction, thereby cause active constituents of medicine content to reduce in ceftazime, color and luster is strengthened, and polymeric impurities content raises.This test example is for investigating the prepared ceftazime crystalline compounds of the present invention and the thermal stability difference of ceftazime of the prior art.
In this test example, each sample is numbered:
Trial target 1: the ceftazime crystalline compounds that the embodiment of the present invention 1 is prepared;
Trial target 2: the ceftazime crystalline compounds that the embodiment of the present invention 5 is prepared;
Reference substance 1: according to the method for CN1775784A embodiment 1, ceftazidime pentahydrate is carried out the ceftazidime pentahydrate that obtains after purifying;
Reference substance 2: the ceftazidime pentahydrate crystal obtaining according to the method for CN101607966A embodiment 1.
By each sample be exposed to respectively that relative humidity is 75%, temperature is under the environment of 60 DEG C, (size exclusive chromatography is according to second of pharmacopeia in 2005 to adopt size exclusive chromatography to measure the content of high molecular polymer, the relevant condition of annex VH is measured), the results are shown in Table 1.
Table 1, heat stability test result
| Time | Content | Trial target 1 | |
Reference substance 1 | |
| 0 day | The content (%) of polymkeric substance | 0.01 | 0.02 | 0.09 | 0.03 |
| 7 days | The content (%) of polymkeric substance | 0.02 | 0.02 | 0.18 | 0.19 |
| 14 days | The content (%) of polymkeric substance | 0.02 | 0.03 | 0.22 | 0.27 |
| 21 days | The content (%) of polymkeric substance | 0.03 | 0.04 | 0.30 | 0.31 |
| 28 days | The content (%) of polymkeric substance | 0.03 | 0.03 | 0.33 | 0.36 |
As can be seen from the above table, adopt the thermostability of the ceftazime compound that method of the present invention makes to be significantly better than adopting the method for prior art to carry out the ceftazidime pentahydrate crystal obtaining after purifying.
The ceftazime compound of other embodiment of the present invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Test example 2
Fluidity test
This test example has been investigated the mobility of the ceftazime compound of the present invention and prior art.
This test example is carried out the mobility of assess sample by the slope of repose of working sample, concrete grammar is as follows: sample thief particle, from fixing little funnel, flow in circular watch-glass, until obtain the highest cone, measure cone height H and radius R, calculate slope of repose α by tan α==H/R, the results are shown in Table 2, slope of repose is larger, and mobility is poorer.Refer to table 2.
Table 2, fluidity test result
| ? | Sample 1 | |
Sample 3 | |
| Slope of repose (°) | 45° | 46° | 62° | 64° |
Wherein: sample 1 is the product of the embodiment of the present invention 1;
The ceftazidime pentahydrate of sample 3 for making according to the method for CN102391289A embodiment 8;
The ceftazidime pentahydrate of sample 4 for making according to the method for CN1775784A embodiment 1.
As known from Table 2, compared with ceftazime of the prior art, the prepared ceftazime compound of the present invention has good mobility, is conducive to improve the accuracy of packing, and is easy to mix while mixing with other composition.
Test example 3
Pharmacokinetics test
1, instrument and reagent
Agilent1100Series high performance liquid chromatograph, Agilent company of the U.S. produces, and comprising: G1310A HPLC pump, G1313A automatic sampler, G1314A ultraviolet wavelengthtunable detector, G1310A chromatographic working station.
Ceftazidime for inj investigational agent (ceftazidime for inj that example of formulations 2 of the present invention makes); Ceftazidime for inj contrast medicine (ceftazidime for inj making according to the prescription of example of formulations 2 of the present invention and method, difference is that ceftazime used is the ceftazidime pentahydrate making according to the method for CN1775784A embodiment 1).In test, acetonitrile used is chromatographically pure, and other reagent are analytical pure, and test water is distilled water.The Healthy Human Serum that blank plasma provides for Beijing Red Cross Society blood station.
2, method and result
2.1 chromatographic condition
Chromatographic column: A lltin a C
18(53mm × 7mm, 3 μ m, Alltech company of the U.S.); Chromatogram pre-column: Aichram-Bond AQ C
18(2.1mm × 10mm, 5 μ m, Abel Industrise company of the U.S.); Moving phase: 0.02molL
-1potassium primary phosphate-methyl alcohol (85:15, v/v); Flow velocity: 2mLmin
-1, detect wavelength: 254nm; Column temperature: room temperature; Sample size: 20 μ L.
2.2 sample pretreatment
Serum specimen treatment process: the accurate serum sample 500 μ L that draw, put in 5mL centrifuge tube, add perchloric acid (0.5molL
-1) 500 μ L, vortex vibration 1min, in 10000rmin
-1centrifugal 5min, draws supernatant liquor sample introduction and measures.
2.3 pharmacokinetic studies
24 selected healthy male volunteers are the students of university, experimenter's mean age is (21.7 ± 1.6) year, height is (173.9 ± 2.8) cm, body weight is (65.9 ± 4.4) kg, weight index BMI is 21.8 ± 1.5, is normal before health check-up, electrocardiogram(ECG, blood biochemistry, routine blood test and routine urine test.Experimenter tests and within first 1 week, does not take any medicine, medicine-less allergy history and habits of smoking and alcohol drinking.This test is through the approval of Ethics Committee of institute, and the experimenter who participates in test all signs written Informed Consent Form.
24 experimenters are divided into two groups at random, test group and control group, every group 12, respectively at having fasting 12h after light dinner the day before yesterday of taking medicine, after tested administration in morning on the same day, continue fasting to 4h, respectively after administration 4, the 10h standard meal of taking food, can drink water during tested, can not drink tea, coffee and Other Drinks.Experimenter, at experimental session, can only, in special ward activity, can not carry out aggravating activities.Duration of test can not be drunk, smoking.Test group and control group give respectively ceftazime investigational agent and ceftazime contrast medicine, and ceftazime investigational agent and contrast medicine are used respectively after a small amount of physiological saline solution, add in 250mL physiological saline constant speed intravenous drip 30min.Duration of test blood sampling is arranged to before instillation, 5min, drop 30min during drop finishes can and administration 5,15,30,45,60,90,120,180,240,360,480 after finishing, 720min extracting vein blood 5mL, after experimenter's blood sampling, can leave away.4000rmin
-1centrifugal 10min, separation of serum, the blood specimen after administration is measured immediately, and the sample of not surveyed is in-20 DEG C of preservations, and within the stationary phase of sample, measures complete.The average plasma concentration curve recording is shown in Fig. 2.
Can find out the C of investigational agent from the average Plasma Concentration-time curve of ceftazime
maxbe better than contrasting medicine, adopt trapezoidal method to calculate AUC, result shows to be subject to the AUC of reagent to be also better than contrasting medicine.
The ceftazidime for inj that other example of formulations of the present invention is made has also carried out above-mentioned test, and the result of its acquisition is similar.
Claims (10)
1. a ceftazime compound, it is characterized in that, the structural formula of described ceftazime compound is as shown in formula I, and this compound is measured by powder x-ray diffraction assay method, the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle as shown in Figure 1
2. a preparation method for ceftazime compound claimed in claim 1, is characterized in that, the method comprises the steps:
1) prepare crude product solution: ceftazime crude product is added by methyl-sulphoxide and the formulated mixed solvent of methyl alcohol, control 20～30 DEG C of temperature, add activated carbon decolorizing, filter, obtain ceftazime crude product solution, for subsequent use;
2) nucleus generative process: control the temperature of ceftazime crude product solution within the scope of 20～30 DEG C, under agitation add deionized water to stream in this solution, have muddy appearance, obtain turbid solution;
3) crystal growing process: by step 2) turbid solution of gained is placed under ultrasonic field, controls 20～30 DEG C of solution temperatures, drips wherein trichloromethane, crystallize out; Close ultrasonic field, be cooled to 0～5 DEG C, filter, filter cake deionized water wash, vacuum-drying obtains described ceftazime compound.
3. preparation method according to claim 2, is characterized in that, the amount ratio of the ceftazime crude product described in step 1) and described mixed solvent is 1g:5～8ml.
4. preparation method according to claim 3, is characterized in that, in described mixed solvent, the volume ratio of methyl-sulphoxide and methyl alcohol is 3～7:1.
5. preparation method according to claim 2, is characterized in that step 2) described in deionized water and the volume ratio of the mixed solvent described in step 1) be 5:1～10:1.
6. preparation method according to claim 2, is characterized in that, the ultrasonic field described in step 3) is that frequency is that 3.5～6.5kHz, intensity are 0.6Wcm
-2～4Wcm
-2ultrasonic field.
7. preparation method according to claim 2, is characterized in that, the volume ratio of the mixed solvent described in the trichloromethane described in step 3) and step 1) is 7:1～12:1.
8. preparation method according to claim 2, is characterized in that step 2) described stirring velocity is 130～200r/min.
9. preparation method according to claim 2, is characterized in that step 2) described in stream rate of acceleration be 10～15ml/min; Drop rate described in step 3) is 5～8ml/min.
10. a pharmaceutical composition that contains ceftazime compound claimed in claim 1.
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| CN106167498A (en) * | 2016-06-23 | 2016-11-30 | 石药集团中诺药业（石家庄）有限公司 | A kind of new ceftazidime compound |
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