CN106432280A - Medicine ceftazidime crystalline compound for treating surgical operation infection - Google Patents
Medicine ceftazidime crystalline compound for treating surgical operation infection Download PDFInfo
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- CN106432280A CN106432280A CN201610845668.5A CN201610845668A CN106432280A CN 106432280 A CN106432280 A CN 106432280A CN 201610845668 A CN201610845668 A CN 201610845668A CN 106432280 A CN106432280 A CN 106432280A
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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
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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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to the technical field of medicine, and discloses a medicine ceftazidime crystalline compound for treating surgical operation infection. The structural formula of the ceftazidime crystalline compound is shown as the formula (I) (please see the specification); the ceftazidime crystalline compound is measured with the powder X-ray diffraction measuring method, and an X-ray powder diffraction spectrum expressed with the diffraction angle of 2 theta+/-0.2 degree is shown as the figure 1. The crystalline compound is high in purity, low in pyridine and polymer content, good in stability, not prone to moisture absorption and good in mobility, and the solubleness is greatly improved.
Description
Technical field
The invention belongs to pharmaceutical technology field is and in particular to a kind of medicine ceftazidime crystal treating Postoperative infection
Compound.
Background technology
Ceftazidime pentahydrate is anti Bacillus pyocyaneu Flugge effect in the third generation cephalosporin that GlaxoSmithKline PLC company is formulated
Antibiotic the strongest, for the septicemia caused by sensitive gram negative bacilli, lower respiratory infection, abdominal cavity and biliary tract infection, again
Polygamy urinary tract infection and serious skin soft tissue infection etc..For the immunodeficiency person being caused by multiple drug resistance gram negative bacillis
Caused by infection, nosocomial infection and gram negative bacilli or Pseudomonas aeruginosa, central nervous system infection is especially suitable.Its
Structural formula is：
.
In order to ensure human administration's safety, state-promulgated pharmacopoeia specifies, for ceftazidime antibiotic it is desirable to ceftazidime five water
The content of compound is not less than 95%, and impurity pyridine content is not higher than 0.12%, and the content of polymer is not higher than 0.3%, and other are always miscellaneous
Content is not higher than 2.0%, and its color and luster is not higher than No. 6 colors.Beta-Lactam antibiotic, such as penicillin medicine and cephalosporinses medicine
Thing, due to the less stable of parent nucleus, is susceptible to reset, decomposes and polyreaction, the polymer product being formed and allergy
Property shock have close relationship.In penicillin, averagely in 21.44 μ g/g, anaphylaxiss incidence rate is 0.2% to polymeric impurities
；Averagely in 51.24 μ g/g, anaphylaxiss incidence rate is 0.43% to polymeric impurities；Polymeric impurities average out to 76.7 μ g/
During g, allergy rate is 0.74%.Though cephalosporin anaphylaxiss are so serious not as good as penicillin, when polymer is high, same meeting
Human allergy is caused to react.
Ceftazidime chance light, heat, water, oxidation etc. are unstable, are also easy to produce catabolite, particularly suffer from high temperature (50 DEG C of ＞)
In the case of, tend to occur degraded and polyreaction, generate ceftazidime dimer, trimer and polymer etc. polymer,
Thus leading to active constituents of medicine content to reduce, color and luster is strengthened, and polymeric impurities content raises.In addition, expired ceftazidime
Antibiotic, because the resting period is long, also usually makes active constituents of medicine content reduce, darkens, polymer content liter
High.Further, in some cases, because controlling of production process is improper, obtained ceftazidime pentahydrate, ceftazidime
Dimer, trimer and polymer etc. polymer content is especially high.And polymer content high when, easily make human body produce allergy anti-
Should.So for the high ceftazidime pentahydrate of this kind of polymeric impurities content or ceftazidime pharmaceutical preparation it is necessary to enter
One step carries out purification, ceftazidime pentahydrate crystal that obtain high-quality, that purity is high.
CN102924483B discloses a kind of ceftazidime crystalline compounds, its preparation method and its no bacterium mix powder form
Pharmaceutical composition, the preparation method of ceftazidime crystalline compounds comprises the steps：1) prepare crude product solution：By cephalo he
Pyridine crude product adds in the mixed solvent being formulated by dimethyl sulfoxide and oxolane, is stirred to dissolve, and adds activated carbon decolorizing,
Filter, obtain crude product solution, standby；2) prepare recrystallisation solvent：By acetone and ethyl acetate by volume 1-2.5: 11.5 ratio
Example prepares recrystallisation solvent, and described recrystallisation solvent volume is 6-14 times of ceftazidime crude product weight；3) crystallize：Under stirring, to
Step 1) gained crude product solution in stream plus step 2) gained recrystallisation solvent, have solid separate out；After completion of dropping, continue stirring
Mix lower Deca ethanol, separate out to there being crystal；Standing 3-6h, filter, wash with dimethyl sulfoxide, be dried, obtain described in cephalo he
Acridine compound.Compared with prior art, the invention has the advantages that：(1) ceftazidime crystal chemical combination provided by the present invention
Thing purity is high, and has preferable heat stability, and substantially non-hygroscopic；
(2) the preparation method process is simple of ceftazidime provided by the present invention, high income, repeatability is strong, is suitable for industrialization
Produce；(3) the pharmaceutical composition stability containing this ceftazidime crystalline compounds provided by the present invention is fine, thus improving
Drug safety and effectiveness, reduce the incidence rate of untoward reaction.This ceftazidime crystalline compounds uses Cu-K alpha ray
Measure the X-ray powder diffraction spectrogram obtaining as shown in Figure 3.
CN103864819A discloses a kind of ceftazidime compound and its pharmaceutical composition, the system of ceftazidime compound
Preparation Method comprises the steps：1）Preparation crude product solution：Ceftazidime crude product is added and is formulated with methanol by dimethyl sulfoxide
Mixed solvent in, control temperature 20-30 DEG C, add activated carbon decolorizing, filter, obtain ceftazidime crude product solution, standby；2）
Nucleus generating process：In the range of 20-30 DEG C, in this solution, stream adds the temperature controlling ceftazidime crude product solution under agitation
Deionized water, has muddy appearance, obtains turbid solution；3）Crystal growing process：By step 2）The turbid solution of gained is placed in super
Under sound field, control 20-30 DEG C of solution temperature, Deca chloroform thereto, separate out crystal；Close ultrasonic field, be cooled to 0-5
DEG C, filter, filter cake is washed with deionized, vacuum drying obtains described ceftazidime compound.The present invention has excellent as follows
Point：（1）Ceftazidime compound provided by the present invention has preferable heat stability, and polymer content change is little；（2）This
Bright provided ceftazidime has preferable mobility, is conducive to improving the accuracy of subpackage, and mixes with other compositions
When, be easily mixed uniformly；（3）Ceftazidime provided by the present invention has preferable bioavailability.This ceftazidime compound
The X-ray powder diffraction spectrogram being obtained using Cu-K alpha ray measurement is as shown in Figure 4.
Although above-mentioned purification process to some extent solves its purity problem, through further investigation revealed that, by
In ceftazidime during depositing, particularly under conditions of high temperature (50 DEG C of ＞), tend to occur degraded and polyreaction, with
The prolongation of resting period, its high polymer content increases, so that the risk that human body produces anaphylactic reaction is increased.
Ceftazidime is clinically typically used in the form of Ceftazidime for Injection sterilized powder.Injection head
His pyridine of spore is usually ceftazidime and pharmaceutic adjuvant mixing is aseptic subpackaged forms, and has that grain diameter is larger, and mixing is uneven, dress
Amount difference is big, and during leading to use, effective active composition ceftazidime is not easy accurate quantitative analysis.Simultaneously because ceftazidime
Purity is different so that Ceftazidime for Injection has the various problems such as color and luster, degraded, polymerization and stability, untoward reaction wind
Danger increases.
The present inventor, with existing ceftazidime crude product as raw material, through lot of experiments, has been obtained one kind and has been different from existing skill
The ceftazidime compound of the novel crystal forms of art, and by test, surprisingly find this crystalline compounds purity height, pyridine and polymerization
Thing content is low, good stability, and is difficult moisture absorption, good fluidity, substantially increases its dissolubility.Made using this crystal-form compound
Dry suspension good fluidity, impurity content low, good stability.
Content of the invention
It is an object of the invention to provide a kind of medicine ceftazidime crystalline compounds treating Postoperative infection, this crystalline substance
Not only purity is high for body compound, and pyridine and polymer content are low, good stability, and it is difficult moisture absorption, mobility, dissolubility etc.
It is substantially better than prior art.
For realizing the purpose of the present invention, the present invention adopts the following technical scheme that：
A kind of medicine ceftazidime crystalline compounds treating Postoperative infection, the knot of described ceftazidime crystalline compounds
As shown in formula I, this crystalline compounds is measured structure formula with powder X-ray diffraction algoscopy, the X being represented with the 2 θ ± 0.2 ° angles of diffraction
Ray powder diffraction as shown in figure 1,
Formula（）.
The present invention also provides a kind of preparation method of the medicine ceftazidime crystalline compounds treating Postoperative infection, should
Method comprises the steps：
Prepare 35 DEG C of ceftazidime crude product saturated aqueous solution, be subsequently adding the mixed solvent of ethyl acetate, carbon tetrachloride, stirring
After uniformly, stir in cooling, be simultaneously introduced acetone, after being cooled to 0 DEG C, stop stirring, stand growing the grain 1-2 hour, filter, very
Sky obtains ceftazidime crystal after 4-6 hour is dried.
Described ceftazidime crude product can be the cephalo as disclosed in CN102391289A for the method using prior art
Ceftazidime pentahydrate or commercially available ceftazidime pentahydrate raw material that the synthetic method of his pyridine prepares
Medicine.
In above-mentioned preparation method, wherein, described ethyl acetate, the mixed solvent volume of carbon tetrachloride are ceftazidime crude product
The 40-60% of saturated aqueous solution volume.Described ethyl acetate, the volume ratio of carbon tetrachloride are 2:1.Described cooling rate is 7-9
DEG C/h, mixing speed is 80-100 rev/min.Described acetone volume is ethyl acetate, the mixed solvent volume of carbon tetrachloride
4-6 times.
The present invention also provides a kind of ceftazidime dry suspension, described compositionss contain cephalo provided by the present invention he
The ceftazidime crystal-form compound that the preparation method of pyridine crystal-form compound or the present invention is obtained.
Described ceftazidime dry suspension, in parts by weight, by the ceftazidime of 100 weight portions, 1300-1340 weight
The cane sugar powder of part, 130-150 Hypromellose, the xanthan gum composition of 130-150 weight portion.
Preferably, described ceftazidime dry suspension, in parts by weight, by the ceftazidime of 100 weight portions, 1320 weights
The cane sugar powder of amount part, 140 Hypromellose, the xanthan gum composition of 140 weight portions.
Described ceftazidime dry suspension, is prepared from by following preparation method：
1）Sieve：Sucrose, ceftazidime are crossed 60 mesh sieves, 80 mesh sieves crossed by Hypromellose and xanthan gum, standby；
2）Premix：Weigh the ceftazidime of recipe quantity and cane sugar powder mixes 20 minutes；
3）Always mix：Recipe quantity Hypromellose and xanthan gum is added to be sufficiently mixed uniformly；
4）Middle product examine is tested；
5）Packaging, full inspection warehousing after passing.
Compared with prior art, the invention has the advantages that：
（1）Not only purity is high for ceftazidime crystalline compounds provided by the present invention, and pyridine and polymer content are low, stability
Good, and it is difficult moisture absorption, and mobility, dissolubility etc. are substantially better than prior art；
（2）The preparation method process is simple of ceftazidime provided by the present invention, high income, repeatability is strong, is suitable for industrialization
Produce；
（3）Dry suspension good fluidity containing this ceftazidime crystal-form compound provided by the present invention, impurity content are low, steady
Qualitative good.
Brief description
Fig. 1 is the X-ray powder diffraction figure of ceftazidime crystalline compounds of the present invention；
Fig. 2 is the heat analysis collection of illustrative plates of ceftazidime crystalline compounds of the present invention；
Fig. 3 is the X-ray powder diffraction collection of the ceftazidime crystallization of patent CN102924483B embodiment preparation；
Fig. 4 is the X-ray powder diffraction collection of the ceftazidime crystallization of patent CN103864819A embodiment preparation.
Specific embodiment
With embodiment, technical scheme is described in detail below, it will help the technical side to the present invention
The advantage of case, effect have and further understand, embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim is determining.
The preparation of embodiment 1 ceftazidime crystalline compounds
Prepare 35 DEG C of ceftazidime crude product saturated aqueous solution, be subsequently adding ceftazidime crude product saturated aqueous solution volume 40%
Ethyl acetate, the mixed solvent of carbon tetrachloride, described ethyl acetate, the volume ratio of carbon tetrachloride are 2:1, after stirring,
Stir in cooling, cooling rate be 7 DEG C/h, mixing speed be 80 revs/min, be simultaneously introduced volume be ethyl acetate, four
The acetone of 4 times of the mixed solvent volume of chlorination carbon, stops stirring after being cooled to 0 DEG C, stands growing the grain 1-2 hour, filters, vacuum
Ceftazidime crystal is obtained after 4-6 hour is dried.
Measured with powder X-ray diffraction algoscopy, the X-ray powder diffraction collection being represented with the 2 θ ± 0.2 ° angles of diffraction is such as
Shown in Fig. 1, at 2.8 °, 3.6 °, 4.5 °, 7.5 °, 9.0 °, 11.9 °, 14.5 °, 18.6 °, 27.0 °, show characteristic diffraction peak.
Measuring moisture using Ka Shi aquametry is 14.13 wt%, substantially identical with theoretical value.
Measured using thermogravimetric analysiss, result is as shown in Fig. 2 crystal water content is 14.15wt%, substantially identical with theoretical value.
The preparation of embodiment 2 ceftazidime crystalline compounds
Prepare 35 DEG C of ceftazidime crude product saturated aqueous solution, be subsequently adding ceftazidime crude product saturated aqueous solution volume 50%
Ethyl acetate, the mixed solvent of carbon tetrachloride, described ethyl acetate, the volume ratio of carbon tetrachloride are 2:1, after stirring,
Stir in cooling, cooling rate be 8 DEG C/h, mixing speed be 90 revs/min, be simultaneously introduced volume be ethyl acetate, four
The acetone of 5 times of the mixed solvent volume of chlorination carbon, stops stirring after being cooled to 0 DEG C, stands growing the grain 1-2 hour, filters, vacuum
Ceftazidime crystal is obtained after 4-6 hour is dried.
Measured with powder X-ray diffraction algoscopy, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of embodiment 3 ceftazidime crystalline compounds
Prepare 35 DEG C of ceftazidime crude product saturated aqueous solution, be subsequently adding ceftazidime crude product saturated aqueous solution volume 60%
Ethyl acetate, the mixed solvent of carbon tetrachloride, described ethyl acetate, the volume ratio of carbon tetrachloride are 2:1, after stirring,
Stir in cooling, cooling rate be 9 DEG C/h, mixing speed be 100 revs/min, be simultaneously introduced volume be ethyl acetate,
The acetone of 6 times of the mixed solvent volume of carbon tetrachloride, stops stirring after being cooled to 0 DEG C, stands growing the grain 1-2 hour, filters, very
Sky obtains ceftazidime crystal after 4-6 hour is dried.
Measured with powder X-ray diffraction algoscopy, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of embodiment 4 ceftazidime crystalline compounds
Prepare 35 DEG C of ceftazidime crude product saturated aqueous solution, be subsequently adding ceftazidime crude product saturated aqueous solution volume 40%
Ethyl acetate, the mixed solvent of carbon tetrachloride, described ethyl acetate, the volume ratio of carbon tetrachloride are 2:1, after stirring,
Stir in cooling, cooling rate be 8 DEG C/h, mixing speed be 100 revs/min, be simultaneously introduced volume be ethyl acetate,
The acetone of 5 times of the mixed solvent volume of carbon tetrachloride, stops stirring after being cooled to 0 DEG C, stands growing the grain 1-2 hour, filters, very
Sky obtains ceftazidime crystal after 4-6 hour is dried.
Measured with powder X-ray diffraction algoscopy, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of embodiment 5 ceftazidime crystalline compounds
Prepare 35 DEG C of ceftazidime crude product saturated aqueous solution, be subsequently adding ceftazidime crude product saturated aqueous solution volume 60%
Ethyl acetate, the mixed solvent of carbon tetrachloride, described ethyl acetate, the volume ratio of carbon tetrachloride are 2:1, after stirring,
Stir in cooling, cooling rate be 7 DEG C/h, mixing speed be 80 revs/min, be simultaneously introduced volume be ethyl acetate, four
The acetone of 4 times of the mixed solvent volume of chlorination carbon, stops stirring after being cooled to 0 DEG C, stands growing the grain 1-2 hour, filters, vacuum
Ceftazidime crystal is obtained after 4-6 hour is dried.
Measured with powder X-ray diffraction algoscopy, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
【Example of formulations 1】Ceftazidime dry suspension
In parts by weight, prescription composition is as follows：100 parts of ceftazidime, 1320 parts of sucrose, 140 parts of Hypromellose, xanthan
140 parts of glue.
Ceftazidime is the ceftazidime crystal-form compound that the embodiment of the present invention 1 is obtained.
Preparation method：
1）Sieve：Sucrose, ceftazidime are crossed 60 mesh sieves, 80 mesh sieves crossed by Hypromellose and xanthan gum, standby；
2）Premix：Weigh the ceftazidime of recipe quantity and cane sugar powder mixes 20 minutes；
3）Always mix：Recipe quantity Hypromellose and xanthan gum is added to be sufficiently mixed uniformly；
4）Middle product examine is tested；
5）Packaging, full inspection warehousing after passing.
【Example of formulations 2】Ceftazidime dry suspension
In parts by weight, prescription composition is as follows：100 parts of ceftazidime, 1300 parts of sucrose, 150 parts of Hypromellose, xanthan gum
150 parts.
Preparation method：With example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 2
His pyridine crystal formation.
【Example of formulations 3】Ceftazidime dry suspension
In parts by weight, prescription composition is as follows：100 parts of ceftazidime, 1340 parts of sucrose, 130 parts of Hypromellose, xanthan gum
150 parts.
Preparation method：With example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 3
His pyridine crystal formation.
【Example of formulations 4】Ceftazidime dry suspension
In parts by weight, prescription composition is as follows：100 parts of ceftazidime, 1300 parts of sucrose, 130 parts of Hypromellose, xanthan gum
130 parts.
Preparation method：With example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 4
His pyridine crystal formation.
【Example of formulations 5】Ceftazidime dry suspension
In parts by weight, prescription composition is as follows：100 parts of ceftazidime, 1340 parts of sucrose, 150 parts of Hypromellose, xanthan gum
150 parts.
Preparation method：With example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 5
His pyridine crystal formation.
Trial target 1：Ceftazidime crystalline compounds prepared by the embodiment of the present invention 1；
Trial target 2：Ceftazidime crystalline compounds prepared by the embodiment of the present invention 4；
Reference substance 1：Method according to CN102924483B embodiment 1 is obtained ceftazidime crystalline compounds；
Reference substance 2：Method according to CN103864819A embodiment 1 is obtained ceftazidime compound；
Reference substance 3：Method according to CN105560194A embodiment 1 is obtained ceftazidime；
Reference substance 4：Method according to CN105585582A embodiment 1 is obtained ceftazidime.
Experimental example 1：Heat stabilization test
It is, in the environment of 75%, temperature is 60 DEG C, to have according in CN105560194A that each sample is respectively exposed to relative humidity
Pass material, impurity pyridine, the detection method of polymer detect to items, the results are shown in Table 1：
Table 1 heat stabilization test result
Pyridine is two class noxious substances, and pyridine can stimulate human eye, skin and respiratory tract, to human central nervous system, liver,
Kidney, gastrointestinal all have an impact, and consciousness of personality can be caused to reduce.If pyridine residual quantity is high, more serious impact can be produced on human body.Logical
Cross the security test to ceftazidime medicine, pyridine residual limit of safety in ceftazidime medicine not can exceed that
0.12%.Contain pyridine groups due in ceftazidime structure, medicine, in placement process, can gradually decompose impurity pyridine and go out
Come, particularly the ceftazidime of stability difference, in placement process, pyridine residual quantity can increase comparatively fast, and this has relatively to human body
Big harm.
The height of drug quality is directly connected to the health of millions upon millions of working people's bodies, is also related to China's economic construction
Effect, the consolidation of national defence and nationality flourishing；It has been far from the thing of medical industry enterprise scope itself, but entirely
The national, major issue in the world.Those skilled in the art all clearly know, in the present age that pharmaceutical technology is flourishing, drug safety standard quilt
Constantly lifted, the purity also more and more higher of prepared medicine, be effectively reduced impurity content, even the several percentage of zero point
Point it is also possible to effectively reduce the generation of untoward reaction, therefore impurity content to drug quality and people's drug safety to closing weight
Will.Medicine needs to store and transport just can cure the sickness to save the patient from production to the process of circulation, therefore, medicine in storage and transportation
Quality be particularly important, stability is the key determining drug quality quality, in medicine storage and transportation, stable
Property bad, impurity change directly affect greatly people's drug safety.
As can be seen from the above table, the relevant material of ceftazidime crystalline compounds of the present invention, pyridine, polymer equal size are equal
Very low, and heat stability is significantly better than the ceftazidime being obtained after purification using the method for prior art, is effectively lifted
The stability of drug safety and storage, reduces the generation of untoward reaction.
Above-mentioned test is also carried out to the ceftazidime crystalline compounds of other embodiments of the present invention, its result phase obtaining
Seemingly.
Experimental example 2：Fluidity test
This experimental example evaluates the mobility of sample by the angle of repose of determination sample, and concrete grammar is as follows：Take sample particle, from
Flow in fixing little funnel in the surface plate of circle, until obtaining highest cone, measure cone height H and radius R,
Calculate α angle of repose by tan α=H/R, the results are shown in Table 2, angle of repose is bigger, mobility is poorer.
Table 2 fluidity test result
As known from Table 2, compared with ceftazidime of the prior art, ceftazidime compound flow of the present invention significantly improves,
Be conducive to improving the accuracy of subpackage, and be easily mixed when mixing with other compositions uniformly.
Experimental example 3：Dissolubility test
Add appropriate distilled water in the low capacity bottle with constant temperature jacket, add ceftazidime at 20 DEG C to not re-dissolved
Till, start magnetic stirrer, continuously stirred under constant temperature, system is in the state of two-phase coexistent all the time in experimentation, 70
In the liquid phase of system after minute, the concentration of ceftazidime is the dissolubility at a temperature of this.It is sampled after 2 hours analyzing, take
The close meansigma methodss of adjacent two times result as measured value of experiment, before sampling, in order that solid-liquid is sufficiently separated, stop stirring after,
Not molten ceftazidime is deposited to the bottom of low capacity bottle, extracts a small amount of upper clear supernate with syringe, with 0.45 micron of filter
Filter, take sample from filtrate, measure the content of ceftazidime by HPLC（Concentration（mg/ml））.The results are shown in Table 3.
Under table 3 room temperature, ceftazidime crystal compound of the present invention and the water solublity of prior art crystal formation contrast
From table 3 it can be seen that the water solublity of ceftazidime crystal compound of the present invention is compared with prior art, has and significantly carry
High.
Experimental example 4：Wettability test
Each sample opening is put in clean culture dish, spreads out into≤thick the thin layer of 5mm, each two parts, be respectively put into constant humidity hermetic container
In, place 10 days under conditions of relative humidity 75% and 92.5% at 25 DEG C, sampled in the 5th day and the 10th day, pass through
The moisture of loss on drying experiment measurement each sample, result of the test was compared with 0 day, and experimental result is shown in Table 4.
Table 4 hygroscopicity test results
As can be seen from the above table, ceftazidime crystalline compounds of the present invention are substantially non-hygroscopic under high humidity conditions, and it is in high humidity
Stability under environment is substantially better than the ceftazidime obtaining using the purification process process of prior art.
Above-mentioned experimental example 1-4 is also carried out to the ceftazidime crystal-form compound of other embodiments of the present invention, it obtains
Result is similar.
Experimental example 5：Prescription screening is tested（Using dry suspension preparation method of the present invention preparation）
Table 5 prescription screening experimental result
As can be seen from the above table, the ceftazidime dry suspension that the present invention is obtained（Prescription six）Not only mobility, and polymer,
Always miscellaneous content significantly reduces.
Experimental example 6：Preparation influence factor tests
Formulation test product 1：Ceftazidime dry suspension prepared by invention formulation embodiment 1；
Formulation test product 2：Ceftazidime dry suspension prepared by invention formulation embodiment 3.
Hot test takes trial target, and opening is put in sealing clean container, places 10 days, by stability at a temperature of 60 DEG C of degree
High spot reviews project is detected.
High wet test takes trial target, and opening is put in constant-humidity clean container（Relative humidity 90% ± 5%）Place 10 days, by steady
Qualitative high spot reviews project is detected.
Highlight test takes trial target, and opening is put in lighting box, places 10 days, by stability emphasis under the conditions of 4500LX
Investigation project is detected.
Table 6 preparation influence factor's result of the test
Found by result above, the compositionss dry suspension stream containing this ceftazidime crystal-form compound prepared by the present invention
Dynamic property is good, impurity content is low, good stability.
Above-mentioned test is also carried out to the ceftazidime dry suspension of present invention other example of formulations, its result obtaining
Similar.
Claims (1)
1. a kind of medicine ceftazidime crystalline compounds treating Postoperative infection it is characterised in that：Described ceftazidime
The structural formula of crystalline compounds as shown in formula I, this crystalline compounds with powder X-ray diffraction algoscopy measure, with 2 θ ±
X-ray powder diffraction pattern that 0.2 ° of angle of diffraction represents as shown in figure 1,
Formula（）.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610845668.5A CN106432280A (en) | 2016-09-23 | 2016-09-23 | Medicine ceftazidime crystalline compound for treating surgical operation infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610845668.5A CN106432280A (en) | 2016-09-23 | 2016-09-23 | Medicine ceftazidime crystalline compound for treating surgical operation infection |
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| EP0267427B1 (en) * | 1986-10-07 | 1992-03-18 | BIOCHEMIE Gesellschaft m.b.H. | Process for the preparation of cephalosporin derivatives |
| CN101607966A (en) * | 2008-06-19 | 2009-12-23 | 上海新先锋药业有限公司 | The preparation method of ceftazidime pentahydrate |
| CN102924483A (en) * | 2012-10-31 | 2013-02-13 | 海南合瑞制药股份有限公司 | Ceftazidime crystal compound, preparation method of compound and pharmaceutical composition of compound in sterile mixed powder form |
| CN103030651A (en) * | 2012-12-25 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing ceftazidime hydrochloride |
| CN103044457A (en) * | 2012-10-22 | 2013-04-17 | 深圳华润九新药业有限公司 | Method for purifying ceftazidime |
| CN103864819A (en) * | 2014-03-31 | 2014-06-18 | 悦康药业集团有限公司 | Ceftazidime compound and pharmaceutical composition thereof |
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| US4525587A (en) * | 1982-12-27 | 1985-06-25 | Eli Lilly And Company | Process for preparing a cephalosporin compound |
| EP0267427B1 (en) * | 1986-10-07 | 1992-03-18 | BIOCHEMIE Gesellschaft m.b.H. | Process for the preparation of cephalosporin derivatives |
| CN101607966A (en) * | 2008-06-19 | 2009-12-23 | 上海新先锋药业有限公司 | The preparation method of ceftazidime pentahydrate |
| CN103044457A (en) * | 2012-10-22 | 2013-04-17 | 深圳华润九新药业有限公司 | Method for purifying ceftazidime |
| CN102924483A (en) * | 2012-10-31 | 2013-02-13 | 海南合瑞制药股份有限公司 | Ceftazidime crystal compound, preparation method of compound and pharmaceutical composition of compound in sterile mixed powder form |
| CN103030651A (en) * | 2012-12-25 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing ceftazidime hydrochloride |
| CN103864819A (en) * | 2014-03-31 | 2014-06-18 | 悦康药业集团有限公司 | Ceftazidime compound and pharmaceutical composition thereof |
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Application publication date: 20170222 |