CN106317081A - Anti-inflection pharmaceutical ceftazidime crystal compound and ceftazidime pharmaceutical composition - Google Patents
Anti-inflection pharmaceutical ceftazidime crystal compound and ceftazidime pharmaceutical composition Download PDFInfo
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- CN106317081A CN106317081A CN201610697050.9A CN201610697050A CN106317081A CN 106317081 A CN106317081 A CN 106317081A CN 201610697050 A CN201610697050 A CN 201610697050A CN 106317081 A CN106317081 A CN 106317081A
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- ceftazidime
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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
- 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
Abstract
The invention belongs to the technical field of medicine and discloses an anti-inflection pharmaceutical ceftazidime crystal compound and a ceftazidime pharmaceutical composition. The ceftazidime crystal compound has a structural formula (I) as shown below, and by measuring the crystal compound by powder X-ray diffraction measurement, an X-ray powder diffraction pattern represented by 2Theta+/-0.2 DEG is shown as in 1. The crystal compound has high purity, low pyridine and polymer content and good stability, rarely adsorbs moisture, has good mobility and has greatly improved solubility; the pharmaceutical composition made with the crystal compound has high purity, low impurity content and good clarity, subpackaging efficiency and small content non-uniformity in the production can be guaranteed, occurrence of adverse reaction is greatly reduced, and the stability is better.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of anti-infectives ceftazidime crystalline compounds and medicine group thereof
Compound.
Background technology
Ceftazidime pentahydrate is anti Bacillus pyocyaneu Flugge effect in the third generation cephalosporin that GlaxoSmithKline PLC company formulates
The strongest antibiotic, is used for sensitivity septicemia, lower respiratory infection, abdominal cavity and biliary tract infection caused by gram negative bacilli, answers
Polygamy urinary tract infection and serious skin soft tissue infection etc..For the immunodeficiency person caused by multiple drug resistance gram negative bacilli
Infect, central nervous system infection caused by nosocomial infection and gram negative bacilli or Pseudomonas aeruginosa 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 total
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 cephalosporins
Medicine, due to the less stable of parent nucleus, is susceptible to reset, decompose and polyreaction, the polymer product formed and mistake
Quick property shock has close relationship.In penicillin, polymeric impurities is averagely when 21.44 μ g/g, and anaphylaxis incidence rate is
0.2%；Polymeric impurities is averagely when 51.24 μ g/g, and anaphylaxis incidence rate is 0.43%；Polymeric impurities average out to 76.7
During μ g/g, allergy rate is 0.74%.Though cephalosporin anaphylaxis is so serious not as good as penicillin, but during polymer height, equally
Human allergy can be caused to react.
Ceftazidime meets the instability such as light, heat, water, oxidation, is easily generated catabolite, particularly suffers high temperature (＞ 50 DEG C)
In the case of, tend to occur degraded and polyreaction, generate ceftazidime dimer, trimer and polymer etc. polymer,
Thus causing active constituents of medicine content to reduce, color and luster is strengthened, and polymeric impurities content raises.It addition, expired ceftazidime
Antibiotic, owing to the resting period is long, the most usually makes active constituents of medicine content reduce, darkens, and polymer content raises.
Further, in some cases, owing to controlling of production process is improper, obtained ceftazidime pentahydrate, ceftazidime dimerization
Thing, trimer and polymer etc. polymer content is the highest.And during polymer content height, easily make human body produce anaphylaxis.
So for the high ceftazidime pentahydrate of this kind of polymeric impurities content or ceftazidime pharmaceutical preparation, it is necessary to further
It is purified, ceftazidime pentahydrate crystal that obtain high-quality, that purity is high.
CN102924483B discloses a kind of ceftazidime crystalline compounds, its preparation method and without 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 by the formulated mixed solvent of dimethyl sulfoxide and oxolane, is stirred to dissolve, addition 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 preparation recrystallisation solvent, described recrystallisation solvent volume is 6～14 times of ceftazidime crude product weight；3) crystallization: under stirring, Xiang Bu
Rapid 1) in the crude product solution of gained, stream adds step 2) gained recrystallisation solvent, there is solid to separate out；After dropping, continue under agitation
Dropping ethanol, separates out to there being crystal；Stand 3～6h, filter, wash with dimethyl sulfoxide, be dried, obtain described ceftazidime
Compound.Compared with prior art, present invention have the advantage that (1) ceftazidime provided by the present invention crystalline compounds is pure
Degree height, and there is preferable heat stability, and the most non-hygroscopic；(2) preparation method of ceftazidime provided by the present invention
Technique is simple, and yield is high, and repeatability is strong, is suitable for industrialized production；(3) provided by the present invention containing this ceftazidime crystal
The pharmaceutical composition stability of compound is fine, thus improves drug safety and effectiveness, reduces sending out of untoward reaction
Raw rate.The X-ray powder diffractogram that the use Cu-K alpha ray measurement of this ceftazidime crystalline compounds obtains is as shown in Figure 3.
CN103864819A discloses a kind of ceftazidime compound and pharmaceutical composition, the system of ceftazidime compound
Preparation Method comprises the steps: 1) prepare crude product solution: ceftazidime crude product is added 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 generates process: the temperature of control ceftazidime crude product solution is in the range of 20～30 DEG C, under agitation in this solution
Stream adds deionized water, has muddy appearance, obtains turbid solution；3) crystal growing process: by step 2) turbid solution of gained puts
Under ultrasonic field, control solution temperature 20～30 DEG C, drip chloroform wherein, separate out crystal；Close ultrasonic field, be cooled to
0～5 DEG C, filtering, filter cake is washed with deionized, and vacuum drying obtains described ceftazidime compound.The present invention have as
Lower advantage: (1) ceftazidime provided by the present invention compound has preferable heat stability, and polymer content change is little；(2)
Ceftazidime provided by the present invention has preferable mobility, be conducive to improve subpackage accuracy, and with other composition
It is easily mixed during mixing uniformly；(3) ceftazidime provided by the present invention has preferable bioavailability.This ceftazidime
The X-ray powder diffractogram that compound use Cu-K alpha ray measurement obtains is as shown in Figure 4.
Although above-mentioned purification process to some extent solves its purity problem, but through further investigation revealed that, by
In ceftazidime during depositing, particularly under conditions of high temperature (＞ 50 DEG C), tend to occur degraded and polyreaction, with
The prolongation of resting period, its high polymer content increases, and the risk making human body produce anaphylactic reaction increases.
Ceftazidime is typically to use with the form of ceftazidime for injection sterilized powder clinically.Injection head
, there is grain diameter relatively big, mix uneven in his pyridine usually ceftazidime of spore and pharmaceutic adjuvant mixing is aseptic subpackaged forms, dress
Amount difference is big, and during causing using, effective active composition ceftazidime is not easy accurate quantitative analysis.Simultaneously because ceftazidime
Purity is different so that ceftazidime for injection also exists color and luster, degrades, is polymerized and the various problems such as stability, untoward reaction wind
Danger increases.
The present inventor is with existing ceftazidime crude product as raw material, through lot of experiments, has prepared one and has been different from existing skill
The ceftazidime compound of the novel crystal forms of art, and by test, surprisingly find that this crystalline compounds purity is high, pyridine and polymerization
Thing content is low, good stability, and is difficult to moisture absorption, good fluidity, substantially increases its dissolubility.This crystalline compounds is utilized to make
Pharmaceutical composition not only purity high, impurity content is low, clarity good, and can guarantee that the subpackage efficiency in production, loading amount are poor
Different little, adverse reaction rate is substantially reduced, and stability is more preferable.
Summary of the invention
The first object of the present invention is to provide a kind of anti-infectives ceftazidime crystalline compounds, this crystalline compounds
Not only purity is high, and pyridine and polymer content are low, good stability, and it is difficult to moisture absorption, and mobility, dissolubility etc. are substantially better than
Prior art.
The second object of the present invention is to provide the preparation method of described ceftazidime crystalline compounds, the method technique
Simply, yield is high, and repeatability is strong, is suitable for industrialized production.
The third object of the present invention is to provide a kind of ceftazidime medicinal composition, and described pharmaceutical composition contains this
Invent the ceftazidime crystalline compounds that the preparation method of ceftazidime crystalline compounds or the present invention provided prepares.This medicine
Compositions not only purity is high, impurity content is low, clarity good, and can guarantee that the subpackage efficiency in production, content uniformity are little,
Adverse reaction rate is substantially reduced, and stability is more preferable.
For realizing the first object of the present invention, the present invention adopts the following technical scheme that
A kind of anti-infectives ceftazidime crystalline compounds, it is characterised in that described ceftazidime crystalline compounds
Structural formula as shown in formula I, this crystalline compounds with powder X-ray diffraction algoscopy measure, with 2 θ ± 0.2 ° angle of diffraction tables
The X-ray powder diffraction pattern shown as it is shown in figure 1,
For realizing the second object of the present invention, the present invention adopts the following technical scheme that
The preparation method of a kind of anti-infectives ceftazidime crystalline compounds of the present invention, it is characterised in that should
Method comprises the steps:
1) by ceftazidime dissolving crude product in the ethanol of 10-25 DEG C, the mixed solvent A of water；
2) first with speed addition N-Methyl pyrrolidone and the mixed solvent B of dichloromethane, the limit edged of 15-24ml/min
Stirring, controls temperature 10-25 DEG C, growing the grain 0.5-1 hour；
3) again with speed addition N-Methyl pyrrolidone and the mixed solvent C of dichloromethane, the growing the grain 2-of 10-15ml/min
After 5 hours, it is cooled to-5 DEG C with the speed of 15-20 DEG C/h, then stirring and crystallizing, growing the grain 1-3 hour；
4) filter, washing, 35-45 DEG C, drying under reduced pressure within 3-5 hour, obtain ceftazidime crystalline compounds.
In the present invention, described ceftazidime crude product can be the method such as CN102391289A institute public affairs using prior art
The ceftazidime pentahydrate that the synthetic method of the ceftazidime opened prepares, it is also possible to be commercially available ceftazidime five hydration
Raw material medicine.
In the preparation method of the present invention, wherein, step 1) described in the 4-that volume is ceftazidime weight of mixed solvent A
8 times, ethanol is 1:2.5 with the volume ratio of water.
Step 2) described in 5-7 times that volume is ceftazidime weight of mixed solvent B, N-Methyl pyrrolidone and dichloro
The volume ratio of methane is 1:4.
Step 3) described in 8-10 times that volume is ceftazidime weight of mixed solvent C, N-Methyl pyrrolidone and two
The volume ratio of chloromethanes is 1:3.
For realizing the third object of the present invention, the present invention adopts the following technical scheme that
A kind of ceftazidime medicinal composition, it is characterised in that described pharmaceutical composition contains provided by the present invention
The ceftazidime crystalline compounds that the preparation method of ceftazidime crystalline compounds or the present invention prepares.
Described pharmaceutical composition is possibly together with natrium carbonicum calcinatum.
In described pharmaceutical composition, ceftazidime crystalline compounds and natrium carbonicum calcinatum weight ratio are 5-7:1.
Described pharmaceutical composition makes aseptic powder injection after aseptic subpackaged.
Compared with prior art, present invention have the advantage that
(1) ceftazidime crystalline compounds not only purity provided by the present invention is high, and pyridine and polymer content are low, stable
Property is good, and it is difficult to moisture absorption, and mobility, dissolubility etc. are substantially better than prior art.
(2) the preparation method technique of ceftazidime provided by the present invention is simple, and yield is high, and repeatability is strong, is suitable for work
Industry metaplasia is produced；
(3) the not only purity of the pharmaceutical composition containing this ceftazidime crystalline compounds provided by the present invention height, impurity
Content is low, clarity good, and can guarantee that the subpackage efficiency in production, content uniformity are little, and adverse reaction rate is substantially reduced,
Stability is more preferable.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of the ceftazidime crystalline compounds of the present invention.
Fig. 2 is the thermal analysis curue spectrum of the ceftazidime crystalline compounds of the present invention.
Fig. 3 is the X-ray powder diffraction spectrum of ceftazidime crystallization prepared by patent CN102924483B embodiment.
Fig. 4 is the X-ray powder diffraction spectrum of ceftazidime crystallization prepared by patent CN103864819A embodiment.
Detailed description of the invention
By embodiment, technical scheme is described in detail below, it will help the technical side to the present invention
The advantage of case, effect have further to be understood, and embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim determines.
The preparation of embodiment 1 ceftazidime crystalline compounds
1) by ceftazidime dissolving crude product in the ethanol of 6 times that 15 DEG C of volumes are ceftazidime weight, the mixed solvent A of water
In, ethanol is 1:2.5 with the volume ratio of water；
2) first speed with 20ml/min add the N-Methyl pyrrolidone of 6 times that volume total amount is ceftazidime weight with
The mixed solvent B of dichloromethane, N-Methyl pyrrolidone is 1:4 with the volume ratio of dichloromethane, stirring while adding, controls temperature
15 DEG C, growing the grain 0.5 hour；
3) again with the speed of 12ml/min add the N-Methyl pyrrolidone of 9 times that volume total amount is ceftazidime weight with
The mixed solvent C of dichloromethane, the volume ratio of N-Methyl pyrrolidone and dichloromethane is 1:3, and growing the grain is after 4 hours, with 20 DEG C/
Hour speed be cooled to-5 DEG C, then stirring and crystallizing, growing the grain 2 hours；
4) filter, washing, 40 DEG C, drying under reduced pressure within 4 hours, obtain ceftazidime crystalline compounds.
Measure by powder X-ray diffraction algoscopy, exist with the X-ray powder diffraction spectrum that the 2 θ ± 0.2 ° angles of diffraction represent
8.1 °, 10.0 °, 15.2 °, 19.2 °, 20.2 °, 20.7 °, 22.7 °, show characteristic diffraction peak at 27.0 °.
Elementary analysis:
Measured value: C 41.50%, H 3.48%, N 13.20%, O 17.59%, S 10.07%.
Theoretical value: C 41.51%, H 3.49%, N 13.18%, O 17.59%, S 10.08%.
Elementary analysis result is basically identical with theoretical value.
Using Ka Shi aquametry to measure moisture is 14.13wt%, the most identical with theoretical value.
Employing thermogravimetric analysis measures, and result, as in figure 2 it is shown, crystal water content is 14.15wt%, is kissed substantially with theoretical value
Close.
The preparation of embodiment 2 ceftazidime crystalline compounds
1) by ceftazidime dissolving crude product in the ethanol of 8 times that 10 DEG C of volumes are ceftazidime weight, the mixed solvent A of water
In, ethanol is 1:2.5 with the volume ratio of water；
2) first speed with 15ml/min add the N-Methyl pyrrolidone of 7 times that volume total amount is ceftazidime weight with
The mixed solvent B of dichloromethane, N-Methyl pyrrolidone is 1:4 with the volume ratio of dichloromethane, stirring while adding, controls temperature
25 DEG C, growing the grain 0.5 hour；
3) N-Methyl pyrrolidone of 10 times that volume total amount is ceftazidime weight is added again with the speed of 10ml/min
With the mixed solvent C of dichloromethane, N-Methyl pyrrolidone is 1:3 with the volume ratio of dichloromethane, and growing the grain is after 5 hours, with 15
DEG C/h speed be cooled to-5 DEG C, then stirring and crystallizing, growing the grain 1 hour；
4) filter, washing, 35 DEG C, drying under reduced pressure within 5 hours, obtain ceftazidime crystalline compounds.
Measure by powder X-ray diffraction algoscopy, same with the X-ray powder diffraction spectrum that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of embodiment 3 ceftazidime crystalline compounds
1) by ceftazidime dissolving crude product in the ethanol of 4 times that 25 DEG C of volumes are ceftazidime weight, the mixed solvent A of water
In, ethanol is 1:2.5 with the volume ratio of water；
2) first speed with 24ml/min add the N-Methyl pyrrolidone of 5 times that volume total amount is ceftazidime weight with
The mixed solvent B of dichloromethane, N-Methyl pyrrolidone is 1:4 with the volume ratio of dichloromethane, stirring while adding, controls temperature
10 DEG C, growing the grain 1 hour；
3) again with the speed of 15ml/min add the N-Methyl pyrrolidone of 8 times that volume total amount is ceftazidime weight with
The mixed solvent C of dichloromethane, the volume ratio of N-Methyl pyrrolidone and dichloromethane is 1:3, and growing the grain is after 2 hours, with 20 DEG C/
Hour speed be cooled to-5 DEG C, then stirring and crystallizing, growing the grain 3 hours；
4) filter, washing, 45 DEG C, drying under reduced pressure within 3 hours, obtain ceftazidime crystalline compounds.
Measure by powder X-ray diffraction algoscopy, same with the X-ray powder diffraction spectrum that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of embodiment 4 ceftazidime crystalline compounds
1) by ceftazidime dissolving crude product in the ethanol of 4 times that 10 DEG C of volumes are ceftazidime weight, the mixed solvent A of water
In, ethanol is 1:2.5 with the volume ratio of water；
2) first speed with 15ml/min add the N-Methyl pyrrolidone of 5 times that volume total amount is ceftazidime weight with
The mixed solvent B of dichloromethane, N-Methyl pyrrolidone is 1:4 with the volume ratio of dichloromethane, stirring while adding, controls temperature
10 DEG C, growing the grain 0.5 hour；
3) again with the speed of 10ml/min add the N-Methyl pyrrolidone of 8 times that volume total amount is ceftazidime weight with
The mixed solvent C of dichloromethane, the volume ratio of N-Methyl pyrrolidone and dichloromethane is 1:3, and growing the grain is after 2 hours, with 15 DEG C/
Hour speed be cooled to-5 DEG C, then stirring and crystallizing, growing the grain 1-3 hour；
4) filter, washing, 35 DEG C, drying under reduced pressure within 3 hours, obtain ceftazidime crystalline compounds.
Measure by powder X-ray diffraction algoscopy, same with the X-ray powder diffraction spectrum that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of embodiment 5 ceftazidime crystalline compounds
1) by ceftazidime dissolving crude product in the ethanol of 8 times that 25 DEG C of volumes are ceftazidime weight, the mixed solvent A of water
In, ethanol is 1:2.5 with the volume ratio of water；
2) first speed with 24ml/min add the N-Methyl pyrrolidone of 7 times that volume total amount is ceftazidime weight with
The mixed solvent B of dichloromethane, N-Methyl pyrrolidone is 1:4 with the volume ratio of dichloromethane, stirring while adding, controls temperature
25 DEG C, growing the grain 1 hour；
3) N-Methyl pyrrolidone of 10 times that volume total amount is ceftazidime weight is added again with the speed of 15ml/min
With the mixed solvent C of dichloromethane, N-Methyl pyrrolidone is 1:3 with the volume ratio of dichloromethane, and growing the grain is after 5 hours, with 20
DEG C/h speed be cooled to-5 DEG C, then stirring and crystallizing, growing the grain 3 hours；
4) filter, washing, 45 DEG C, drying under reduced pressure within 5 hours, obtain ceftazidime crystalline compounds.
Measure by powder X-ray diffraction algoscopy, same with the X-ray powder diffraction spectrum that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
[example of formulations 1] ceftazidime aseptic powder injection
Preparation method (with reference to CN102924483)
1, interior packaging material processes
The cleaning of antibiotic glass bottle, plug, aluminium lid technique routinely, drying, sterilizing, standby；
2, concrete steps
(1) the ceftazidime crystal prepared by the natrium carbonicum calcinatum of recipe quantity and embodiment 1 is weighed, mixed in sterile chamber
Close uniformly；
(2) in the middle of, product examine is tested；
(3) carry out aseptic subpackaged by specification；
(4) evacuation, tamponade, lid is rolled；
(5) packaging, Quan Jian, warehouse-in.
[example of formulations 2] ceftazidime aseptic powder injection
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 2
His pyridine crystal.
[example of formulations 3] ceftazidime aseptic powder injection
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 3
His pyridine crystal.
[example of formulations 4] ceftazidime aseptic powder injection
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 4
His pyridine crystal.
[example of formulations 5] ceftazidime aseptic powder injection
Preparation method: with example of formulations 1, except that ceftazidime used is the cephalo prepared by embodiment 5
His pyridine crystal.
Trial target 1: the ceftazidime crystalline compounds prepared by the embodiment of the present invention 1.
Trial target 2: the ceftazidime crystalline compounds prepared by the embodiment of the present invention 4.
Reference substance 1: prepare ceftazidime crystalline compounds according to the method for CN102924483B embodiment 1.
Reference substance 2: prepare ceftazidime compound according to the method for CN103864819A embodiment 1.
Reference substance 3: prepare ceftazidime according to the method for CN105560194A embodiment 1.
Reference substance 4: prepare ceftazidime according to the method for CN105585582A embodiment 1.
Experimental example 1: heat stabilization test
Each sample is respectively exposed to relative humidity be 75%, in the environment of temperature is 60 DEG C, according to CN105560194A
In have related substance, impurity pyridine, the detection method of polymer to detect every, 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
System, liver, kidney, gastrointestinal all have an impact, and consciousness of personality can be caused to reduce.If pyridine residual quantity is high, can human body be produced more serious
Impact.By the security test to ceftazidime medicine, pyridine residual limit of safety in ceftazidime medicine can not surpass
Cross 0.12%.Owing to containing pyridine groups in ceftazidime structure, medicine, in placement process, can gradually decompose impurity pyridine and go out
Coming, the particularly ceftazidime of poor stability, in placement process, pyridine residual quantity can increase comparatively fast, and human body is had relatively by this
Big harm.
The height of drug quality is directly connected to the health of millions upon millions of working people's health, 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 the scope of medical industry enterprise own, but whole
National, the major issue in the world.Those skilled in the art the most clearly know, in the present age that pharmaceutical technology is flourishing, and drug safety standard quilt
Constantly promoting, the purity of prepared medicine is more and more higher, is 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
Want.Medicine needs storage and transport just can cure the sickness to save the patient from production to the process of circulation, therefore, and 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, use the present invention method prepare ceftazidime crystalline compounds have related substance, pyrrole
Pyridine, polymer equal size are the lowest, and heat stability is significantly better than the head using the method for prior art to obtain after being purified
His pyridine of spore, effectively improves the stability of drug safety and storage, reduces the generation of untoward reaction.
The ceftazidime crystalline compounds of other embodiments of the present invention is also carried out above-mentioned test, its result phase obtained
Seemingly.
Experimental example 2: fluidity test
This experimental example is by measuring the mobility evaluating sample angle of repose of sample, and concrete grammar is as follows: take sample
Grain, flows in the surface plate of circle from fixing little funnel, until obtain the highest cone, measure cone height H and
Radius R, calculates α angle of repose by tan α=H/R, the results are shown in Table 2, and angle of repose is the biggest, and mobility is the poorest.
Table 2 fluidity test result
| Trial target 1 | Trial target 2 | Reference substance 1 | Reference substance 2 | Reference substance 3 | Reference substance 4 | |
| Angle of repose | 30° | 31° | 58° | 46° | 62° | 49° |
Ceftazidime compound flow as known from Table 2, compared with ceftazidime of the prior art, prepared by the present invention
Property significantly improve, be conducive to improving the accuracy of subpackage, and be easily mixed uniform when mix with other composition.
Experimental example 3: dissolubility test
In the low capacity bottle with constant temperature jacket, add appropriate distilled water, at 20 DEG C, add ceftazidime to no longer
Till dissolving, starting magnetic stirrer, continuously stirred under constant temperature, in experimentation, system is in the shape of two-phase coexistent all the time
State, the dissolubility at a temperature of the concentration of ceftazidime is this in the liquid phase of system after 70 minutes.It is sampled after 2 hours point
Analysis, takes the close meansigma methods of adjacent two times result as measured value of experiment, before sampling, in order to make solid-liquid be sufficiently separated, stops stirring
After mixing, the most 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
Filter filters, and takes sample, measured the content (concentration (mg/ml)) of ceftazidime by HPLC from filtrate.The results are shown in Table 3.
Under table 3 room temperature, ceftazidime crystal compound of the present invention contrasts with the water solublity of prior art crystal formation
| Sample | Content for the first time | Content for the second time | Meansigma methods |
| Trial target 1 | 7.34 | 7.35 | 7.345 |
| Trial target 2 | 7.29 | 7.31 | 7.3 |
| Reference substance 1 | 4.28 | 4.31 | 4.295 |
| Reference substance 2 | 4.33 | 4.34 | 4.335 |
| Reference substance 3 | 3.28 | 3.30 | 3.29 |
| Reference substance 4 | 2.78 | 2.79 | 2.785 |
| Commercially available | 3.48 | 3.50 | 3.49 |
From table 3 it can be seen that the water solublity of ceftazidime crystal compound of the present invention is compared with prior art, have notable
Improve.
Experimental example 4: wettability test
Each sample opening is put in clean culture dish, spread out into≤thick for 5mm thin layer, each two parts, be respectively put into constant humidity airtight
In container, 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,
Measured the moisture of each sample by loss on drying experiment, result of the test 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, the ceftazidime crystalline compounds that prepared by the present invention is not inhaled
Wet, its stability under high humidity environment is substantially better than and uses the purification process of prior art to process the ceftazidime obtained.
Experimental example 5: injectable powder influence factor tests
Formulation test product 1: the ceftazidime aseptic powder injection prepared by invention formulation embodiment 1.
Formulation test product 2: the ceftazidime aseptic powder injection prepared by invention formulation embodiment 3.
Preparations. Control product 1: prepare ceftazidime aseptic powder injection according to the method for CN102924483B example of formulations 1.
Preparations. Control product 2: prepare ceftazidime powder pin according to the method for CN103864819A example of formulations 1.
Preparations. Control product 3: prepare ceftazidime powder pin according to the method for CN102875576A example of formulations 1.
Preparations. Control product 4: prepare ceftazidime powder pin according to the method for CN103027894A embodiment 1.
Preparations. Control product 5: prepare ceftazidime powder pin according to the method for CN101810623B embodiment 1.
Above-mentioned formulation test product and reference substance are simulated listing packaging, places under the conditions of high temperature 60 DEG C, illumination 4500Lx
Within 10 days, carry out influence factor's experiment investigation, the results are shown in Table 5.
Being found by result above, sample prepared by the present invention not only purity is high, impurity content is low, clarity good, Er Qieneng
Ensure that the subpackage efficiency in producing, content uniformity are little, good stability.
The ceftazidime aseptic powder injection of other example of formulations of the present invention is also carried out above-mentioned test, its result obtained
Similar.
Experimental example 6: anaphylaxis test guinea pig maximization test (GPMT):
Packet: take healthy albino guinea-pig 300, body weight 300g～500g, male and female dual-purpose, be randomly divided into 10 groups, i.e. preparation
Trial target 1, formulation test product 2, preparations. Control product 1, preparations. Control product 2, preparations. Control product 3, preparations. Control product 4, preparations. Control
Product 5, commercial preparation, 1%2,4-dinitrochlorobenzene positive controls, 0.9% sodium chloride injection negative control group, often organize 30
Only.Test first 24 hours and shave except shoulder back 4cm × 6cm region hair.Induction: go to hair-fields by 75% ethanol cleaning, make 6 point symmetries
Intradermal injection, at a distance of 1cm, dosage is 0.1ml.Shaving again after 7 days, by 75% ethanol cleaning, if there is not irritant reaction, often
One trial zone, with 10% sodium lauryl sulphate paraffin liquid pretreatment, is smeared at local patch for first 24 hours, massage trial zone skin
Skin, after 24 hours, immerses 2cm × 4cm filter paper test sample or negative controls, positive control solution to the most saturated, is affixed on globefish
Mus dorsal injection position, sealing 48 hours.Excite: complete 14 days in induction, shaving at the unused mistake of veutro of Cavia porcellus left and right, use
75% ethanol cleaning, immerses 2cm × 2cm filter paper in test sample or negative controls, positive control solution to saturated, is affixed on
Shaving district, sealing 24 hours.Observe: thing will be sticked and take off latter 1,24 and 48 hours, and observe respectively and stick place's erythema and edema feelings
Condition, and score.Wherein ceftazidime for injection dosage is identical.
Standards of grading
Standards of grading
After attack, 48h is to guinea pig skin allergy result of the test:
As can be seen here, pharmaceutical composition containing this ceftazidime crystalline compounds provided by the present invention and prior art
Compare anaphylaxis incidence rate to significantly reduce.
Claims (9)
1. an anti-infectives ceftazidime crystalline compounds, it is characterised in that described ceftazidime crystalline compounds
Structural formula is as shown in formula I, and this crystalline compounds powder X-ray diffraction algoscopy measures, and represents with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction pattern as it is shown in figure 1,
2. the preparation method of the anti-infectives ceftazidime crystalline compounds described in a claim 1, it is characterised in that should
Method comprises the steps:
1) by ceftazidime dissolving crude product in the mixed solvent A of the second alcohol and water of 10-25 DEG C；
2) first with speed addition N-Methyl pyrrolidone and the mixed solvent B of dichloromethane of 15-24ml/min, limit edged stirs
Mix, control temperature 10-25 DEG C, growing the grain 0.5-1 hour；
3) again with speed addition N-Methyl pyrrolidone and the mixed solvent C of dichloromethane of 10-15ml/min, growing the grain 2-5 is little
Shi Hou, is cooled to-5 DEG C with the speed of 15-20 DEG C/h, then stirring and crystallizing, growing the grain 1-3 hour；
4) filter, washing, 35-45 DEG C, drying under reduced pressure within 3-5 hour, obtain ceftazidime crystalline compounds.
Preparation method the most according to claim 2, it is characterised in that step 1) described in the volume of mixed solvent A be head
4-8 times of his pyridine weight of spore, ethanol is 1:2.5 with the volume ratio of water.
Preparation method the most according to claim 2, it is characterised in that step 2) described in the volume of mixed solvent B be head
5-7 times of his pyridine weight of spore, N-Methyl pyrrolidone is 1:4 with the volume ratio of dichloromethane.
Preparation method the most according to claim 2, it is characterised in that step 3) described in the volume of mixed solvent C be head
8-10 times of his pyridine weight of spore, N-Methyl pyrrolidone is 1:3 with the volume ratio of dichloromethane.
6. a ceftazidime medicinal composition, it is characterised in that described pharmaceutical composition contains the head described in claim 1
His pyridine crystalline compounds of spore.
Pharmaceutical composition the most according to claim 6, it is characterised in that described pharmaceutical composition is possibly together with Carbon Dioxide
Sodium.
Pharmaceutical composition the most according to claim 7, it is characterised in that ceftazidime crystal in described pharmaceutical composition
Compound and natrium carbonicum calcinatum weight ratio are 5-7:1.
9. according to the pharmaceutical composition described in any one of claim 6-8, it is characterised in that described pharmaceutical composition is through aseptic
Aseptic powder injection is made after subpackage.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4525587A (en) * | 1982-12-27 | 1985-06-25 | Eli Lilly And Company | Process for preparing a cephalosporin compound |
| EP0267427A1 (en) * | 1986-10-07 | 1988-05-18 | 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 |
-
2016
- 2016-08-22 CN CN201610697050.9A patent/CN106317081B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4525587A (en) * | 1982-12-27 | 1985-06-25 | Eli Lilly And Company | Process for preparing a cephalosporin compound |
| EP0267427A1 (en) * | 1986-10-07 | 1988-05-18 | 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 |
Non-Patent Citations (1)
| Title |
|---|
| 刘煜婷，等: "头孢他啶五水化合物结晶工艺的改进", 《黑龙江医药》 * |
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