CN106432272A - Method for preparing drug ceftibuten crystal compound for treating surgical operation infection - Google Patents
Method for preparing drug ceftibuten crystal compound for treating surgical operation infection Download PDFInfo
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- CN106432272A CN106432272A CN201610837278.3A CN201610837278A CN106432272A CN 106432272 A CN106432272 A CN 106432272A CN 201610837278 A CN201610837278 A CN 201610837278A CN 106432272 A CN106432272 A CN 106432272A
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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
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine and discloses a method for preparing a drug ceftibuten crystal compound for treating surgical operation infection. The structural formula of the prepared ceftibuten crystal compound is as shown in formula (I). The crystal compound is measured according to a powder X-ray diffraction measuring method. An X-ray powder diffraction atlas expressed by a diffraction angle at 2theta+/-0.2 degrees is as shown in figure 1. The ceftibuten crystal compound prepared according to the method has the advantages of high purity, low polymer content, high stability, difficulty in absorbing moisture, excellent liquidity and greatly improved solubility.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of medicine Ceftibuten preparing treatment Postoperative infection
The method of crystalline compounds.
Background technology
Ceftibuten (Ceftibuten) is that the third generation developed by Yan Yeyi company of Japan is administered orally broad-spectrum cephalosporin, right
Most of gram-Negative bacilluses and some positive coccus have stronger antibacterial action, to plasmid-mediated beta-lactamase height
Stable, and there is post antibiotic effect；Have that has a broad antifungal spectrum, antibacterial activity be strong, bioavilability high, for treatment by
The various infection that sensitive strain causes, including the infection of the upper respiratory tract, ALRI, the urinary system that oozes infection, enteritis and stomach and intestine
Scorching etc..
The chemical name of Ceftibuten for (+)-(6R, 7R)-7 β-[(Z)-2-(2-amino-4-thiazole)-4-carboxyl-2-
(Z)-crotonamide]-8-oxygen-5-sulphur-1-nitrogen bicyclic [4.2.0] oct-2-ene-2-carboxylic acid two water thing, structural formula such as formula (I) institute
Show：
Formula（）.
Beta-Lactam antibiotic, such as penicillin medicine and Cephalosporins, due to the less stable of parent nucleus, hold
Easily resetting, decomposing and polymerisation, the polymer product being formed and anaphylactic shock have close relationship.In penicillin
Polymeric impurities is averagely when 21.44 μ g/g, and allergic reaction incidence is 0.2%；Polymeric impurities is averagely at 51.24 μ g/g
When, allergic reaction incidence is 0.43%；During polymeric impurities average out to 76.7 μ g/g, allergy rate is 0.74%.Cynnematin
Though allergic reaction is so serious not as good as penicillin, but during polymer height, human allergy can be caused equally to react.
Ceftibuten meets the instability such as light, heat, water, oxidation, is easily generated catabolite, particularly suffers the situation of high temperature
Under, tend to occur degraded and polymerisation, generate Ceftibuten dimer, trimer and polymer etc. polymer, thus lead
Causing active constituents of medicine content to reduce, color and luster is strengthened, and polymeric impurities content raises.In addition, expired Ceftibuten antibiotic,
Owing to the resting period is long, also usually making active constituents of medicine content reduce, darkening, polymer content raises.Further, exist
In some cases, owing to controlling of production process is improper, obtained Ceftibuten dihydrate, Ceftibuten dimer, trimerization
Thing and polymer etc. polymer content is high especially.And during polymer content height, easily make human body produce allergic reaction.So for
The high Ceftibuten dihydrate of this kind of polymeric impurities content or Ceftibuten pharmaceutical preparation, it is necessary to carry out pure further
Change, Ceftibuten dihydrochloride dihydrate crystal that obtain high-quality, that purity is high.
Bring tired additionally, the poorly water-soluble of Ceftibuten, mobility are bad, have hygroscopicity etc. to the preparation of preparation
Difficulty, the defects such as it is low that its capsule prepared mostly exists dissolution rate, and stability is bad, and polymer content is high.
US4812561 discloses crystal hydrate of a kind of oral cephalosporin and combinations thereof, its disclosed crystallization
Hydrate is dihydrate, trihydrate or its mixture, and the preparation method of this crystalline hydrate is：By dissolution of raw material at sour water
In solution, make the pH of solution in about room temperature（Specifically at 0-70 DEG C）Rise（Specifically rise to pH1.5-5.0）To separate crystallization.Must
When wanting, stirring mixture makes crystallization complete.Isolate wet crystallization, under room temperature and about atmospheric pressure, be not less than in relative humidity
The inert gas of 15% is dried.The crystalline hydrate that the method prepares has the stability of height, and accelerated test confirms,
After one month, it remains to keep the usefulness of 97.8%.Present invention also offers the composition of a kind of energy stable for extended periods of time, discovery
By this hydrate load snap fit capsule and seal with gelatin band its pole can be made not easy to change and inactivation.The preparation of capsule of the present invention
Specific as follows：By hydrate and the additive of pharmacologically effective dose（Such as filler, lubricant）Mix mutually, be then charged into capsule,
The periphery of capsule lid and the whole junction of body coats aqueous gelatin solution, is dried and forms gelatin band.Snap fit capsule can be common
Commodity capsule, does not has the restriction of special size and color, can contain fuel and/or pigment.But, applicant is through substantial amounts of
Experimental study confirms, the impurity content of the crystalline hydrate of gained of the present invention, especially polymer content are still very high, its flowing
Property, dissolubility also need improve.Although the capsule purity preparing and stability are preferable, but its dissolution rate, polymeric impurities
Content is unsatisfactory.
Preparation method the method that CN105153198A discloses a kind of Ceftibuten is a kind of new to prepare Ceftibuten
Method, its yield is high, and purity is high, easy and simple to handle, is the production technology of a green cleaning, is suitable for the industry of certain scale
Metaplasia is produced.HPLC purity 98.5%-99.2%, its diffraction numerical value is close with US4812561 after measured, gained crystalline hydrate miscellaneous
Matter content, especially polymer content are high, and its mobility, dissolubility are also poor.
CN104546862A discloses a kind of Ceftibuten pharmaceutical composition and preparation method thereof, and wherein capsule is by cephalo
Cloth alkene, amylum pregelatinisatum, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, superfine silica gel powder and talcum powder are through specific preparation
Method is made.The capsule that it is prepared by applicant has carried out dissolution rate, defects inspecting and stability test, finds its dissolution rate
Difference, impurity content is high, and stability is also very poor.
EP3031450A1 discloses a kind of Ceftibuten capsule, it comprises adhesive, disintegrant, lubricant, helps stream
Agent, prescription disclosed in embodiment is that two water Ceftibutens, magnesium stearate, microcrystalline cellulose, cataloid, hydroxyacetic acid form sediment
Powder sodium, by controlling the particle diameter of two water Ceftibutens, solves owing to Ceftibuten low aqueous solubility causes the dissolution rate of preparation not
Good, affect a difficult problem for drug absorption, ceftibuten preparation newly developed is easy to and rapid dispersion in vivo, have high absorption with
Bioavilability.The capsule that it is prepared by applicant has carried out defects inspecting and stability test, finds that its impurity content is high, surely
Qualitative also poor, dissolution rate needs to be improved further.
WO2013151518A1 discloses and a kind of comprises the different composition with high water solubility pH agent of at least two
Ceftibuten capsule preparations, described preparation comprises except at least one pharmaceutically acceptable excipient and tablet composition.Can
Disintegrant, glidant, lubricant and bonding can be comprised with the pharmaceutically acceptable excipient using in the preparation in the present invention
Agent, its capsule dissolution rate preparing is higher, but finds that its impurity, polymer content are higher through test, and less stable.
The present inventor is with existing Ceftibuten crude product as raw material, through lot of experiments, has prepared one and has been totally different from existing
There is technology（Such as US4812561, CN105153198A, commercially available prod etc.）The Ceftibuten crystalline compounds of novel crystal forms, and
By test, surprisingly finding that this crystalline compounds purity is high, polymer content is low, good stability, and is difficult to moisture absorption, mobility
Good, substantially increase its dissolubility.The pharmaceutical composition not only purity utilizing this crystalline compounds to make is high, impurity content is low,
Clarity is good, and can guarantee that the packing efficiency in production, content uniformity are little, and adverse reaction rate is substantially reduced, stability
More preferably.
Content of the invention
It is an object of the invention to provide the preparation method of described Ceftibuten crystalline compounds, the letter of the method technique
Single, yield is high, and repeatability is strong, is suitable for industrialized production.
For realizing the purpose of the present invention, the present invention adopts the following technical scheme that：
A kind of method of medicine Ceftibuten crystalline compounds preparing treatment Postoperative infection, the method includes walking as follows
Suddenly：
Take Ceftibuten bulk drug, add in the methyl alcohol of uniform temperature, the mixed solvent A of dimethylformamide, obtain solution；So
After in the horizontal direction of the liquid level of gained solution apply stationary magnetic field, and under conditions of this stationary magnetic field in solution drip
Acetone, ethyl acetate, the mixed solvent B of ether；After being added dropwise to complete, standing 3-5 hour, filtering, filter cake ethanol washs, vacuum
It is dried 2-4 hour, obtain described Ceftibuten crystalline compounds；
Shown in the structural formula such as formula (I) of the Ceftibuten crystalline compounds preparing, this crystalline compounds powder x-ray diffraction is surveyed
Determine method measure, the X-ray powder diffraction pattern representing with the 2 θ ± 0.2 ° angles of diffraction as it is shown in figure 1,
Formula（）.
In the present invention, described Ceftibuten bulk drug can be the Ceftibuten disclosed in method using prior art
The Ceftibuten for preparing of synthetic method, it is also possible to be commercially available Ceftibuten bulk drug.
In preparation method of the present invention, wherein, described uniform temperature is 15-25 DEG C.Described mixed solvent A volume（ml）For head
Spore cloth alkene bulk drug weight (g) 6-8 times, methyl alcohol and dimethylformamide volume ratio are 1:2.5.Described magnetic field intensity is 0.8T-
1.5T.Described mixed solvent B volume（ml）For Ceftibuten bulk drug weight (g) 8-10 times, acetone, ethyl acetate and ether
Volume ratio is 2:3:5.
The present invention also provides a kind of Ceftibuten pharmaceutical composition, and described pharmaceutical composition contains described in claim 1
Ceftibuten crystalline compounds.
Consisting of of described Ceftibuten pharmaceutical composition：Ceftibuten 1 weight portion, arginine 0.01-0.03 weight
Part.
Consisting of of described Ceftibuten pharmaceutical composition：Ceftibuten 1 weight portion, arginine 0.02 weight portion.
Described Ceftibuten pharmaceutical composition is prepared from by following preparation method：
（1）Weigh Ceftibuten crystal and arginine in proportion, be sufficiently mixed；
（2）Dispense in the cillin bottle to sterilizing and jump a queue.
Compared with prior art, the invention have the advantages that：
（1）Ceftibuten crystalline compounds not only purity prepared by the present invention is high, and polymer content is low, good stability, and
It is difficult to moisture absorption, and mobility, dissolubility etc. are substantially better than prior art；
（2）The preparation method technique of Ceftibuten provided by the present invention is simple, and yield is high, and repeatability is strong, is suitable for industrialization
Produce；
（3）Pharmaceutical composition containing this Ceftibuten crystalline compounds not only purity provided by the present invention is high, impurity content
Low, clarity good, and can guarantee that the packing efficiency in production, content uniformity are little, adverse reaction rate is substantially reduced, stable
Property is more preferable.
Brief description
Fig. 1 is the X-ray powder diffraction figure of Ceftibuten crystalline compounds prepared by the present invention.
Fig. 2 is the thermal analysis curue spectrum of Ceftibuten crystalline compounds prepared by the present invention.
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 and further understand, embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim determines.
The preparation of embodiment 1 Ceftibuten crystalline compounds
Taking Ceftibuten bulk drug, the volume adding 15 DEG C is the methyl alcohol of Ceftibuten weight 6 times, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then the level side of liquid level at gained solution
Upwards apply the stationary magnetic field that magnetic field intensity is 0.8T, and dropping volume is cephalo in solution under conditions of this stationary magnetic field
8 times of acetone of cloth alkene weight, ethyl acetate, the mixed solvent of ether, the volume ratio of acetone, ethyl acetate and ether is 2:3:5；Drip
After adding into, standing 3-5 hour, filtering, filter cake ethanol washs, and is vacuum dried 2-4 hour, obtains described Ceftibuten brilliant
Body compound.
Measure by powder x-ray diffraction determination method（The same US4812561 of assay method）, represent with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction spectrum（Fig. 1）5.0 °, 7.2 °, 10.0 °, 12.1 °, 14.7 °, 18.2 °, 21.5 °, 22.3 °, 23.6 °,
25.0 °, 27.1 °, 28.4 °, 28.7 °, 30.5 °, show characteristic diffraction peak at 31.2 °.
Using Ka Shi aquametry to measure moisture is 8.08wt%, substantially identical with theoretical value.
Using thermogravimetric analysis to measure, result is as in figure 2 it is shown, crystal water content is 8.07wt%, substantially identical with theoretical value.
The preparation of embodiment 2 Ceftibuten crystalline compounds
Taking Ceftibuten bulk drug, the volume adding 20 DEG C is the methyl alcohol of Ceftibuten weight 7 times, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then the level side of liquid level at gained solution
Upwards apply the stationary magnetic field that magnetic field intensity is 1.2T, and dropping volume is cephalo in solution under conditions of this stationary magnetic field
9 times of acetone of cloth alkene weight, ethyl acetate, the mixed solvent of ether, the volume ratio of acetone, ethyl acetate and ether is 2:3:5；Drip
After adding into, standing 3-5 hour, filtering, filter cake ethanol washs, and is vacuum dried 2-4 hour, obtains described Ceftibuten brilliant
Body compound.
Measure by powder x-ray diffraction determination method, 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 Ceftibuten crystalline compounds
Taking Ceftibuten bulk drug, the volume adding 25 DEG C is the methyl alcohol of Ceftibuten weight 8 times, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then the level side of liquid level at gained solution
Upwards apply the stationary magnetic field that magnetic field intensity is 1.5T, and dropping volume is cephalo in solution under conditions of this stationary magnetic field
10 times of acetone of cloth alkene weight, ethyl acetate, the mixed solvent of ether, the volume ratio of acetone, ethyl acetate and ether is 2:3:5；
After being added dropwise to complete, standing 3-5 hour, filtering, filter cake ethanol washs, and is vacuum dried 2-4 hour, obtains described Ceftibuten
Crystalline compounds.
Measure by powder x-ray diffraction determination method, 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 Ceftibuten crystalline compounds
Taking Ceftibuten bulk drug, the volume adding 15 DEG C is the methyl alcohol of Ceftibuten weight 7 times, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then the level side of liquid level at gained solution
Upwards applying magnetic field intensity is, the stationary magnetic field of 1.2T, and in solution, dropping volume is head under conditions of this stationary magnetic field
Spore 10 times of acetone of cloth alkene weight, ethyl acetate, the mixed solvent of ether, the volume ratio of acetone, ethyl acetate and ether is 2:3:
5；After being added dropwise to complete, standing 3-5 hour, filtering, filter cake ethanol washs, and is vacuum dried 2-4 hour, obtains described cephalo cloth
Alkene crystalline compounds.
Measure by powder x-ray diffraction determination method, 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 Ceftibuten crystalline compounds
Taking Ceftibuten bulk drug, the volume adding 25 DEG C is the methyl alcohol of Ceftibuten weight 6 times, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then the level side of liquid level at gained solution
Upwards apply the stationary magnetic field that magnetic field intensity is 0.8T, and dropping volume is cephalo in solution under conditions of this stationary magnetic field
9 times of acetone of cloth alkene weight, ethyl acetate, the mixed solvent of ether, the volume ratio of acetone, ethyl acetate and ether is 2:3:5；Drip
After adding into, standing 3-5 hour, filtering, filter cake ethanol washs, and is vacuum dried 2-4 hour, obtains described Ceftibuten brilliant
Body compound.
Measure by powder x-ray diffraction determination method, same with the X-ray powder diffraction spectrum that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
Example of formulations 1：The preparation of Ceftibuten pharmaceutical composition：
Consist of：Ceftibuten crystal 1 weight portion prepared by the present invention, arginine 0.01 weight portion.
Preparation method is：
（1）Weigh Ceftibuten crystal and arginine in proportion, be sufficiently mixed；
（2）Dispense in the cillin bottle to sterilizing and jump a queue.
Example of formulations 2：The preparation of Ceftibuten pharmaceutical composition：
Consist of：Ceftibuten crystal 1 weight portion prepared by the present invention, arginine 0.02 weight portion.
Preparation method is：
（1）Weigh Ceftibuten crystal and arginine in proportion, be sufficiently mixed；
（2）Dispense in the cillin bottle to sterilizing and jump a queue.
Example of formulations 3：The preparation of Ceftibuten pharmaceutical composition：
Consist of：Ceftibuten crystal 1 weight portion prepared by the present invention, arginine 0.03 weight portion.
Preparation method is：
（1）Weigh Ceftibuten crystal and arginine in proportion, be sufficiently mixed；
（2）Dispense in the cillin bottle to sterilizing and jump a queue.
Trial target 1：Ceftibuten crystalline compounds prepared by the embodiment of the present invention 1；
Trial target 2：Ceftibuten crystalline compounds prepared by the embodiment of the present invention 4；
Reference substance 1：Prepare Ceftibuten crystalline compounds according to the method for CN105153198A embodiment 1；
Reference substance 2：Prepare Ceftibuten crystalline compounds according to the method for US4812561 example 2.
Experimental example 1：Fluidity test
This experimental example is evaluated the mobility of sample by measuring the angle of repose of sample, and concrete grammar is as follows：Take sample particle, from
Fixing little funnel flowing in the surface plate of circle, until obtaining cone the highest, measuring cone height H and radius R,
Calculating angle of repose α by tan α=H/R, the results are shown in Table 1, angle of repose is bigger, and mobility is poorer.
Table 1 fluidity test result
As known from Table 1, compared with Ceftibuten of the prior art, the Ceftibuten compound flow prepared by the present invention shows
Write and improve, the beneficially preparation of preparation, dissolution rate, the raising of bioavilability.
Experimental example 2：Dissolubility test
Add appropriate distilled water in the low capacity bottle with constant temperature jacket, add Ceftibuten to not re-dissolved at 25 DEG C
Till, starting magnetic stirrer, continuously stirred under constant temperature, in experimentation, system is in the state of two-phase coexistent all the time, and 70
After Fen Zhong system liquid phase in the concentration of Ceftibuten be this at a temperature of solubility.It is sampled after 2 hours analyzing, take
The close mean value of adjacent two times result is as measured value of experiment, before sampling, in order to make solid-liquid be sufficiently separated, after stopping stirring,
Not molten Ceftibuten is deposited to the bottom of low capacity bottle, by a small amount of upper clear supernate of syringe extraction, with the filter of 0.45 micron
Filter, from filtrate, take sample, measured the content of Ceftibuten by HPLC（Concentration（mg/ml））.The results are shown in Table 2.
Under table 2 room temperature, Ceftibuten crystal compound of the present invention and the water-soluble of prior art crystal formation contrast
From table 2 it can be seen that the water solubility of Ceftibuten crystal-form compound prepared by the present invention is compared with prior art, has and significantly carry
High.
Experimental example 3：Wettability test
Each sample opening is put in clean culture dish, spread out into≤thick the thin layer of 5mm, each two parts, be respectively put into constant humidity closed container
In, 25 DEG C respectively at relative humidity 75% and 92.5% under conditions of place 10 days, in the 5th day and the 10th day sample, to take
Xie Erfa measures the moisture of each sample, and result of the test compared with 0 day, and experimental result is shown in Table 3.
Table 3 hygroscopicity test results
As can be seen from the above table, the Ceftibuten crystalline compounds that prepared by the present invention is substantially non-hygroscopic under high humidity conditions, its
Stability under high humidity environment is substantially better than the Ceftibuten using prior art.
Experimental example 4：Influence factor is tested
Trial target and reference substance are simulated listing packaging, at high temperature 60 DEG C, illumination 4500Lx, high humidity（RH90%±5%）Under the conditions of
Place 10 days, detect by stability high spot reviews project, compare with 0 day sample, the results are shown in Table 4.
Table 4 compounds affect factorial experiments result
The height of drug quality is directly connected to the health of millions upon millions of working people's health, is also related to the one-tenth of 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 the whole people
Race, the major issue in the world.Those skilled in the art all clearly know, and in the present age that pharmaceutical technology is flourishing, drug safety standard is not by
Disconnected lifting, the purity of prepared medicine is also more and more higher, is effectively reduced impurity content, even several percentage points of zero point,
Also can be effectively reduced the generation of bad reaction, therefore impurity content is most important to drug quality and people's drug safety.
Medicine needs storage and transport just can cure the sickness to save the patient from producing the process of circulation, therefore, and medicine in storage and transportation
Quality is particularly important, and stability is the key determining drug quality quality, in medicine storage and transportation, and stability
Bad, impurity change directly affects greatly people's drug safety.
As can be seen from the above table, use the Ceftibuten crystalline compounds that the method for the present invention prepares has related substance, poly-
Compound equal size is all very low, and stability is significantly better than the Ceftibuten of prior art, effectively improve drug safety and
The stability of storage, reduces the generation of bad reaction.
Being also carried out above-mentioned experimental example 1-4 to the Ceftibuten crystalline compounds of other embodiments of the present invention, it obtains
Result is similar.
Experimental example 6：Composition influence factor is tested
Formulation test product 1：Ceftibuten pharmaceutical composition prepared by invention formulation embodiment 1.
Formulation test product 2：Ceftibuten pharmaceutical composition prepared by invention formulation embodiment 2.
By formulation test product simulation listing packaging, at high temperature 60 DEG C, illumination 4500Lx, high humidity（RH90%±5%）Under the conditions of
Place 10 days, detect by stability high spot reviews project, compare with 0 day sample, the results are shown in Table 5.
Table 5 preparation influence factor result of the test
Found by result above, the pharmaceutical composition purity containing this Ceftibuten crystalline compounds prepared by the present invention is high,
Impurity content is low, good stability.
Above-mentioned test is also carried out to the Ceftibuten pharmaceutical composition of other example of formulations of the present invention, its knot obtaining
Really similar.
Claims (5)
1. the method for the medicine Ceftibuten crystalline compounds preparing treatment Postoperative infection, it is characterised in that include
Following steps：Take Ceftibuten bulk drug, add in the methyl alcohol of uniform temperature, the mixed solvent A of dimethylformamide, obtain molten
Liquid；Then in the horizontal direction of the liquid level of gained solution, apply stationary magnetic field, and to solution under conditions of this stationary magnetic field
Middle dropping acetone, ethyl acetate, the mixed solvent B of ether；After being added dropwise to complete, standing 3-5 hour, filtering, filter cake ethanol is washed
Wash, be vacuum dried 2-4 hour, obtain described Ceftibuten crystalline compounds；
The Ceftibuten crystalline compounds preparing is measured by powder x-ray diffraction determination method, the X representing with the 2 θ ± 0.2 ° angles of diffraction
Ray powder diffraction is as shown in Figure 1.
2. the method for the medicine Ceftibuten crystalline compounds of preparation treatment Postoperative infection according to claim 1,
It is characterized in that：Described uniform temperature is 15-25 DEG C.
3. the method for the medicine Ceftibuten crystalline compounds of preparation treatment Postoperative infection according to claim 1,
It is characterized in that：Described mixed solvent A volume is Ceftibuten weight 6-8 times, and methyl alcohol and dimethylformamide volume ratio are 1:
2.5.
4. the method for the medicine Ceftibuten crystalline compounds of preparation treatment Postoperative infection according to claim 1,
It is characterized in that：Described magnetic field intensity is 0.8T-1.5T.
5. the method for the medicine Ceftibuten crystalline compounds of preparation treatment Postoperative infection according to claim 1,
It is characterized in that：Described mixed solvent B volume is Ceftibuten weight 8-10 times, the volume ratio of acetone, ethyl acetate and ether
It is 2:3:5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023278945A1 (en) * | 2021-07-01 | 2023-01-05 | Qpex Biopharma, Inc. | Crystalline forms of ceftibuten |
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| EP2815743A1 (en) * | 2013-06-21 | 2014-12-24 | Sanovel Ilac Sanayi ve Ticaret A.S. | Ceftibuten formulations |
| CN105153198A (en) * | 2015-09-17 | 2015-12-16 | 浙江华方药业股份有限公司 | Preparation method of ceftibuten |
| EP3031450A1 (en) * | 2014-12-12 | 2016-06-15 | Sanovel Ilac Sanayi ve Ticaret A.S. | Ceftibuten capsule compositions |
| WO2016116892A1 (en) * | 2015-01-24 | 2016-07-28 | Wockhardt Limited | Antibacterial compositions |
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