CN106397455B - A kind of anti-infectives Ceftibuten crystalline compounds and combinations thereof - Google Patents
A kind of anti-infectives Ceftibuten crystalline compounds and combinations thereof Download PDFInfo
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- CN106397455B CN106397455B CN201610768969.2A CN201610768969A CN106397455B CN 106397455 B CN106397455 B CN 106397455B CN 201610768969 A CN201610768969 A CN 201610768969A CN 106397455 B CN106397455 B CN 106397455B
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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
- 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
- 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 pharmaceutical technology field, a kind of anti-infectives Ceftibuten crystalline compounds and combinations thereof are disclosed.Shown in the structural formula such as formula (I) of the Ceftibuten crystalline compounds, which is measured with powder x-ray diffraction measuring method, as shown in Figure 1 with the X-ray powder diffraction pattern that the 2 θ ± 0.2 ° angles of diffraction indicate.The crystalline compounds purity is high, and polymer content is low, and stability is good, and not easy to moisture absorption, good fluidity, substantially increases its dissolubility.Low using capsule dissolubility height, impurity content made of the crystalline compounds, stability is good.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of anti-infectives Ceftibuten crystalline compounds and combinations thereof
Object.
Background technology
Ceftibuten (Ceftibuten) is to take orally broad-spectrum cephalosporin by the third generation of Yan Yeyi company of Japan development, right
Most of gram-Negative bacillus and some positive coccus have stronger antibacterial action, to plasmid-mediated beta-lactamase height
Stablize, and there is post antibiotic effect；Have the characteristics that has a broad antifungal spectrum, antibacterial activity are strong, bioavilability is high, for treat by
Various infection caused by sensitive strain, including the infection of the upper respiratory tract, lower respiratory tract infection, the urinary system that oozes infection, enteritis and stomach and intestine
Inflammation etc..
The chemical name of Ceftibuten is (+)-(6R, 7R) -7 β-[(Z) -2- (2- amino -4- thiazoles) -4- carboxyls -2-
(Z)-crotonamide] the bicyclic two water object of [4.2.0] oct-2-ene -2- carboxylic acids of -8- oxygen -5- sulphur -1- nitrogen, structural formula such as formula (I) institute
Show：
Beta-Lactam antibiotic, as penicillin medicine and Cephalosporins hold since the stability of parent nucleus is poor
Rearrangement, decomposition and polymerisation easily occurs, being formed by polymer product and anaphylactic shock has close relationship.In penicillin
Polymeric impurities are average in 21.44 μ g/g, and allergic reaction incidence is 0.2%；Polymeric impurities are average in 51.24 μ g/g
When, allergic reaction incidence is 0.43%；When 76.7 μ g/g of polymeric impurities average out to, allergy rate is 0.74%.Cephalosporin
Though allergic reaction is so serious not as good as penicillin, when polymer is high, can equally human allergy be caused to react.
It is unstable that Ceftibuten meets light, heat, water, oxidation etc., is also easy to produce catabolite, especially by high temperature the case where
Under, degradation and polymerisation are tended to occur, Ceftibuten dimer, trimer and polymer etc. polymer are generated, to lead
Active constituents of medicine content is caused to reduce, color and luster is reinforced, and polymeric impurities content increases.In addition, expired Ceftibuten antibiotic,
Since the resting period is long, also usually makes the reduction of active constituents of medicine content, darken, polymer content increases.In addition,
In some cases, since controlling of production process is improper, obtained Ceftibuten dihydrate, Ceftibuten dimer, trimerization
Object and polymer etc. polymer content are especially high.And polymer content it is high when, easily make human body generate allergic reaction.So for
The high Ceftibuten dihydrate of this kind of polymeric impurities content or Ceftibuten pharmaceutical preparation, it is necessary to further carry out pure
Change, Ceftibuten dihydrochloride dihydrate crystal that obtain high-quality, that purity is high.
In addition, the poorly water-soluble of Ceftibuten, mobility are bad, it is tired to be brought to the preparation of preparation with hygroscopicity etc.
Mostly there is the defects of dissolution rate is low, and stability is bad, and polymer content is high in difficulty, the capsule prepared.
US4812561 discloses a kind of crystal hydrate of oral cephalosporin and combinations thereof, disclosed crystallization
Hydrate is or mixtures thereof dihydrate, trihydrate, and the preparation method of the crystalline hydrate is：By dissolution of raw material in sour water
In solution, the pH of solution is made to rise (specifically rising to pH1.5-5.0) in about room temperature (specifically at 0-70 DEG C) to separate crystallization.It must
When wanting, stirring mixture keeps crystallization complete.Wet crystallization is isolated, under room temperature and about atmospheric pressure, is not less than in relative humidity
It is dry in 15% inert gas.There is crystalline hydrate made from this method the stability of height, accelerated experiment to confirm,
After one month, remain to keep 97.8% efficiency.The present invention also provides a kind of compositions of energy stable for extended periods of time, find
This hydrate, which is packed into snap fit capsule, and is sealed with gelatin band can make its pole not easy to change and inactivate.The preparation of capsule of the present invention
It is specific as follows：The hydrate of pharmacologically effective dose and additive (such as filler, lubricant) are mixed, capsule is then charged into,
Aqueous gelatin solution is coated on the periphery of capsule lid and the entire junction of body, and drying forms gelatin band.Snap fit capsule can be common
Commodity capsule, the limitation of not special size and color can contain fuel and/or pigment.But applicant is by a large amount of
Experimental study confirms that the impurity content of the crystalline hydrate of present invention gained, especially polymer content is still very high, flowing
Property, dissolubility also need to be improved.Although capsule purity obtained and stability are preferable, its dissolution rate, polymeric impurities
Content is unsatisfactory.
It is a kind of new to prepare Ceftibuten that CN105153198A, which discloses a kind of preparation method this method of Ceftibuten,
Method, high income, purity is high, easy to operate, is a clean production technology of green, 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
Impurity content, especially polymer content are high, and 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 prepared by specific
Method is made.The capsule that applicant prepares it 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 are that two water Ceftibutens, magnesium stearate, microcrystalline cellulose, colloidal silicon dioxide, hydroxyacetic acid form sediment
Powder sodium is solved by controlling the grain size of two water Ceftibutens since Ceftibuten low aqueous solubility leads to the dissolution rate of preparation not
It is good, influence the problem of drug absorption, ceftibuten preparation newly developed is easy in vivo and rapid dispersion, have high absorption and
Bioavilability.The capsule that applicant prepares it has carried out defects inspecting and stability test, finds its impurity content height, surely
Qualitative also poor, dissolution rate needs to be further increased.
It includes at least two different compositions with high water solubility pH agent that WO2013151518A1, which is disclosed a kind of,
Ceftibuten capsule preparations, the preparation include in addition at least one pharmaceutically acceptable excipient and tablet composition.It can
Can include disintegrant, glidant, lubricant and bonding with the pharmaceutically acceptable excipient used in the preparation of the present invention
Agent, capsule dissolution rate obtained is higher, but it is found through experiment that its impurity, polymer content are higher, and stability is poor.
The present inventor, by a large number of experiments, has been made one kind and has been totally different from now using existing Ceftibuten crude product as raw material
There are the Ceftibuten crystalline compounds of the novel crystal forms of technology (such as US4812561, CN105153198A, commercial product), and
By experiment, surprisingly find that the crystalline compounds purity is high, polymer content is low, and stability is good, and not easy to moisture absorption, mobility
It is good, substantially increase its dissolubility.Low using capsule dissolubility height, impurity content made of the crystalline compounds, stability is good.
Invention content
The first object of the present invention is to provide a kind of anti-infectives Ceftibuten crystalline compounds, the crystalline compounds
Not only purity is high, and polymer content is low, and stability is good, and it is not easy to moisture absorption, and mobility, dissolubility etc. are substantially better than existing skill
Art.
The second object of the present invention is to provide the preparation method of the Ceftibuten crystalline compounds, this method technique
Simply, high income, repeatability is strong, is suitable for industrialized production.
The third object of the present invention is to provide a kind of Ceftibuten capsule, and the capsule contains provided by the present invention
Ceftibuten crystalline compounds made from the preparation method of Ceftibuten crystalline compounds or the present invention.Capsule dissolubility height,
Impurity content is low, and stability is good.
The first purpose to realize the present invention, the present invention adopt the following technical scheme that：
A kind of anti-infectives Ceftibuten crystalline compounds, which is characterized in that the Ceftibuten crystalline compounds
Structural formula such as formula (I) shown in, the crystalline compounds with powder x-ray diffraction measuring method measure, with 2 θ ± 0.2 ° angle of diffraction tables
The X-ray powder diffraction pattern shown as shown in Figure 1,
The second purpose to realize the present invention, the present invention adopt the following technical scheme that：
A kind of preparation method of anti-infectives Ceftibuten crystalline compounds of the present invention, which is characterized in that should
Method includes the following steps：
(1) Ceftibuten crude product is ground, crosses 80~100 mesh sieve, be then added to the mixed of dimethyl sulfoxide and ethyl alcohol
It closes in solution, stirs 15~25 minutes；
(2) dimethyl sulfoxide is added in stirring, while being warming up to 30-35 DEG C；
(3) after solution adds, 2-3 hours are stood, agitation and dropping deionized water is at the uniform velocity added dropwise in 1h；
(4) cool down after being added dropwise to complete, stir 1-2h, stand 3-5h and precipitate crystal, filter, vacuum drying obtains Ceftibuten
Crystal.
In the present invention, the Ceftibuten crude product can be the Ceftibuten disclosed in the method using the prior art
The Ceftibuten that synthetic method is prepared can also be commercially available Ceftibuten bulk pharmaceutical chemicals.
In preparation method of the present invention, wherein the mixed liquor volume of dimethyl sulfoxide described in step 1) and ethyl alcohol is cephalo
The volume ratio of 5-7 times (g/ml) of cloth alkene weight, dimethyl sulfoxide and ethyl alcohol is 4.5:1.
Dimethyl sulfoxide volume described in step 2) is 2-4 times (g/ml) that volume is Ceftibuten weight.
Mixing speed described in step 3) is 80-100 revs/min, and the temperature of the deionized water of dropwise addition is 0 DEG C -5 DEG C, is gone
The volume of ionized water is 6-8 times (g/ml) of Ceftibuten weight.
- 10 DEG C -5 DEG C are cooled in step 4), the mixing speed is 20-30 revs/min.
Third purpose to realize the present invention, the present invention adopt the following technical scheme that：
A kind of Ceftibuten capsule, which is characterized in that the capsule contains Ceftibuten crystal provided by the present invention
Ceftibuten crystalline compounds made from the preparation method of compound or the present invention.
The Ceftibuten capsule, in parts by weight, by Ceftibuten crystalline compounds, the 80- of 100-200 parts by weight
The superfine silica gel powder composition of the microcrystalline cellulose of 100 parts by weight, the croscarmellose sodium of 8-12 parts by weight, 2-4 parts by weight.
The Ceftibuten capsule, in parts by weight, the crystallite by the Ceftibuten of 150 parts by weight, 90 parts by weight are fine
Tie up element, the superfine silica gel powder of the croscarmellose sodium of 9 parts by weight, 3 parts by weight forms.
The Ceftibuten capsule, is prepared by following preparation method：
1) feedstock processing：Ceftibuten is crossed into 80 mesh sieve with vibration screen-dividing machine, it is spare；
2) microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, superfine silica gel powder are crossed to 60 mesh sieve respectively, it is spare；
3) it weighs：Weighing supplementary material is carried out according to prescription；
4) it premixes：Cross-linked carboxymethyl cellulose sodium of the microcrystalline cellulose of recipe quantity, superfine silica gel powder and 1/3 recipe quantity is added
Into mixing machine, motor operating frequency 200r/min is set, opens mixing machine and mixes 30 minutes；
5) total mixed：Cross-linked carboxymethyl cellulose sodium of the Ceftibuten of recipe quantity and 2/3 recipe quantity is added in mixing machine,
Motor operating frequency 200r/min is set, opens mixing machine and mixes 10 minutes；Then pre- mixed microcrystalline cellulose, micro mist is added
Motor operating frequency 150r/min is arranged in cross-linked carboxymethyl cellulose sodium of silica gel and 1/3 recipe quantity, opens mixing machine and mixes 20 points
Clock；
6) Autocapsulefillingmachine is filling；
7) it packs.
Compared with prior art, the invention has the advantages that：
(1) not only purity is high for Ceftibuten crystalline compounds provided by the present invention, and polymer content is low, and stability is good,
And it is not easy to moisture absorption, and mobility, dissolubility etc. are substantially better than the prior art.
(2) preparation method of Ceftibuten provided by the present invention is simple for process, high income, and repeatability is strong, is suitable for work
Industry metaplasia is produced；
(3) capsule dissolubility provided by the present invention containing the Ceftibuten crystalline compounds is high, impurity content is low, surely
It is qualitative good.
Description of the drawings
Fig. 1 is the X-ray powder diffraction figure of the Ceftibuten crystalline compounds of the present invention.
Fig. 2 is the heat analysis collection of illustrative plates of the Ceftibuten crystalline compounds of the present invention.
Specific implementation mode
Technical scheme of the present invention is described in detail with embodiment below, it will help to the technical side of the present invention
, there are a further understanding in the advantages of case, effect, and embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim determines.
The preparation of 1 Ceftibuten crystalline compounds of embodiment
(1) Ceftibuten crude product is ground, crosses 80~100 mesh sieve, it is Ceftibuten weight to be then added to volume
6 times of dimethyl sulfoxide and the mixed solution of ethyl alcohol in, the volume ratio of dimethyl sulfoxide and ethyl alcohol is 4.5:1, stir 15~25 points
Clock；
(2) volume is added as 3 times of dimethyl sulfoxide of Ceftibuten weight in stirring, while being warming up to 30-35 DEG C；
(3) after solution adds, 2-3 hour are stood, 0 DEG C of deionized water of dropwise addition under conditions of 90 revs/min of stirrings, go from
The volume of sub- water is 7 times of Ceftibuten weight, is at the uniform velocity added dropwise in 1h；
(4) it is cooled to 0 DEG C after being added dropwise to complete, continues to stir 1-2h under 25 revs/min of stir speed (S.S.), stands 3-5h analysis
Go out crystal, filter, vacuum drying obtains Ceftibuten crystal.
(the same US4812561 of assay method) is measured with powder x-ray diffraction measuring method, is indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction collection shows feature diffraction at 8.0 °, 11.4 °, 13.8 °, 15.1 °, 17.5 °, 19.9 °, 27.9 °
Peak.
Elemental analysis：
Measured value：C40.36%, H4.08%, N12.53%, O28.68%, S14.37%.
Theoretical value：C40.35%, H4.06%, N12.55%, O28.67%, S14.36%.
Elemental analysis result and theoretical value are almost the same.
It uses Cattell aquametry to measure moisture as 8.08wt%, coincide substantially with theoretical value.
It is measured using thermogravimetric analysis, the results are shown in Figure 2, crystal water content 8.07wt%, coincide substantially with theoretical value.
The preparation of 2 Ceftibuten crystalline compounds of embodiment
(1) Ceftibuten crude product is ground, crosses 80~100 mesh sieve, it is Ceftibuten weight to be then added to volume
5 times of dimethyl sulfoxide and the mixed solution of ethyl alcohol in, the volume ratio of dimethyl sulfoxide and ethyl alcohol is 4.5:1, stir 15~25 points
Clock；
(2) volume is added as 4 times of dimethyl sulfoxide of Ceftibuten weight in stirring, while being warming up to 30-35 DEG C；
(3) after solution adds, 2-3 hour are stood, 5 DEG C of deionized water of dropwise addition under conditions of 80 revs/min of stirrings, go from
The volume of sub- water is 6 times of Ceftibuten weight, is at the uniform velocity added dropwise in 1h；
(4) it is cooled to 5 DEG C after being added dropwise to complete, continues to stir 1-2h under 20 revs/min of stir speed (S.S.), stands 3-5h analysis
Go out crystal, filter, vacuum drying obtains Ceftibuten crystal.
It is measured with powder x-ray diffraction measuring method, it is same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
Embodiment 1.
The preparation of 3 Ceftibuten crystalline compounds of embodiment
(1) Ceftibuten crude product is ground, crosses 80~100 mesh sieve, it is Ceftibuten weight to be then added to volume
7 times of dimethyl sulfoxide and the mixed solution of ethyl alcohol in, the volume ratio of dimethyl sulfoxide and ethyl alcohol is 4.5:1, stir 15~25 points
Clock；
(2) volume is added as 2 times of dimethyl sulfoxide of Ceftibuten weight in stirring, while being warming up to 30-35 DEG C；
(3) after solution adds, 2-3 hours are stood, 0 DEG C of deionized water is added dropwise under conditions of 100 revs/min of stirrings, goes
The volume of ionized water is 8 times of Ceftibuten weight, is at the uniform velocity added dropwise in 1h；
(4) it is cooled to -10 DEG C DEG C after being added dropwise to complete, continues to stir 1-2h under 30 revs/min of stir speed (S.S.), stands 3-
5h is precipitated crystal, and filtering, vacuum drying obtains Ceftibuten crystal.
It is measured with powder x-ray diffraction measuring method, it is same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
Embodiment 1.
The preparation of 4 Ceftibuten crystalline compounds of embodiment
(1) Ceftibuten crude product is ground, crosses 80~100 mesh sieve, it is Ceftibuten weight to be then added to volume
5 times of dimethyl sulfoxide and the mixed solution of ethyl alcohol in, the volume ratio of dimethyl sulfoxide and ethyl alcohol is 4.5:1, stir 15~25 points
Clock；
(2) volume is added as 2 times of dimethyl sulfoxide of Ceftibuten weight in stirring, while being warming up to 30-35 DEG C；
(3) after solution adds, 2-3 hour are stood, 0 DEG C of deionized water of dropwise addition under conditions of 80 revs/min of stirrings, go from
The volume of sub- water is 6 times of Ceftibuten weight, is at the uniform velocity added dropwise in 1h；
(4) it is cooled to -10 DEG C DEG C after being added dropwise to complete, continues to stir 1-2h under 20 revs/min of stir speed (S.S.), stands 3-
5h is precipitated crystal, and filtering, vacuum drying obtains Ceftibuten crystal.
It is measured with powder x-ray diffraction measuring method, it is same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
Embodiment 1.
The preparation of 5 Ceftibuten crystalline compounds of embodiment
(1) Ceftibuten crude product is ground, crosses 80~100 mesh sieve, it is Ceftibuten weight to be then added to volume
7 times of dimethyl sulfoxide and the mixed solution of ethyl alcohol in, the volume ratio of dimethyl sulfoxide and ethyl alcohol is 4.5:1, stir 15~25 points
Clock；
(2) volume is added as 4 times of dimethyl sulfoxide of Ceftibuten weight in stirring, while being warming up to 30-35 DEG C；
(3) after solution adds, 2-3 hours are stood, 5 DEG C of deionized water is added dropwise under conditions of 100 revs/min of stirrings, goes
The volume of ionized water is 8 times of Ceftibuten weight, is at the uniform velocity added dropwise in 1h；
(4) it is cooled to 5 DEG C after being added dropwise to complete, continues to stir 1-2h under 30 revs/min of stir speed (S.S.), stands 3-5h analysis
Go out crystal, filter, vacuum drying obtains Ceftibuten crystal.
It is measured with powder x-ray diffraction measuring method, it is same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
Embodiment 1.
【Example of formulations 1】Ceftibuten capsule
In parts by weight, composition is as follows：
| Prescription | Dosage (in parts by weight) |
| Ceftibuten | 100 |
| Microcrystalline cellulose | 80 |
| Croscarmellose sodium | 8 |
| Superfine silica gel powder | 2 |
Ceftibuten is head made from the preparation method of Ceftibuten crystalline compounds provided by the present invention or the present invention
Spore cloth alkene crystalline compounds.
Preparation method：
1) feedstock processing：Ceftibuten is crossed into 80 mesh sieve with vibration screen-dividing machine, it is spare；
2) microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, superfine silica gel powder are crossed to 60 mesh sieve respectively, it is spare；
3) it weighs：Weighing supplementary material is carried out according to prescription；
4) it premixes：Cross-linked carboxymethyl cellulose sodium of the microcrystalline cellulose of recipe quantity, superfine silica gel powder and 1/3 recipe quantity is added
Into mixing machine, motor operating frequency 200r/min is set, opens mixing machine and mixes 30 minutes；
5) total mixed：Cross-linked carboxymethyl cellulose sodium of the Ceftibuten of recipe quantity and 2/3 recipe quantity is added in mixing machine,
Motor operating frequency 200r/min is set, opens mixing machine and mixes 10 minutes；Then pre- mixed microcrystalline cellulose, micro mist is added
Motor operating frequency 150r/min is arranged in cross-linked carboxymethyl cellulose sodium of silica gel and 1/3 recipe quantity, opens mixing machine and mixes 20 points
Clock；
6) Autocapsulefillingmachine is filling；
7) it packs.
【Example of formulations 2】Ceftibuten capsule
In parts by weight, composition is as follows：
Ceftibuten is head made from the preparation method of Ceftibuten crystalline compounds provided by the present invention or the present invention
Spore cloth alkene crystalline compounds.
Preparation method：With example of formulations 1, except that Ceftibuten used is the cephalo prepared by embodiment 2
Cloth alkene crystal.
【Example of formulations 3】Ceftibuten capsule
In parts by weight, composition is as follows：
| Prescription | Dosage (in parts by weight) |
| Ceftibuten | 150 |
| Microcrystalline cellulose | 90 |
| Croscarmellose sodium | 10 |
| Superfine silica gel powder | 3 |
Ceftibuten is head made from the preparation method of Ceftibuten crystalline compounds provided by the present invention or the present invention
Spore cloth alkene crystalline compounds.
Preparation method：With example of formulations 1, except that Ceftibuten used is the cephalo prepared by embodiment 3
Cloth alkene crystal.
【Example of formulations 4】Ceftibuten capsule
In parts by weight, composition is as follows：
| Prescription | Dosage (in parts by weight) |
| Ceftibuten | 200 |
| Microcrystalline cellulose | 80 |
| Croscarmellose sodium | 12 |
| Superfine silica gel powder | 2 |
Ceftibuten is head made from the preparation method of Ceftibuten crystalline compounds provided by the present invention or the present invention
Spore cloth alkene crystalline compounds.
Preparation method：With example of formulations 1, except that Ceftibuten used is the cephalo prepared by embodiment 4
Cloth alkene crystal.
【Example of formulations 5】Ceftibuten capsule
In parts by weight, composition is as follows：
| Prescription | Dosage (in parts by weight) |
| Ceftibuten | 200 |
| Microcrystalline cellulose | 100 |
| Croscarmellose sodium | 12 |
| Superfine silica gel powder | 4 |
Ceftibuten is head made from the preparation method of Ceftibuten crystalline compounds provided by the present invention or the present invention
Spore cloth alkene crystalline compounds.
Preparation method：With example of formulations 1, except that Ceftibuten used is the cephalo prepared by embodiment 5
Cloth alkene crystal.
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：Ceftibuten crystalline compounds are made according to the method for CN105153198A embodiments 1.
Reference substance 2：Ceftibuten crystalline compounds are made according to the method for US4812561 examples 2.
Experimental example 1：Fluidity test
This experimental example evaluates the mobility of sample by the angle of repose of determination sample, and the specific method is as follows：Take sample
Grain, flows into from fixed small funnel in circular surface plate, until obtaining highest cone, measure cone height H and
Radius R calculates 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.
1 fluidity test result of table
| Trial target 1 | Trial target 2 | Reference substance 1 | Reference substance 2 | |
| Angle of repose | 33° | 34° | 50° | 42° |
As known from Table 1, compared with Ceftibuten in the prior art, the Ceftibuten compound flow prepared by the present invention
Property significantly improves, and is conducive to the preparation of preparation, the raising of dissolution rate, bioavilability.
Experimental example 2：Dissolubility test
Suitable distilled water is added in the low capacity bottle with constant temperature jacket, Ceftibuten is added at 25 DEG C to no longer
Until dissolving, start magnetic stirrer, persistently stirred under constant temperature, system is in the shape of two-phase coexistent always during the experiment
State, the solubility of the concentration of Ceftibuten as at this temperature in the liquid phase of system after 70 minutes.It is sampled after 2 hours point
Analysis, takes similar in adjacent two times result that average value is as measured value of experiment, before sampling, in order to make solid-liquid be sufficiently separated, stops stirring
After mixing, not molten Ceftibuten is deposited to the bottom of low capacity bottle, a small amount of upper clear supernate is extracted with syringe, with 0.45 micron
Filter filters, and sample is taken from filtrate, the content (concentration (mg/ml)) of Ceftibuten is measured by HPLC.It the results are shown in Table 2.
Ceftibuten crystal compound of the present invention compares table 2 with the water-soluble of prior art crystal form at room temperature
| Sample | First time content | Second of content | Average value |
| Trial target 1 | 0.08 | 0.08 | 0.08 |
| Trial target 2 | 0.09 | 0.08 | 0.085 |
| Reference substance 1 | 0.009 | 0.01 | 0.0095 |
| Reference substance 2 | 0.01 | 0.008 | 0.009 |
| It is commercially available | 0.01 | 0.01 | 0.01 |
From table 2 it can be seen that the water solubility of Ceftibuten crystal compound of the present invention is compared with prior art, have significantly
It improves.
Experimental example 3：Wettability test
Each sample opening is set in clean culture dish, each two parts, it is closed to be respectively put into constant humidity at the thin layer of≤5mm thickness for booth
It in container, places 10 days under conditions of 25 DEG C respectively at relative humidity 75% and 92.5%, was sampled in the 5th day and the 10th day,
The moisture of each sample is measured with Fischer's method, for test result compared with 0 day, experimental result is shown in Table 3.
3 hygroscopicity test results of table
As can be seen from the above table, the Ceftibuten crystalline compounds that prepared by the present invention are not inhaled substantially under high humidity conditions
Wet, the stability under high humidity environment is substantially better than the Ceftibuten using the prior art.
Experimental example 4：Influence factor is tested
By trial target and reference substance simulation listing packaging, in 60 DEG C of high temperature, illumination 4500Lx, high humidity (RH90% ± 5%)
Under the conditions of place 10 days, be detected by stability high spot reviews project, compared with 0 day sample, the results are shown in Table 4.
4 compounds affect factorial experiments result of table
The height of drug quality is directly related to the health of millions upon millions of working people's bodies, is also related to economic construction of China
Effect, national defence consolidation and nationality it is flourishing；It has been far from the thing of medical industry enterprise range itself, but entire
National, the world the major issue.Those skilled in the art clearly know, in the present age of pharmaceutical technology prosperity, drug safety standard quilt
Constantly being promoted, the purity of prepared drug is also higher and higher, is effectively reduced impurity content, even the several percentages of zero
Point, it is possibility to have effect ground reduces the generation of adverse reaction, therefore impurity content to drug quality and people's drug safety to closing weight
It wants.Drug is from production to needing in the process of circulation to store and transport just cure the sickness to save the patient, therefore, drug in storage and transportational process
Quality be particularly important, stability be the key that determine drug quality quality, drug storage and transportational process in, stablize
Property it is bad, impurity variation directly affects people's drug safety greatly.
As can be seen from the above table, the related substance of Ceftibuten crystalline compounds made from method using the present invention, poly-
Close that object equal size is very low, and stability is significantly better than the Ceftibuten of the prior art, effectively improve drug safety and
The stability of storage reduces the generation of adverse reaction.
Above-mentioned experimental example 1-4 has also been carried out to the Ceftibuten crystalline compounds of other embodiments of the present invention, has been obtained
As a result similar.
Experimental example 5：Prescription screening experiment (is prepared) using capsule preparation method thereof of the present invention
5 prescription screening experimental result of table
As can be seen from the above table, not only mobility, dissolution rate are good for Ceftibuten capsule (prescription 11) produced by the present invention,
And polymer, total miscellaneous content significantly reduce.
Experimental example 6：Preparation influence factor is tested
Formulation test product 1：Ceftibuten capsule prepared by invention formulation embodiment 1.
Formulation test product 2：Ceftibuten capsule prepared by invention formulation embodiment 3.
Preparations. Control product 1：(Ceftibuten is city to the Ceftibuten capsule prepared according to the method for EP3031450 embodiments 1
Sell, art methods be made or the method for the present invention be made, influence factor test result is almost the same).
Preparations. Control product 2：Ceftibuten capsule (Ceftibuten is made according to the method for WO2013151518A1 embodiments 1
It is made for commercially available, art methods or the method for the present invention is made, influence factor test result is almost the same).
Preparations. Control product 3：Ceftibuten capsule is made according to the method for CN104546862A embodiments 2, and (Ceftibuten is
Commercially available, art methods are made or the method for the present invention is made, and influence factor test result is almost the same).
Preparations. Control product 4：Ceftibuten capsule is made according to the method for US4812561 examples 9.
By formulation test product and preparations. Control product simulation listing packaging, in 60 DEG C of high temperature, illumination 4500Lx, high humidity
It places 10 days under the conditions of (RH90% ± 5%), is detected by stability high spot reviews project, compared with 0 day sample, as a result seen
Table 6.
6 preparation influence factor test result of table
It is found by result above, the capsule dissolubility containing the Ceftibuten crystalline compounds prepared by the present invention is high,
Impurity content is low, and stability is good.
Above-mentioned experiment is also carried out to the Ceftibuten capsule of the other example of formulations of the present invention, the result phase obtained
Seemingly.
Claims (10)
1. a kind of anti-infectives Ceftibuten crystalline compounds, which is characterized in that the Ceftibuten crystalline compounds
Shown in structural formula such as formula (I), which is measured with powder x-ray diffraction measuring method, is indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction pattern as shown in Figure 1,
Formula（）.
2. a kind of preparation method of anti-infectives Ceftibuten crystalline compounds described in claim 1, which is characterized in that should
Method includes the following steps：
1）Ceftibuten crude product is ground, 80~100 mesh sieve is crossed, is then added to the mixed solution of dimethyl sulfoxide and ethyl alcohol
In, it stirs 15~25 minutes；
2）Dimethyl sulfoxide is added in stirring, while being warming up to 30-35 DEG C；
3）After solution adds, 2-3 hours are stood, agitation and dropping deionized water is at the uniform velocity added dropwise in 1h；
4）Cool down after being added dropwise to complete, stir 1-2h, stands 3-5h and precipitate crystal, filter, vacuum drying obtains Ceftibuten crystal.
3. preparation method according to claim 2, which is characterized in that step 1）Described in dimethyl sulfoxide and ethyl alcohol mixing
Liquor capacity is 5-7 times of Ceftibuten weight, and the volume ratio of dimethyl sulfoxide and ethyl alcohol is 4.5:1.
4. preparation method according to claim 2, which is characterized in that step 2）Described in dimethyl sulfoxide volume be cephalo
2-4 times of cloth alkene weight.
5. preparation method according to claim 2, which is characterized in that step 3）Described in mixing speed be 80-100 turn/
Minute, the temperature of the deionized water of dropwise addition is 0 DEG C -5 DEG C, and the volume of deionized water is 6-8 times of Ceftibuten weight.
6. preparation method according to claim 2, which is characterized in that step 4）In be cooled to -10 DEG C -5 DEG C, the stirring
Speed is 20-30 revs/min.
7. a kind of Ceftibuten capsule, which is characterized in that the capsule contains Ceftibuten crystallization described in claim 1
Close object.
8. Ceftibuten capsule according to claim 7, which is characterized in that in parts by weight, by 100-200 parts by weight
Ceftibuten crystalline compounds, the microcrystalline cellulose of 80-100 parts by weight, the croscarmellose sodium of 8-12 parts by weight, 2-
The superfine silica gel powder of 4 parts by weight forms.
9. Ceftibuten capsule according to claim 7 or 8, which is characterized in that in parts by weight, by 150 parts by weight
The superfine silica gel powder group of Ceftibuten, the microcrystalline cellulose of 90 parts by weight, the croscarmellose sodium of 9 parts by weight, 3 parts by weight
At.
10. Ceftibuten capsule according to claim 9, which is characterized in that be prepared by following preparation method：
1）Feedstock processing：Ceftibuten is crossed into 80 mesh sieve with vibration screen-dividing machine, it is spare；
2）Microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, superfine silica gel powder are crossed to 60 mesh sieve respectively, it is spare；
3）It weighs：Weighing supplementary material is carried out according to prescription；
4）Premix：Cross-linked carboxymethyl cellulose sodium of the microcrystalline cellulose of recipe quantity, superfine silica gel powder and 1/3 recipe quantity is added to mixed
In conjunction machine, motor operating frequency 200r/min is set, opens mixing machine and mixes 30 minutes；
5）It is total mixed：Cross-linked carboxymethyl cellulose sodium of the Ceftibuten of recipe quantity and 2/3 recipe quantity is added in mixing machine, is arranged
Motor operating frequency 200r/min opens mixing machine and mixes 10 minutes；Then pre- mixed microcrystalline cellulose, superfine silica gel powder is added
And 1/3 recipe quantity cross-linked carboxymethyl cellulose sodium, be arranged motor operating frequency 150r/min, open mixing machine mix 20 minutes；
6）Autocapsulefillingmachine is filling；
7）Packaging.
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| PE20000879A1 (en) * | 1998-04-29 | 2000-09-23 | Dsm Nv | METHOD TO CRYSTALLIZE A ß-LACTAMIC ANTIBIOTIC |
| JP4510957B2 (en) * | 1999-09-01 | 2010-07-28 | 大塚化学株式会社 | Method for producing cephem compound |
| JP4535530B2 (en) * | 1999-09-20 | 2010-09-01 | 大塚化学株式会社 | Method for producing 3-sulfonyloxy-3-cephem compound |
| CN101467979A (en) * | 2007-12-29 | 2009-07-01 | 北京琥珀光华医药科技开发有限公司 | Ceftibuten sustained-release capsule |
| US9006421B2 (en) * | 2013-03-14 | 2015-04-14 | Cubist Pharmaceuticals, Inc. | Cephalosporin compositions and methods of manufacture |
| EP3031450A1 (en) * | 2014-12-12 | 2016-06-15 | Sanovel Ilac Sanayi ve Ticaret A.S. | Ceftibuten capsule compositions |
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