CN109734726A - A kind of refining methd of three hydrations cefixime crystal - Google Patents
A kind of refining methd of three hydrations cefixime crystal Download PDFInfo
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Abstract
The invention discloses the refining methds that one kind three is hydrated cefixime crystal, it include: at a temperature of 15~35 DEG C, acid solution is added dropwise into the Cefixime mixed salt solution that mass concentration is 0.01~0.05g/mL and stirs, by Cefixime mixed salt solution solution pH value adjustment to 2.95~3.15, growing the grain 1~8 hour after solution spontaneous nucleation generates precipitating, filtrate is obtained by filtration；Three hydration Cefiximes are added into filtrate, obtains reaction solution, is stirred to react liquid, start slow acid supplemented solution when pH value rises, stop acid supplemented solution between 2.00~2.40 until pH value reaches, growing the grain 0.5~3 hour, be filtered, washed, dry after obtain three hydration cefixime crystals.Three high hydration cefixime crystals of the available stability of this method, repeatability is high, small by extraneous factor interference, is the effective ways for preparing high stability three and being hydrated cefixime crystal.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to the reactive crystallization preparation method technical field of cephalosporin, especially relate to
And one kind three is hydrated the refining methd of cefixime crystal.
Background technique
Three hydration Cefixime (cefiximetridytrate), alias Cefspan (Suprax/Cefspan), Da Lifen,
Mortopl is peaceful, promise hundred is excellent, is a kind of oral Third generation Cephalosporins antibiotic, is widely approved in the world at present
And clinical application, as a kind of important oral cephalosporin product, Cefixime have has a broad antifungal spectrum, antibacterial action it is strong,
Efficiently, resistance to enzyme, the advantages that dosage is small.Cefixime chemical name: [6R- [6 Α, 7 Β (Z)]] -7- [[(2- amino -4- thiazolyl)
[(carboxymethoxyl) imino group] acetyl group] amino] -3- vinyl -8- oxo -5- thia -1- azabicyclo [4.2.0] -2- is pungent
Alkene -2- carboxylic acid；English name: (6R, 7R) -7- (2- (2-Amino-4-thiazolyl) gloxylamido) -8-oxo-3-
vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid；Molecular formula:
C16H15N5O7S2·3H2O；Molecular weight: 507；CAS NO:125110-14-7；Character: three hydration Cefiximes are white to yellowish
Color crystalline powder, tasteless or tool are slight special smelly.It is dissolved in methanol, dimethyl sulfoxide, is slightly soluble in acetone, be insoluble in ethyl alcohol,
It is almost insoluble in water, ethyl acetate, ether, hexane.PH value is generally 2.6~4.1, and fusing point is 218~225 DEG C.
The final step technique of Cefixime preparation method belongs to reactive crystallization scope at present.Reactive crystallization has nucleation
The features such as rate is fast causes the crystallinity of product not easy to control, for drug, it is more difficult to obtain the high crystallization of stability and produce
Object.And unformed anhydrous Cefixime (C is often obtained in reaction crystallization process16H15N5O7S2；Molecular weight: 453；
CAS NO:79350-37-1) and make the bad stability of final product.So optimization crystallization processes are high steady to obtain high-purity
Qualitative three hydrations Cefixime crystalline solid has great importance.
Summary of the invention
The object of the present invention is to provide the refining methds that one kind three is hydrated cefixime crystal, to solve existing production work
Skill is difficult to obtain the problem of three high hydration cefixime crystal of stability.
A kind of refining methd of three hydrations cefixime crystal provided in an embodiment of the present invention, this method comprises:
Step 1: molten to the Cefixime salt mixing that mass concentration is 0.01~0.05g/mL at a temperature of 15~35 DEG C
It is added dropwise and acid solution and stirs in liquid, wherein the Cefixime mixed salt solution is the mixed of Cefixime salt and acetone and water
The mixed solution for closing solution or Cefixime salt and water, by Cefixime mixed salt solution pH value adjustment to 2.95~3.15, to
Solution spontaneous nucleation generates after precipitating growing the grain 1~8 hour, and filtrate is obtained by filtration；
Step 2: three hydration Cefiximes are added in Xiang Suoshu filtrate, obtains reaction solution, the reaction solution is stirred, to PH
Value starts slow acid supplemented solution when rising, and stops acid supplemented solution between 2.00~2.40 until pH value reaches, growing the grain 0.5~3 is small
When, be filtered, washed, dry after obtain three hydration cefixime crystals.
Preferably, the three hydrations Cefixime includes three hydration Cefixime crystal seeds.
Preferably, the three hydrations Cefixime includes the three hydration Cefiximes prepared by three hydration Cefixime crystal seeds
Crystal seed dispersion liquid.
Preferably, the quality of the three hydrations Cefixime crystal seed is 1.0~5.0g.
Preferably, the three hydrations Cefixime crystal seed first passes through milled processed or in advance successively by being ground up, sieved place
Reason.
Preferably, the mass concentration of the Cefixime mixed salt solution is 0.02~0.04g/mL.
Preferably, it is molten to respectively include hydrochloric acid solution, acetum, sulfuric acid solution and phosphoric acid for the acid in step 1 and step 2
One of liquid or a variety of combinations.
Preferably, the mass fraction of the acid solution in step 1 and step 2 is 1.0wt%~8.0wt%.
Preferably, the mixing time in step 2 is 10~30min.
Preferably, stop acid supplemented solution when pH value reaches between 2.10~2.30 in step 2.
The present invention has the following advantages and effects with respect to the prior art:
The refining methd of the three hydration cefixime crystals provided according to the present invention, three high hydrations of available stability
Cefixime crystal, while can guarantee whiteness, size distribution, mobility, heap density, content, moisture and the molten indexs symbol such as residual
Close States Pharmacopoeia specifications.Take and first make solution by reactive crystallization spontaneous nucleation, after spontaneous nucleation product is filtered to remove, filtrate after
The continuous mode carried out plus crystal seed hair induction crystallizes, three stable hydration Cefiximes of available product characteristics are brilliant by this way
Body, this method repeatability is high, interfered by extraneous factor it is small, be prepare that high stability three is hydrated cefixime crystal have efficacious prescriptions
Method.
It should be understood that above general description and following detailed description be only it is exemplary and explanatory, not
It can the limitation present invention.
Detailed description of the invention
In order to illustrate more clearly of technical solution of the present invention, letter will be made to attached drawing needed in the embodiment below
Singly introduce, it should be apparent that, for those of ordinary skills, without any creative labor,
It is also possible to obtain other drawings based on these drawings.
Fig. 1 is the Cefixime anhydride scanning electron microscope (SEM) photograph that step 1 of the embodiment of the present invention generates；
Fig. 2 is the three hydration Cefixime scanning electron microscope (SEM) photographs that step 2 of the embodiment of the present invention generates；
Fig. 3 is the Cefixime that step 1 of the embodiment of the present invention generates and the three hydration Cefiximes that step 2 generates
XRD diagram；
Fig. 4 is the TG of the Cefixime that step 1 of the embodiment of the present invention generates and the three hydration Cefiximes that step 2 generates
Figure.
Specific embodiment
A kind of refining methd of three hydrations cefixime crystal provided in an embodiment of the present invention:
Step 1: molten to the Cefixime salt mixing that mass concentration is 0.01~0.05g/mL at a temperature of 15~35 DEG C
It is added dropwise and acid solution and stirs in liquid, wherein the Cefixime mixed salt solution is the mixed of Cefixime salt and acetone and water
The mixed solution for closing solution or Cefixime salt and water, by Cefixime mixed salt solution pH value adjustment to 2.95~3.15, to
Solution spontaneous nucleation generates after precipitating growing the grain 1~8 hour, and filtrate is obtained by filtration.
In the step, the crystal of generation is anhydrous cefixime crystal, and gained filtrate is Cefixime salt saturated solution.
In the specific implementation process, the acid solution of step 1 can be hydrochloric acid solution, acetum, sulfuric acid solution and phosphoric acid
One of solution or a variety of combinations, the mass fraction of acid solution are 1.0wt%~8.0wt%, and the rate of acid supplemented solution is 2
~8mL/min.Mixing speed in step 1 is 50~250rpm.In the specific implementation process, mixing speed can be selected
Select any constant airspeed in 50~250rpm.
In a kind of possible embodiment, the mass concentration of Cefixime mixed salt solution preferably 0.02~0.04g/
mL。
Step 2: three hydration Cefiximes are added in Xiang Suoshu filtrate, obtains reaction solution, the reaction solution is stirred, to PH
Value starts slow acid supplemented solution when rising, and stops acid supplemented solution between 2.00~2.40 until pH value reaches, growing the grain 0.5~3 is small
When, be filtered, washed, dry after obtain three hydration cefixime crystals.
In the specific implementation process, three hydration heads are added into the filtrate that step 1 obtains i.e. Cefixime salt saturated solution
Spore gram oxime obtains reaction solution, stirs the reaction solution, starts slow acid supplemented solution when pH value rises, until pH value reaches 2.00
Stop acid supplemented solution between~2.40, growing the grain 0.5~3 hour, be filtered, washed, dry after obtain three hydration cefixime crystals.
Wherein, the acid in step 2 can for one of hydrochloric acid solution, acetum, sulfuric acid solution and phosphoric acid solution or
A variety of combinations, the mass fraction of acid solution are 1.0wt%~8.0wt%, and the rate of acid supplemented solution is 2~8mL/min.
In the specific implementation process, three hydration Cefiximes being added in step 2 can be three hydration Cefixime crystal seeds
Or the three hydration Cefixime crystal seed dispersion liquids prepared by three hydration Cefixime crystal seeds.Three hydration Cefixime crystal seeds can be pre-
It first passes through milled processed or successively by being ground up, sieved processing, quality is in 1.0~5.0g.Three hydration Cefiximes are brilliant
Kind of dispersion liquid can be the dispersion of Cefixime saturated solution mother liquor or deionized water dispersion, dispersing mode can for ultrasonic disperse,
It is dispersed with stirring or ultrasonic disperse and the combination being dispersed with stirring, the jitter time of dispersion liquid is 5~30min, the volume of dispersion liquid
It can be between 40~100mL.
In a kind of possible embodiment, mixing time in step 2 is 10~30min, mixing speed is 50~
250rpm.In the specific implementation process, mixing speed can choose any constant airspeed in 50~250rpm.
In a kind of possible embodiment, in step 2 when acid supplemented solution, until pH value reaches between 2.10~2.30
When stop acid supplemented solution.
In a kind of possible embodiment, growing the grain 1~2 hour in step 2.
In a kind of possible embodiment, Step 1: the temperature in step 2 is constant.
The crystal that step 2 obtains is respectively put into cillin bottle in stability of drug products Acceleration study case, 60 DEG C of set temperature
Stablize 10 days another batch be set as stablizing at 25 DEG C 90 days, respectively to stablize the related content of material of front and back cefixime crystal with
Content, moisture are analyzed.The mobility of product, size distribution, whiteness, molten residual value, moisture value are measured.Such as 1 institute of table
Show, the three hydration cefixime crystals which obtains, largest single impurity≤0.10% before stablizing, before stablizing it is total it is miscellaneous≤
0.20%, stablize largest single impurity≤0.25% after 10 days, always miscellaneous after stablizing 10 days≤1.20%, whiteness >=80, granularity: unimodal narrow
10 days front and back content >=95.0%, moisture 10%~12%, angle of repose≤40 ° are stablized in 60~100 μm of distribution.25 DEG C are stablized 90
Largest single impurity≤0.40% after it, always miscellaneous after stablizing 90 days≤1.50%, obviously becoming do not occur in other indexs such as whiteness, mobility
Change.The data of three hydration Cefiximes of existing production technology preparation are as shown in table 2, compare the data of Tables 1 and 2, can be with
, it is evident that the quality such as stability of three hydration cefixime crystals that refining methd provided by the invention obtains are substantially better than now
There is production technology product.
The three hydration Cefixime product data tables that 1 present invention process of table obtains
The existing production technology of table 2 obtains three hydration Cefixime product data tables
Using the three hydration cefixime crystals high the present invention can obtain stability, while it can guarantee whiteness, granularity
Distribution, mobility, heap density, content, moisture and the molten indexs such as residual meet States Pharmacopoeia specifications.It takes and solution is first made to pass through reaction knot
Brilliant spontaneous nucleation, after spontaneous nucleation product is filtered to remove, filtrate continue plus crystal seed hair induction crystallization mode, by this
Three stable hydration cefixime crystals of the available product characteristics of mode, this method repeatability is high, small by extraneous factor interference,
It is the effective ways for preparing high stability three and being hydrated cefixime crystal.
Embodiment 1
The Cefixime salting liquid that 1500mL initial mass concentration is 0.03g/mL is added in the first step in 2L reaction kettle,
Solvent is using water as the water of main component, acetone mixed solvent.Install pH meter in reaction unit additional, the initial pH of solution is on 5.20 left sides
The right side, mixing speed 200rpm stablize after 20 DEG C ± 2 DEG C after solution temperature, start that matter is added with 4.0mL/min acid addition rate
Measure the hydrochloric acid solution that score is 2.0wt%；Stop adding hydrochloric acid solution when pH stable is 3.05 or so, crystallize at this time, reacts
There should be solid product appearance in kettle, maintain the mixing speed growing the grain of 200rpm 4 hours.Mother liquor is filtered after growing the grain,
Collection of products, filtrate return to crystallizer and are ready for reacting in next step.
Second step, to filtering after the three hydration Cefixime crystal seeds of 2.0g are added in clear filtrate and 50mL mother liquor configures
Crystal seed dispersion liquid, for crystal seed by being ground up, sieved pretreatment, reaction solution is added after being dispersed with stirring 10min in dispersion liquid in crystal seed
In.After the reaction solution stirring 20min of crystal seed dispersion liquid is added, starts to continue with 4.0mL/min acid addition rate plus hydrochloric acid solution is straight
Reach to pH value and terminal 2.20 is added dropwise.Keep solution temperature and mixing speed constant, growing the grain 1.5h.
Second step product is filtered, washed, is dried in vacuo, three hydration cefixime crystals are obtained.It will obtain three hydration heads
Spore gram oxime crystal is respectively put into cillin bottle in stability of drug products Acceleration study case, 60 DEG C of set temperature stablize 10 days another batch set
It is set at 25 DEG C and stablizes 90 days, the related content of material and content, moisture of stablizing front and back cefixime crystal are divided respectively
Analysis.The mobility of product, size distribution, whiteness, molten residual value, moisture value are measured, measurement result is as shown in table 1.
The crystal that the first step of the present invention obtains is anhydrous cefixime crystal, as shown in Figure 1；Second step obtain crystal be
Three hydration cefixime crystals, as shown in Figure 2；The XRD spectrum for the crystal that second step generates is as shown in figure 3, TG map such as Fig. 4 institute
Show, Fig. 3 and Fig. 4 can illustrate, it is high-crystallinity crystal that second step product three, which is hydrated cefixime crystal, and first step product is anhydrous
Cefixime is unformed solid, TG map can calculate in second step product each molecule contain that there are three the crystallizations water.
Embodiment 2
Difference from example 1 is that only the initial mass concentration of Cefixime salting liquid is in the first step
0.01g/mL。
Embodiment 3
Difference from example 1 is that only the initial mass concentration of Cefixime salting liquid is in the first step
0.02g/mL。
Embodiment 4
Difference from example 1 is that only the initial mass concentration of Cefixime salting liquid is in the first step
0.04g/mL。
Embodiment 5
Difference from example 1 is that only the initial mass concentration of Cefixime salting liquid is in the first step
0.05g/mL。
Embodiment 6
Difference from example 1 is that only Step 1: it is 15 DEG C that temperature is constant in two.
Embodiment 7
Difference from example 1 is that only Step 1: it is 25 DEG C that temperature is constant in two.
Embodiment 8
Difference from example 1 is that only Step 1: it is 30 DEG C that temperature is constant in two.
Embodiment 9
Difference from example 1 is that only mixing speed is 50rpm.
Embodiment 10
Difference from example 1 is that only mixing speed is 100rpm.
Embodiment 11
Difference from example 1 is that only mixing speed is 250rpm.
Embodiment 12
Difference from example 1 is that only acid addition rate is 2.0mL/min.
Embodiment 13
Difference from example 1 is that only acid addition rate is 3.0mL/min.
Embodiment 14
Difference from example 1 is that only acid addition rate is 6.0mL/min.
Embodiment 15
Difference from example 1 is that only acid addition rate is 8.0mL/min.
Embodiment 16
Difference from example 1 is that only spontaneous nucleation pH value is 2.95.
Embodiment 17
Difference from example 1 is that only spontaneous nucleation pH value is 3.10.
Embodiment 18
Difference from example 1 is that only the mass fraction of hydrochloric acid solution is 1.0wt%.
Embodiment 19
Difference from example 1 is that only the mass fraction of hydrochloric acid solution is 2.0wt%.
Embodiment 20
Difference from example 1 is that only the mass fraction of hydrochloric acid solution is 6.0wt%.
Embodiment 21
Difference from example 1 is that only the mass fraction of hydrochloric acid solution is 8.0wt%.
Embodiment 22
Difference from example 1 is that only Seed charge is 1.0g.
Embodiment 23
Difference from example 1 is that only Seed charge is 4.0g.
Embodiment 24
Difference from example 1 is that only Seed charge is 5.0g.
Embodiment 25
Difference from example 1 is that only dispersion liquid volume is 40mL in second step.
Embodiment 26
Difference from example 1 is that only dispersion liquid volume is 60mL in second step.
Embodiment 27
Difference from example 1 is that only dispersion liquid volume is 100mL in second step.
Embodiment 28
Difference from example 1 is that only crystal seed jitter time in dispersion liquid is 5min in second step.
Embodiment 29
Difference from example 1 is that only crystal seed jitter time in dispersion liquid is 8min in second step.
Embodiment 30
Difference from example 1 is that only crystal seed jitter time in dispersion liquid is 12min in second step.
Embodiment 31
Difference from example 1 is that only crystal seed jitter time in dispersion liquid is 15min in second step.
Embodiment 32
Difference from example 1 is that only the reaction solution mixing time after second step addition crystal seed is 10min.
Embodiment 33
Difference from example 1 is that only the reaction solution mixing time after second step addition crystal seed is 15min.
Embodiment 34
Difference from example 1 is that only the reaction solution mixing time after second step addition crystal seed is 25min.
Embodiment 35
Difference from example 1 is that only the reaction solution mixing time after second step addition crystal seed is 30min.
Embodiment 36
Difference from example 1 is that only the growing the grain terminal of second step is pH value 2.00.
Embodiment 37
Difference from example 1 is that only the growing the grain terminal of second step is pH value 2.10.
Embodiment 38
Difference from example 1 is that only the growing the grain terminal of second step is pH value 2.30.
Embodiment 39
Difference from example 1 is that only the growing the grain terminal of second step is pH value 2.40.
Embodiment 40
Difference from example 1 is that only the rearing crystal time of second step is 0.5h.
Embodiment 41
Difference from example 1 is that only the rearing crystal time of second step is 1.0h.
Embodiment 42
Difference from example 1 is that only the rearing crystal time of second step is 2.0h.
Embodiment 43
Difference from example 1 is that only the rearing crystal time of second step is 3.0h.
Same and similar part may refer to each other between each embodiment in this specification.
Those skilled in the art will readily occur to of the invention its after considering specification and the disclosure invented here of practice
Its embodiment.This application is intended to cover any variations, uses, or adaptations of the invention, these modifications, purposes or
Person's adaptive change follows general principle of the invention and including the undocumented common knowledge in the art of the present invention
Or conventional techniques.The description and examples are only to be considered as illustrative, and true scope and spirit of the invention are by following
Claim is pointed out.
Invention described above embodiment is not intended to limit the scope of the present invention..
Claims (10)
1. the refining methd that one kind three is hydrated cefixime crystal, which is characterized in that
Step 1: at a temperature of 15~35 DEG C, in the Cefixime mixed salt solution for being 0.01~0.05g/mL to mass concentration
Acid solution is added dropwise and stirs, wherein the Cefixime mixed salt solution is that Cefixime salt and the mixing of acetone and water are molten
The mixed solution of liquid or Cefixime salt and water, by Cefixime mixed salt solution pH value adjustment to 2.95~3.15, to solution
Spontaneous nucleation generates after precipitating growing the grain 1~8 hour, and filtrate is obtained by filtration；
Step 2: three hydration Cefiximes are added in Xiang Suoshu filtrate, obtains reaction solution, the reaction solution is stirred, on pH value
Start slow acid supplemented solution when rising, stops acid supplemented solution between 2.00~2.40 until pH value reaches, growing the grain 0.5~3 hour, mistake
Three hydration cefixime crystals are obtained after filter, washing, drying.
2. the refining methd of three hydrations cefixime crystal as described in claim 1, which is characterized in that the three hydrations cephalo
Gram oxime includes three hydration Cefixime crystal seeds.
3. the refining methd of three hydrations cefixime crystal as described in claim 1, which is characterized in that the three hydrations cephalo
Gram oxime includes the three hydration Cefixime crystal seed dispersion liquids prepared by three hydration Cefixime crystal seeds.
4. the refining methd of three hydrations cefixime crystal as claimed in claim 2 or claim 3, which is characterized in that three hydration
The quality of Cefixime crystal seed is 1.0~5.0g.
5. the refining methd of three hydrations cefixime crystal as claimed in claim 2 or claim 3, which is characterized in that three hydration
Cefixime crystal seed first passes through milled processed or in advance successively by being ground up, sieved processing.
6. the refining methd of three hydrations cefixime crystal as described in claim 1, which is characterized in that the Cefixime salt
The mass concentration of mixed solution is 0.02~0.04g/mL.
7. the refining methd of three hydrations cefixime crystal as described in claim 1, which is characterized in that step 1 and step 2
In acid solution respectively include one of hydrochloric acid solution, acetum, sulfuric acid solution and phosphoric acid solution or a variety of combinations.
8. the refining methd of three hydrations cefixime crystal as described in claim 1, which is characterized in that step 1 and step 2
In the mass fraction of acid solution be 1.0wt%~8.0wt%.
9. the refining methd of three hydrations cefixime crystal as described in claim 1, which is characterized in that the stirring in step 2
Time is 10~30min.
10. it is as described in claim 1 three hydration cefixime crystal refining methd, which is characterized in that in step 2 until
Stop acid supplemented solution when pH value reaches between 2.10~2.30.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998006723A1 (en) * | 1996-08-14 | 1998-02-19 | Biochemie Gesellschaft Mbh | Amine salts |
| CN101220040A (en) * | 2008-01-30 | 2008-07-16 | 四川方向药业有限责任公司 | Preparation of cefixime cephalosporin and fine purification method |
| CN102516262A (en) * | 2011-12-20 | 2012-06-27 | 浙江国邦药业有限公司 | Method for crystallizing cefixime trihydrate |
| CN107286183A (en) * | 2017-07-11 | 2017-10-24 | 广州白云山医药集团股份有限公司白云山化学制药厂 | A kind of process for purification of Cefixime |
-
2019
- 2019-01-30 CN CN201910090991.XA patent/CN109734726B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998006723A1 (en) * | 1996-08-14 | 1998-02-19 | Biochemie Gesellschaft Mbh | Amine salts |
| CN101220040A (en) * | 2008-01-30 | 2008-07-16 | 四川方向药业有限责任公司 | Preparation of cefixime cephalosporin and fine purification method |
| CN102516262A (en) * | 2011-12-20 | 2012-06-27 | 浙江国邦药业有限公司 | Method for crystallizing cefixime trihydrate |
| CN107286183A (en) * | 2017-07-11 | 2017-10-24 | 广州白云山医药集团股份有限公司白云山化学制药厂 | A kind of process for purification of Cefixime |
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| Title |
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| 宋晓鹏 等: "头孢克肟溶析结晶过程球形生长机理探究", 《化学工业与工程》 * |
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