CN109734727A - A method of cefathiamidine crystal is prepared by controlling crystal seed crystal form - Google Patents
A method of cefathiamidine crystal is prepared by controlling crystal seed crystal form Download PDFInfo
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- CN109734727A CN109734727A CN201910091317.3A CN201910091317A CN109734727A CN 109734727 A CN109734727 A CN 109734727A CN 201910091317 A CN201910091317 A CN 201910091317A CN 109734727 A CN109734727 A CN 109734727A
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Abstract
The method that the invention discloses a kind of to prepare cefathiamidine crystal by controlling crystal seed crystal form, it matches the solubility of cefathiamidine and the supersolubility curve under different temperatures, mixing speed, different acetone rate of addition by measurement different temperatures and acetone-water solvent, obtains the Metastable zone of cefathiamidine crystal；Configure cefathiamidine solution, it is constant to control the cefathiamidine solution temperature, mixing speed, dissolved agent acetone is added dropwise into the cefathiamidine solution, stop acetone when actual concentrations enter Metastable zone to be added, cefathiamidine anhydrous crystal forms or cefathiamidine acetone water solvates crystal seed is added, continues that acetone is added dropwise after 10~60min of growing the grain；The cefathiamidine acetone water solvates crystal of rodlike cefathiamidine anhydride crystal or sheet is obtained after filtration, washing and drying.In this way, the crystal form and crystalline substance habit of cefathiamidine solid product can be controlled well.
Description
Technical field
The present invention relates to cefathiamidine crystal preparing technology fields, more particularly to one kind to prepare head by controlling crystal seed crystal form
The method of spore sulphur amidine crystal.
Background technique
Cefathiamidine, chemical name (6R, 7R) -3- [(acetoxyl group) methyl] -7- [α-(N, N- diisopropylamidinateand sulfenyl)
Acetylamino] -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid betaine, white or off-white color knot
Crystalline substance powder, the molecular weight of anhydride are 472.57900, density 1.45g/cm.Due to its unique betaine structure, not
With being relatively easy to form solvate in solvent.Cefathiamidine belongs to first generation beta-lactam antibiotic, to gram positive bacteria, leather
Blue negative bacterium, Streptococcus viridans etc. have preferable antibacterial action.
Cefathiamidine is easily dissolved water-soluble, and is easy to form hydrate or solvate with solvent, therefore recrystallizing
During purifying cefathiamidine, there is important meaning for the drug effect of product and the property of solid for the control of crystal habit
Justice.The prior art is not directed to crystal habit and the brilliant control practised about the crystallization preparation method of cefathiamidine.
Summary of the invention
The method that the object of the present invention is to provide a kind of to prepare cefathiamidine crystal by controlling crystal seed crystal form.
A kind of method preparing cefathiamidine crystal by controlling crystal seed crystal form provided in an embodiment of the present invention, this method packet
It includes:
Measure solubility and different temperatures, mixing speed, no that different temperatures and acetone-water solvent match lower cefathiamidine
With the supersolubility curve under acetone rate of addition, the Metastable zone of cefathiamidine crystal is obtained；
Configure cefathiamidine solution, wherein the cefathiamidine solution is the mixed solution of cefathiamidine and deionized water
Or the mixed solution of cefathiamidine and deionized water and acetone, it is constant to control the cefathiamidine solution temperature, mixing speed,
Dissolved agent acetone is added dropwise into the cefathiamidine solution, stops acetone when actual concentrations enter Metastable zone and is added, head is added
Spore sulphur amidine anhydrous crystal forms or cefathiamidine acetone water solvates crystal seed, 10~60min of growing the grain continue that acetone is added dropwise later；
The cefathiamidine acetone water of rodlike cefathiamidine anhydride crystal or sheet is obtained after filtration, washing and drying
Solvate crystal.
Preferably, it is constant to control any temperature of the cefathiamidine solution temperature between 0~25 DEG C.
Preferably, it is constant to control any temperature of the cefathiamidine solution temperature between 5~20 DEG C.
Preferably, any mixing speed of the control mixing speed between 50~250rpm is constant.
Preferably, any mixing speed of the control mixing speed between 100~200rpm is constant.
Preferably, the cefathiamidine anhydrous crystal forms of addition or the quality of cefathiamidine acetone water solvates crystal seed are configuration
The cefathiamidine solution in cefathiamidine quality 0.1wt%~1.0wt%.
Preferably, the cefathiamidine anhydrous crystal forms of addition or the quality of cefathiamidine acetone water solvates crystal seed are configuration
The cefathiamidine solution in cefathiamidine quality 0.2wt%~0.8wt%.
Preferably, the drop rate of dissolved agent acetone is 1~5mL/min.
The method provided in an embodiment of the present invention for preparing cefathiamidine crystal by controlling crystal seed crystal form is different by measurement
Temperature and acetone-water solvent match the solubility of lower cefathiamidine under different temperatures, mixing speed, different acetone rate of addition
Supersolubility curve, obtain the Metastable zone of cefathiamidine crystal；Configure cefathiamidine solution, wherein the cefathiamidine is molten
Liquid is the mixed solution or cefathiamidine of cefathiamidine and deionized water and the mixed solution of deionized water and acetone, controls institute
It is constant to state cefathiamidine solution temperature, mixing speed, dissolved agent acetone is added dropwise in Xiang Suoshu cefathiamidine solution, works as actual concentrations
Stop acetone when into Metastable zone to be added, cefathiamidine anhydrous crystal forms or cefathiamidine acetone water solvates crystal seed is added, supports
Continue that acetone is added dropwise after 10~60min of crystalline substance；Obtain after filtration, washing and drying rodlike cefathiamidine anhydride crystal or
The cefathiamidine acetone water solvates crystal of sheet.In this way, the crystalline substance of cefathiamidine solid product can be controlled well
Type, meanwhile, it can control the pattern of crystal, it can control the brilliant of crystal and practise, when the crystal seed of addition is cefathiamidine without crystal
When type, cefathiamidine anhydrous crystal forms can be obtained, cefathiamidine anhydrous crystal forms are rhabdolith；When the crystal seed of addition is cephalo sulphur
When amidine acetone water solvates crystal seed, cefathiamidine acetone water solvates crystal form, cefathiamidine acetone aqueous solvent can be obtained
Compound crystal form is flat crystal.The different crystal forms of same drug can have different drug effects, while crystal crystalline substance habit influences whether crystalline substance
The mobility and stability of body, therefore, the present invention is of great significance for cefathiamidine industrial crystallization.
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 according to a kind of crystal morphology figure of cefathiamidine anhydrous crystal forms provided in an embodiment of the present invention；
Fig. 2 is according to a kind of crystal morphology of cefathiamidine acetone water solvates crystal form provided in an embodiment of the present invention
Figure.
Specific embodiment
A kind of method preparing cefathiamidine crystal by controlling crystal seed crystal form provided in an embodiment of the present invention, this method packet
It includes:
Step 1: the solubility and different temperatures, stirring of measurement different temperatures and the lower cefathiamidine of acetone-water solvent proportion
Supersolubility curve under speed, different acetone rate of addition, obtains the Metastable zone of cefathiamidine crystal.
The solubility that lower cefathiamidine is matched according to different temperatures and acetone-water solvent, obtains solubility equilibria curve, molten
Region between the solution degree profile of equilibrium and supersolubility curve is the Metastable zone of cefathiamidine crystal.
Step 2: configuration cefathiamidine solution, wherein the cefathiamidine solution is the mixed of cefathiamidine and deionized water
The mixed solution for closing solution or cefathiamidine and deionized water and acetone controls the cefathiamidine solution temperature, stirring speed
Constant, dropwise addition dissolved agent acetone in Xiang Suoshu cefathiamidine solution is spent, the stopping acetone addition when actual concentrations enter Metastable zone,
Cefathiamidine anhydrous crystal forms or cefathiamidine acetone water solvates crystal seed is added, continues dropwise addition third after 10~60min of growing the grain
Ketone.Wherein, actual concentrations are the actual concentrations of cefathiamidine after dissolved agent acetone is added.
Control temperature in step 2 it is constant for control temperature in a certain set temperature ± 2 DEG C it is believed that in the setting temperature
It is constant under degree.
In the specific implementation process, it is constant to control any temperature of the temperature of solution between 0~25 DEG C, controls solution temperature
Any temperature spent preferably between 5~20 DEG C is constant.
In the specific implementation process, any mixing speed of the control mixing speed between 50~250rpm is constant, control
Any mixing speed of the mixing speed preferably between 100~200rpm is constant.
In the specific implementation process, the cefathiamidine anhydrous crystal forms or cefathiamidine acetone aqueous solvent being added into solution
The quality of object crystal seed is 0.1wt%~1.0wt% of cefathiamidine quality in the cefathiamidine solution of configuration.A kind of possible
In embodiment, the preferred mass range of the cefathiamidine anhydrous crystal forms of addition or cefathiamidine acetone water solvates crystal seed be with
0.2wt%~0.8wt% of cefathiamidine quality in the cefathiamidine solution set.
In a kind of possible embodiment, the drop rate of dissolved agent acetone is 1~5mL/min.
Step 3: the cefathiamidine of rodlike cefathiamidine anhydride crystal or sheet is obtained after filtration, washing and drying
Acetone water solvates crystal.
In the specific implementation process, when the crystal seed being added in step 2 is cefathiamidine anhydrous crystal forms crystal seed, in step 3
Be filtered, washed, dry after obtain being rodlike cefathiamidine anhydride crystal；The crystal seed being added in step 2 is cefathiamidine
When acetone water solvates crystal seed, be filtered, washed in step 3, dry after obtain be sheet cefathiamidine acetone aqueous solvent
Compound crystal.
It is illustrated so that the crystal seed of addition is cefathiamidine anhydride crystal form as an example:
Embodiment 1
Measure the solubility that different temperatures and acetone-water solvent match lower cefathiamidine first, then measure different temperatures,
Supersolubility curve under mixing speed, different acetone rate of addition, to obtain Metastable zone.By the cefathiamidine solid of 15g
It is dissolved in 20g deionized water and is configured to cefathiamidine solution, the quality of initial cefathiamidine is 15g in solution, controls solution
Temperature at 15 DEG C, mixing speed 150rpm, slowly into solution with 3.0mL/min be added dropwise dissolved agent 90g acetone, it is backward molten
It is added the cefathiamidine anhydride Form seeds of the 0.4wt% of initial cefathiamidine quality (15g) in liquid, growing the grain 30min, later
Continue that 230g acetone is added dropwise.Cefathiamidine anhydride crystal is obtained after filtration, washing and drying.
Embodiment 2
Measure the solubility that different temperatures and acetone-water solvent match lower cefathiamidine first, then measure different temperatures,
Supersolubility curve under mixing speed, different acetone rate of addition, to obtain Metastable zone.By the cefathiamidine of 15g mass
Solid is dissolved in 20g deionized water, control solution temperature at 15 DEG C, mixing speed 150rpm, slowly into solution with
3.0mL/min be added dropwise dissolved agent 90g acetone, backward solution in be added initial cefathiamidine quality (15g) 0.4wt% head
Spore sulphur amidine acetone water solvates Form seeds, growing the grain 30min continue that 230g acetone is added dropwise later.It is filtered, washed, dried
After obtain cefathiamidine anhydride crystal.
Embodiment 3
Difference from example 1 is that it is 0 DEG C that it is constant, which to control solution temperature,.
Embodiment 4
Difference from example 1 is that it is 5 DEG C that it is constant, which to control solution temperature,.
Embodiment 5
Difference from example 1 is that it is 10 DEG C that it is constant, which to control solution temperature,.
Embodiment 6
Difference from example 1 is that it is 20 DEG C that it is constant, which to control solution temperature,.
Embodiment 7
Difference from example 1 is that it is 25 DEG C that it is constant, which to control solution temperature,.
Embodiment 8
Difference from example 1 is that control mixing speed is 50rpm.
Embodiment 9
Difference from example 1 is that control mixing speed is 100rpm.
Embodiment 10
Difference from example 1 is that control mixing speed is 200rpm.
Embodiment 11
Difference from example 1 is that control mixing speed is 250rpm.
Embodiment 12
Difference from example 1 is that Seed charge is initial cefathiamidine solute matter in solution in step 2
The 0.1wt% of amount.
Embodiment 13
Difference from example 1 is that Seed charge is initial cefathiamidine solute matter in solution in step 2
The 0.2wt% of amount.
Embodiment 14
Difference from example 1 is that Seed charge is initial cefathiamidine solute matter in solution in step 2
The 0.8wt% of amount.
Embodiment 15
Difference from example 1 is that Seed charge is initial cefathiamidine solute matter in solution in step 2
The 1.0wt% of amount.
Embodiment 16
Difference from example 1 is that rearing crystal time 10min.
Embodiment 17
Difference from example 1 is that rearing crystal time 20min.
Embodiment 18
Difference from example 1 is that rearing crystal time 40min.
Embodiment 19
Difference from example 1 is that rearing crystal time 60min.
Embodiment 20
Difference from example 1 is that the drop rate of dissolved agent acetone is 1mL/min.
Embodiment 21
Difference from example 1 is that the drop rate of dissolved agent acetone is 2mL/min.
Embodiment 22
Difference from example 1 is that the drop rate of dissolved agent acetone is 4mL/min.
Embodiment 23
Difference from example 1 is that the drop rate of dissolved agent acetone is 5mL/min.
Acetone is common solvent during drug crystallization, has the advantages such as low boiling point, small toxicity, price be suitable, is tying
It is easily removed in the drying process of brilliant product.So during cefathiamidine dilution crystallization, acetone is taken as important molten
It analyses agent to be applied in industrial production, controlling product form of the cefathiamidine in acetone aqueous systems is also cefathiamidine drug crystallization
The key point of process.The method of the present invention for preparing cefathiamidine crystal by controlling crystal seed crystal form, by measuring not
Synthermal and acetone-water solvent matches the solubility of cefathiamidine and different temperatures, mixing speed, different acetone rate of addition
Under supersolubility curve, obtain the Metastable zone of cefathiamidine crystal；Configure cefathiamidine solution, wherein the cefathiamidine
Solution is the mixed solution or cefathiamidine of cefathiamidine and deionized water and the mixed solution of deionized water and acetone, control
The cefathiamidine solution temperature, mixing speed are constant, and dissolved agent acetone is added dropwise in Xiang Suoshu cefathiamidine solution, when practical dense
Degree stops acetone when entering Metastable zone and is added, and cefathiamidine anhydrous crystal forms or cefathiamidine acetone water solvates crystal seed is added,
Continue that acetone is added dropwise after 10~60min of growing the grain；Rodlike cefathiamidine anhydride crystal is obtained after filtration, washing and drying
Or the cefathiamidine acetone water solvates crystal of sheet.In this way, cefathiamidine solid product can be controlled well
Crystal form, meanwhile, it can control the pattern of crystal, it can control the brilliant of crystal and practise, when the crystal seed of addition is that cefathiamidine is anhydrous
When crystal form, cefathiamidine anhydrous crystal forms can be obtained, cefathiamidine anhydrous crystal forms are rhabdolith, as shown in Figure 1；When addition
When crystal seed is cefathiamidine acetone water solvates crystal seed, cefathiamidine acetone water solvates crystal form, cephalo sulphur can be obtained
Amidine acetone water solvates crystal form is flat crystal, as shown in Figure 2.The different crystal forms of same drug can have different drug effects,
Control crystal form is drug in order to obtain with certain drug effect, while crystal crystalline substance practises the mobility and stabilization for influencing whether crystal
Property, control brilliant practise mainly for improving the mobility of product and stability etc..Therefore, the present invention is for cefathiamidine industrial crystallization
It is of great significance.
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 (8)
1. a kind of method for preparing cefathiamidine crystal by controlling crystal seed crystal form, which is characterized in that the described method includes:
It measures different temperatures and acetone-water solvent matches the solubility of cefathiamidine and different temperatures, mixing speed, different third
Supersolubility curve under ketone rate of addition obtains the Metastable zone of cefathiamidine crystal；
Configure cefathiamidine solution, wherein the cefathiamidine solution be cefathiamidine and deionized water mixed solution or
The mixed solution of cefathiamidine and deionized water and acetone, it is constant to control the cefathiamidine solution temperature, mixing speed, to institute
Dropwise addition dissolved agent acetone in cefathiamidine solution is stated, stops acetone when actual concentrations enter Metastable zone and is added, cephalo sulphur is added
Amidine anhydrous crystal forms or cefathiamidine acetone water solvates crystal seed, 10~60min of growing the grain continue that acetone is added dropwise later；
The cefathiamidine acetone aqueous solvent of rodlike cefathiamidine anhydride crystal or sheet is obtained after filtration, washing and drying
Compound crystal.
2. the method as described in claim 1, which is characterized in that control the cefathiamidine solution temperature between 0~25 DEG C
Any temperature it is constant.
3. method according to claim 2, which is characterized in that control the cefathiamidine solution temperature between 5~20 DEG C
Any temperature it is constant.
4. the method as described in claim 1, which is characterized in that any stirring of the control mixing speed between 50~250rpm
Constant airspeed.
5. method as claimed in claim 4, which is characterized in that any between 100~200rpm of control mixing speed stirs
Mix constant airspeed.
6. the method as described in claim 1, which is characterized in that the cefathiamidine anhydrous crystal forms or cefathiamidine acetone water of addition
The quality of solvate crystal seed is 0.1wt%~1.0wt% of cefathiamidine quality in the cefathiamidine solution of configuration.
7. method as claimed in claim 6, which is characterized in that the cefathiamidine anhydrous crystal forms or cefathiamidine acetone water of addition
The quality of solvate crystal seed is 0.2wt%~0.8wt% of cefathiamidine quality in the cefathiamidine solution of configuration.
8. the method as described in claim 1, which is characterized in that the drop rate of dissolved agent acetone is 1~5mL/min.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532165A (en) * | 2010-12-20 | 2012-07-04 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method for cefathiamidine crystals |
| CN103012434A (en) * | 2012-12-14 | 2013-04-03 | 海南合瑞制药股份有限公司 | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof |
| CN108948048A (en) * | 2018-07-26 | 2018-12-07 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefathiamidine |
-
2019
- 2019-01-30 CN CN201910091317.3A patent/CN109734727A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532165A (en) * | 2010-12-20 | 2012-07-04 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method for cefathiamidine crystals |
| CN103012434A (en) * | 2012-12-14 | 2013-04-03 | 海南合瑞制药股份有限公司 | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof |
| CN108948048A (en) * | 2018-07-26 | 2018-12-07 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of cefathiamidine |
Non-Patent Citations (3)
| Title |
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| 丁绪淮，等: "《工业结晶》", 31 October 1985, 化学工业出版社 * |
| 于文国，等: "《生化分离技术》", 31 March 2006, 化学工业出版社 * |
| 天津大学化工原理教研室: "《化工原理》", 31 July 1990, 天津科学技术出版社 * |
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