CN103012472B - Crystal preparation method of creatine phosphate sodium - Google Patents
Crystal preparation method of creatine phosphate sodium Download PDFInfo
- Publication number
- CN103012472B CN103012472B CN201210532765.0A CN201210532765A CN103012472B CN 103012472 B CN103012472 B CN 103012472B CN 201210532765 A CN201210532765 A CN 201210532765A CN 103012472 B CN103012472 B CN 103012472B
- Authority
- CN
- China
- Prior art keywords
- phosphocreatine
- phosphate sodium
- creatine phosphate
- product
- disodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 CN(CC(O)=O)C(NP([*+])([*+])=O)=N Chemical compound CN(CC(O)=O)C(NP([*+])([*+])=O)=N 0.000 description 1
Abstract
The invention discloses a crystallizing method for preparing high-purity creatine phosphate sodium. The crystallizing method comprises the following steps of: dissolving a creatine phosphate sodium crude product in water to prepare a 0.5-1.1 g/ml creatine phosphate sodium aqueous solution, continuously stirring for 30-60 minutes to decolor; after filtering, transferring a filtrate into a crystallizer, controlling a system temperature to be within 5-45 DEG C, and adding an alcohol or ketone organic solvent to perform solvent-out crystallization; after crystallizing, and separating through filtering, washing with a solvent and drying to obtain a creatine phosphate sodium product. The creatine phosphate sodium crystal provided by the invention is high in crystallinity degree, complete in product crystal habit, and uniform in particle size distribution; and a primary particle size is 67.1-70.2 mu m. The product purity reaches more than 99.5%, and a single molar yield during the crystallizing process is more than 98.0%; and the method is simple in process, low in cost and suitable for industrial production.
Description
Technical field
The invention belongs to crystallization technique field, particularly a kind of crystallization preparation method of Disodium phosphocreatine, highly purified Disodium phosphocreatine can be obtained by method of the present invention.
Background technology
The disodium salt that Disodium phosphocreatine (Phosphatee creatine sodium) is phosphocreatine, chemistry N-by name [imino-(phosphine is amino) methyl]-sarcosine disodium salt, molecular formula is C
4h
8n
3o
5na
2p, molecular weight is 255.08, and its chemical structural formula is as follows.
Disodium phosphocreatine is the effective clinical medicine of one that human body supplements high energy compound phosphocreatine, phosphocreatine contains more energy than the adenosine triphyosphate (ATP) of equivalent, to be separated to obtain in nineteen twenty-seven by American scientist Eggleton in mammalian muscle.Phosphocreatine plays a significant role in the energy metabolism of Muscle contraction, and it is cardiac muscle and the chemical energy store of skeletal muscle, and for the resynthesis of ATP, the actomyosin contraction process that is hydrolyzed to of ATP provides energy.Phosphocreatine level is not enough has important clinical meaning in the damage of myocardial contraction and functional rehabilitation ability.Pharmacy expert has carried out chemosynthesis to phosphocreatine, and is made into phosphocreatine sodium salt and is applied to clinical.It is abnormal that Disodium phosphocreatine application is clinically mainly the myocardial metabolism added when heart operation under protection cardiac muscle in cardioplegic solution and ischemia condition.Disodium phosphocreatine as myocardial preservation and energy extender is the substitute products of hexose diphosphate, and its drug effect is about 3.16 times of hexose diphosphate, and clinical efficacy is definite, and security is high.
The production of current Disodium phosphocreatine mainly contains chemical synthesis, enzyme catalysis method and biological extraction method.The problem of separation and purification of products is there is by the method for these methods production Disodium phosphocreatine, the purification process of the Disodium phosphocreatine reported in CN101033237A needs to introduce anionite-exchange resin, and the cost of resin and regeneration cost are relatively high, and safeguard quite consuming time, be unfavorable for suitability for industrialized production; Need in the process for purification of the Disodium phosphocreatine reported in CN101812088A to utilize chromatographic column to carry out separation and purification, equipment and later maintenance cost higher, be unfavorable for use of large-scale production.The Disodium phosphocreatine crystallization and purification method technique reported in CN102558227A is relatively loaded down with trivial details, and need to introduce a large amount of sodium hydroxide and glacial acetic acid, production cost is relatively high, and after Disodium phosphocreatine crystallization purifying, content reaches 99.5%, but once through yield is lower than 93%.With crystallization method purifying phosphoric acid creatine sodium crude product in CN102633833A, but be not suitable for high concentration phosphorus creatine acid sodium water solution, although product purity is more than 99.7%, crystallisation process yield is lower only has 89%, does not also practise the crystalline substance of crystal product, granularity studies.The Disodium phosphocreatine product yield that CN102533880A adopts biological engineering method to obtain is more than 70%, and yield is relatively low, and production cost is relatively high.
There is the problems such as little, the brilliant habit difference of granularity in domestic Disodium phosphocreatine product, main granularity about 35 μm, exists the phenomenon that seriously hardens in production process, operate very difficult.
Summary of the invention
For above problem, the present invention for raw material with Disodium phosphocreatine crude product, provides a kind of crystallization method preparing the Disodium phosphocreatine of purity more than 99.5%, not only can obtain high purity product, and crystal product granularity is large, and brilliant habit is complete.
The crystallization preparation method of Disodium phosphocreatine of the present invention is as follows:
At 20 ~ 30 DEG C, by water-soluble for Disodium phosphocreatine crude product, making concentration is 0.5 ~ 1.1g/ml phosphocreatine sodium water solution, adds activated carbon, and continuously stirring is decoloured for 30 ~ 60 minutes; After filtering, filtrate is moved in crystallizer, and hierarchy of control temperature to 5 ~ 45 DEG C, add alcohols or organic solvent of ketone carries out dilution crystallization, and alcohols or organic solvent of ketone volumetric usage are 2 ~ 5 times of volume of water; Carry out filtering separation, solvent wash, drying after crystallization, obtain Disodium phosphocreatine product.
Described activated carbon content is Disodium phosphocreatine quality 1 ~ 3%.
Described alcohols or organic solvent of ketone are selected from the one of methyl alcohol, ethanol, Virahol, propyl carbinol or acetone, 2 ~ 6 hours organic solvent joining days.
Described cleaning solvent is acetone or alcohol.
Described drying conditions: temperature 40 ~ 60 DEG C, absolute pressure 0.008 ~ 0.1MPa, 2 ~ 6 hours time of drying.
Phosphocreatine sodium crystal provided by the invention, its degree of crystallinity is high, and product crystalline substance is practised complete, and even particle size distribution, main granularity is 67.1 ~ 70.2 μm.Product high pressure liquid chromatography HPLC purity reaches more than 99.5%, and the one way molar yield of crystallisation process is more than 98.0%, and present method technique is simple, and cost is low, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1: the stereoscan photograph (amplifying 1000 times) of Disodium phosphocreatine;
Fig. 2: the stereoscan photograph (amplifying 150 times) of Disodium phosphocreatine.
Embodiment
Embodiment 1
At 20 DEG C, by water-soluble for Disodium phosphocreatine crude product, making concentration is 0.8g/ml phosphocreatine sodium water solution, adds the activated carbon that quality is 2% of Disodium phosphocreatine quality, and continuously stirring is decoloured for 60 minutes; After filtering, filtrate moves in crystallizer, and hierarchy of control temperature to 5 DEG C, adds acetone and carry out dilution crystallization, and control time for adding is 2h, and acetone volumetric usage is 2 times of water; Then carry out filtering separation, use washing with acetone filter cake, by the wet crystal that obtains at 40 DEG C, when absolute pressure is 0.008MPa dry 4 hours.Final crystal HPLC purity is 99.61%, and main granularity is 69.28 μm, crystallisation process one way molar yield 98.0%.
The scanning electron microscopic picture of products obtained therefrom as shown in Figure 1 and Figure 2.
Embodiment 2
At 25 DEG C, by water-soluble for Disodium phosphocreatine crude product, making concentration is 1.1g/ml phosphocreatine sodium water solution, adds the activated carbon that quality is 1% of Disodium phosphocreatine quality, and continuously stirring is decoloured for 30 minutes; After filtering, filtrate moves in crystallizer, and hierarchy of control temperature to 10 DEG C, adds methyl alcohol and carry out dilution crystallization, and control time for adding is 5h, and methyl alcohol volumetric usage is 5 times of water; Then carry out filtering separation, use washing with alcohol filter cake, by the wet crystal that obtains at 60 DEG C, when absolute pressure is 0.1MPa dry 6 hours.Final crystal HPLC purity is 99.50%, and main granularity is 68.05 μm, crystallisation process one way molar yield 99.1%.
Embodiment 3
At 30 DEG C, by water-soluble for Disodium phosphocreatine crude product, making concentration is 0.5g/ml phosphocreatine sodium water solution, adds the activated carbon that quality is 3% of Disodium phosphocreatine quality, and continuously stirring is decoloured for 40 minutes; After filtering, filtrate moves in crystallizer, and hierarchy of control temperature to 25 DEG C, adds ethanol and carry out dilution crystallization, and control time for adding is 3h, and ethanol contend consumption is 2.5 times of water; Then carry out filtering separation, use washing with alcohol filter cake, by the wet crystal that obtains at 40 DEG C, when absolute pressure is 0.02MPa dry 2 hours.Final crystal HPLC purity is 99.58%, and main granularity is 68.35 μm, crystallisation process one way molar yield 99.3%.
Embodiment 4
At 25 DEG C, by water-soluble for Disodium phosphocreatine crude product, making concentration is 1.0g/ml phosphocreatine sodium water solution, adds the activated carbon that quality is 2% of Disodium phosphocreatine quality, and continuously stirring is decoloured for 50 minutes; After filtering, filtrate moves in crystallizer, and hierarchy of control temperature to 45 DEG C, adds Virahol and carry out dilution crystallization, and control time for adding is 3h, and Virahol volumetric usage is 3.5 times of water; Then carry out filtering separation, use washing with acetone filter cake, by the wet crystal that obtains at 50 DEG C, when absolute pressure is 0.04MPa dry 4 hours.Final crystal HPLC purity is 99.53%, and main granularity is 67.05 μm, crystallisation process one way molar yield 99.4%.
Embodiment 5
At 25 DEG C, by water-soluble for Disodium phosphocreatine crude product, making concentration is 0.6g/ml phosphocreatine sodium water solution, adds the activated carbon that quality is 3% of Disodium phosphocreatine quality, and continuously stirring is decoloured for 30 minutes; After filtering, filtrate moves in crystallizer, and hierarchy of control temperature to 15 DEG C, adds Virahol and carry out dilution crystallization, and control time for adding is 4h, and Virahol volumetric usage is 3 times of water; Then carry out filtering separation, use washing with acetone filter cake, by the wet crystal that obtains at 55 DEG C, when absolute pressure is 0.06MPa dry 3 hours.Final crystal HPLC purity is 99.67%, and main granularity is 70.16 μm, crystallisation process one way molar yield 98.6%.
Embodiment 6
At 28 DEG C, by water-soluble for Disodium phosphocreatine crude product, making concentration is 0.75g/ml phosphocreatine sodium water solution, adds the activated carbon that quality is 1% of Disodium phosphocreatine quality, and continuously stirring is decoloured for 40 minutes; After filtering, filtrate moves in crystallizer, and hierarchy of control temperature to 30 DEG C, adds propyl carbinol and carry out dilution crystallization, and control time for adding is 6h, and propyl carbinol volumetric usage is 4 times of water; Then carry out filtering separation, use washing with alcohol filter cake, by the wet crystal that obtains at 45 DEG C, when absolute pressure is 0.08MPa dry 5 hours.Final crystal HPLC purity is 99.72%, and main granularity is 69.26 μm, crystallisation process one way molar yield 98.9%.
Open and the crystallization preparation method of Disodium phosphocreatine that proposes of the present invention, those skilled in the art are by using for reference present disclosure, and the links such as appropriate change raw material, processing parameter realize.Method of the present invention and product are described by preferred embodiment, person skilled obviously can not depart from content of the present invention, spirit and scope method as herein described and product are changed or suitably change with combination, realize the technology of the present invention.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are deemed to be included in spirit of the present invention, scope and content.
Claims (3)
1. a crystallization preparation method for Disodium phosphocreatine, its characterization step is as follows:
At 20 ~ 30 DEG C, by water-soluble for Disodium phosphocreatine crude product, making concentration is 0.5 ~ 1.1g/ml phosphocreatine sodium water solution, adds activated carbon, and continuously stirring is decoloured for 30 ~ 60 minutes; After filtering, filtrate is moved in crystallizer, and hierarchy of control temperature to 5 ~ 45 DEG C, add alcohols or organic solvent of ketone carries out dilution crystallization, and alcohols or organic solvent of ketone volumetric usage are 2 ~ 5 times of volume of water; Carry out filtering separation, solvent wash, drying after crystallization, obtain Disodium phosphocreatine product;
Described activated carbon content is Disodium phosphocreatine quality 1 ~ 3%; Described alcohols or organic solvent of ketone are selected from the one of methyl alcohol, ethanol, Virahol, propyl carbinol or acetone; 2 ~ 6 hours joining days of alcohols or organic solvent of ketone.
2. preparation method as claimed in claim 1, is characterized in that described cleaning solvent is acetone or alcohol.
3. preparation method as claimed in claim 1, is characterized in that described drying conditions is temperature 40 ~ 60 DEG C, absolute pressure 0.008 ~ 0.1MPa, 2 ~ 6 hours time of drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210532765.0A CN103012472B (en) | 2012-12-10 | 2012-12-10 | Crystal preparation method of creatine phosphate sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210532765.0A CN103012472B (en) | 2012-12-10 | 2012-12-10 | Crystal preparation method of creatine phosphate sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103012472A CN103012472A (en) | 2013-04-03 |
| CN103012472B true CN103012472B (en) | 2015-05-20 |
Family
ID=47961622
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210532765.0A Active CN103012472B (en) | 2012-12-10 | 2012-12-10 | Crystal preparation method of creatine phosphate sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103012472B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304597B (en) * | 2013-06-28 | 2015-02-25 | 四川省惠达药业有限公司 | Creatine phosphate sodium compound and preparation method thereof, and pharmaceutical composition of compound and preparation method of composition |
| CN105153222B (en) * | 2015-10-16 | 2017-07-04 | 西南药业股份有限公司 | The purification process of Creatine Phosphate Sodium |
| CN108017668B (en) * | 2016-11-04 | 2020-06-09 | 哈尔滨莱博通药业有限公司 | High-crystal-purity creatine phosphate sodium tetrahydrate hemihydrate and preparation method and application thereof |
| CN106831858B (en) * | 2017-02-08 | 2018-03-13 | 哈尔滨莱博通药业有限公司 | A kind of preparation method of Creatine Phosphate Sodium |
| CN107501320A (en) * | 2017-08-03 | 2017-12-22 | 江苏汉斯通药业有限公司 | The preparation method of Creatine Phosphate Sodium |
| CN110294775B (en) * | 2018-03-23 | 2021-11-26 | 安徽古特生物科技有限公司 | Purification method of creatine phosphate sodium |
| CN111777636B (en) * | 2020-07-09 | 2023-06-16 | 山东罗欣药业集团股份有限公司 | Preparation method of medicine for myocardial protection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101492470A (en) * | 2008-01-22 | 2009-07-29 | 上海慈瑞医药科技有限公司 | Synthesis of phosphocreatine disodium salt |
| CN102295658A (en) * | 2011-06-02 | 2011-12-28 | 重庆莱美药业股份有限公司 | Refining method of disodium phosphocreatine |
| CN102633833A (en) * | 2012-04-06 | 2012-08-15 | 南京臣功制药股份有限公司 | Creatine phosphate sodium preparation method |
-
2012
- 2012-12-10 CN CN201210532765.0A patent/CN103012472B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101492470A (en) * | 2008-01-22 | 2009-07-29 | 上海慈瑞医药科技有限公司 | Synthesis of phosphocreatine disodium salt |
| CN102295658A (en) * | 2011-06-02 | 2011-12-28 | 重庆莱美药业股份有限公司 | Refining method of disodium phosphocreatine |
| CN102633833A (en) * | 2012-04-06 | 2012-08-15 | 南京臣功制药股份有限公司 | Creatine phosphate sodium preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 王景辉.磷酸肌酸二钠盐的制备研究.《中国优秀博硕士学位论文全文数据库(硕士)工程科技I辑》.2004,(第3期),第55-56页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103012472A (en) | 2013-04-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103012472B (en) | Crystal preparation method of creatine phosphate sodium | |
| CN102249977B (en) | 4-hydroxy-2-oxo-1-pyrrolidine acetamide racemate crystal I and preparation method thereof | |
| CN105492618B (en) | Process for preparing 2, 5-furandicarboxylic acid | |
| CN109180749B (en) | Method for preparing high-purity N-acetylneuraminic acid hydrate by using supersaturation crystallization method | |
| CN106146560B (en) | A kind of refining methd of high-purity phosphoric acid specially azoles amine | |
| CN102453011A (en) | Preparation method of high-purity naringenin | |
| CN103288801A (en) | Preparation method for high-purity esomeprazole sodium | |
| CN105646580A (en) | Method for producing pentahydrate s-ornidazole disodium phosphate | |
| CN102344412B (en) | A kind of preparation method of isoniazid para-aminosalicylate | |
| US20070213313A1 (en) | Direct process for the production of an amino acid dihydrochloride | |
| CN108358979B (en) | Purification method of tulathromycin | |
| CN104592053B (en) | A kind of industrialized process for preparing of high-purity sodium pantothenate | |
| CN102557980A (en) | Method for preparing high-purity capsaicine monomer by crystallization | |
| CN112010805B (en) | Refining method of fasudil hydrochloride | |
| CN104447294A (en) | Chiral resolution method of 3-cyclohexene-1-formic acid | |
| CN105085469B (en) | A kind of preparation method of the carboxylic acid of 5 chlorothiophene 2 | |
| CN114853593A (en) | Method for extracting high-purity nervonic acid from acer truncatum buge oil | |
| CN110372528B (en) | Method for purifying valine | |
| CN102766163B (en) | Synthesis method of phosphate monoester of vitamin B1 | |
| CN106187799B (en) | A method of preparing DL-lysine hydrochloride | |
| CN106810458B (en) | A method of it splitting DL-2- aminopropanol and prepares L-2- aminopropanol | |
| CN104450853B (en) | It is a kind of to recycle the method that acetyl DL methionine prepares L methionine | |
| CN103554218B (en) | N (2)-Ala-Gln crystal formation and preparation method thereof | |
| CN114450291B (en) | Preparation method of 5' -guanylate disodium heptahydrate crystal | |
| AU2020368796B2 (en) | Method for separating disodium 5'-inosinate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |