CN112979697A - Creatine phosphate tetrahydrate sodium with good fluidity and preparation method thereof - Google Patents
Creatine phosphate tetrahydrate sodium with good fluidity and preparation method thereof Download PDFInfo
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- CN112979697A CN112979697A CN201911304735.2A CN201911304735A CN112979697A CN 112979697 A CN112979697 A CN 112979697A CN 201911304735 A CN201911304735 A CN 201911304735A CN 112979697 A CN112979697 A CN 112979697A
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- Prior art keywords
- creatine phosphate
- particle size
- sodium
- tetrahydrate
- fluidity
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- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 title claims abstract description 69
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 23
- 239000011734 sodium Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 239000002245 particle Substances 0.000 claims abstract description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000003756 stirring Methods 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 11
- 239000012296 anti-solvent Substances 0.000 claims abstract description 8
- 230000001186 cumulative effect Effects 0.000 claims abstract description 6
- 238000009826 distribution Methods 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 230000003287 optical effect Effects 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 8
- -1 tetrahydrate creatine phosphate Chemical class 0.000 claims description 5
- RNTXMYSPASRLFT-UHFFFAOYSA-L disodium;2-[[n'-[hydroxy(oxido)phosphoryl]carbamimidoyl]-methylamino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(C)C(N)=NP([O-])([O-])=O RNTXMYSPASRLFT-UHFFFAOYSA-L 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 description 10
- HUWYWJSJJDCZRQ-UHFFFAOYSA-L disodium;2-[methyl-(n'-phosphonatocarbamimidoyl)amino]acetic acid;tetrahydrate Chemical compound O.O.O.O.[Na+].[Na+].OC(=O)CN(C)C(N)=NP([O-])([O-])=O HUWYWJSJJDCZRQ-UHFFFAOYSA-L 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 150000004687 hexahydrates Chemical class 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- 150000004685 tetrahydrates Chemical class 0.000 description 4
- 239000002994 raw material Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- PEXCMMDHBIFUIJ-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]acetic acid;sulfuric acid Chemical compound OS(O)(=O)=O.NC(=N)N(C)CC(O)=O PEXCMMDHBIFUIJ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 238000007675 cardiac surgery Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 238000000399 optical microscopy Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010900 secondary nucleation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/222—Amides of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses creatine phosphate tetrahydrate with good fluidity and a preparation method thereof. The good-fluidity creatine phosphate tetrahydrate sodium is characterized in that when the cumulative particle size distribution number reaches 90%, the corresponding particle size D90 is between 200um and 280um, the angle of repose is 20-30 degrees, and the particle morphology is in a cube-like shape under the optical microscope magnification of 100 times. Adding the sodium creatine phosphate tetrahydrate with poor fluidity into 3-5 times of water for dissolving, adding 10-20 times of anti-solvent ethanol into the system after dissolving, quickly stirring at normal temperature for crystallization, filtering to obtain a wet product with small particle size, and then rotationally drying the wet product to obtain the sodium creatine phosphate tetrahydrate dry product with good fluidity, and the preparation is convenient to subpackage.
Description
Technical Field
The invention relates to the technical field of medical chemical drugs, in particular to creatine phosphate tetrahydrate with good fluidity and a preparation method thereof.
Background
Creatine phosphate sodium (disodium phosphocreatine), known by the chemical name N- [ imino (phosphino) methyl ] -N-methylglycine disodium salt, is a myocardial protectant marketed by the italian ohui pharmaceutical factory in 1992, exerts various important physiological effects in vivo in the form of creatine phosphate, and is widely used in the treatment of cardiovascular diseases such as myocardial ischemia or cardiac surgery, heart failure, myocardial infarction and arrhythmia. In 1995, China began to import this product, which is sold under the trade name of Liersystem.
US patent US3036087 example III reports that creatine phosphate has two crystalline forms (shown below), corresponding to the two hydrate states: the hexamolecular crystal water (hexahydrate) and the quartering crystal water (tetrahydrate), and the creatine phosphate sodium is crystallized in the ethanol water to obtain the hexahydrate or directly obtain the tetrahydrate, wherein the hexahydrate can be further dried and dehydrated to obtain the tetrahydrate creatine phosphate sodium. At present, the creatine phosphate sodium sterile powder for medical use which is on the market is creatine phosphate sodium containing four molecular crystal water and does not contain auxiliary materials.
The modern chemical reagent handbook, the third minute volume, the biochemical reagent (II), the chemical industry publisher, 1991, p349 are cited in Chinese patent CN104109171, which reports that hexahydrate is hexagonal flaky crystal and tetrahydrate is needle crystal, and that the angle of repose of hexahydrate and tetrahydrate creatine phosphate sodium salt phosphate obtained by conventional alcohol-water method crystallization is more than 50 degrees.
In the industrial production process of the sterile powder injection preparation, the requirement on the flowability of the raw material medicaments is high for the convenience of split charging, and the angle of repose is generally less than 40 ℃; otherwise, the preparation is difficult to feed in subpackage, or the problem of large loading difference exists. The inventor researches the creatine phosphate sodium tetrahydrate samples on the market, and finds that the crystal habit of the samples is needle-shaped, the particle size D90 corresponding to the cumulative particle size distribution number of 90 percent is between 55 and 70 mu m, the angle of repose is between 47 and 55 degrees, and the flowability is poor.
Obviously, the raw material medicine of creatine phosphate tetrahydrate obtained by the prior art can not meet the ideal requirement of split charging of the preparation.
Disclosure of Invention
In view of the above problems, the present invention discloses a sodium creatine phosphate tetrahydrate with good fluidity and a preparation method thereof to meet the requirement of split charging of preparations.
The fluidity of the raw material medicine is improved, and the method generally starts from two aspects: increasing particle size and improving nodule (and grain morphology under optical microscopy). In terms of particle size, it is common practice to increase the particle size by lowering the stirring speed, extending the crystallization time, etc. (general rule: the larger the particle size, the better the fluidity). In the aspect of particle morphology, the flowability is better when the particle morphology is generally closer to a spherical shape, and the flowability is poor when the particle morphology is acicular.
The creatine phosphate tetrahydrate sodium salt has special variety, great polarity and limited crystallization solvent system selection, and only the alcohol-water system can obtain crystals with better shape. Referring to the crystallization method reported in example III of US3036087, the inventor can only obtain slightly larger D90 than the commercial needle-shaped tetrahydrate crystal by lowering the stirring speed (0-200 rpm) and prolonging the crystallization time (24-96 h) in an alcohol-water system according to the above general idea, wherein the particle size of the sodium creatine phosphate tetrahydrate is obviously increased and the flowability of the non-needle-shaped appearance is obviously improved.
In subsequent experimental studies, the inventor discovers the creatine phosphate tetrahydrate sodium with good fluidity and the preparation method thereof through a reverse thinking mode and opportunity. The sodium creatine phosphate tetrahydrate with good fluidity is characterized in that when the cumulative particle size distribution number reaches 90%, the corresponding particle size D90 is between 200 and 280 mu m, the angle of repose is 20-30 degrees, and the particle appearance is in a cube-like shape under the optical microscope magnification of 100 times. The preparation method of the creatine phosphate tetrahydrate sodium phosphate with good fluidity comprises the steps of adding the creatine phosphate tetrahydrate sodium with poor fluidity into 3-5 times of water for dissolving, adding 10-20 times of anti-solvent ethanol into the system after dissolving, quickly stirring at normal temperature for crystallization, filtering to obtain a wet product with small particle size, and then, rotatably drying the wet product to obtain the creatine phosphate tetrahydrate sodium dry product with large particle size and good fluidity. In the preparation method, the anti-solvent ethanol specifically refers to ethanol containing 0-10% of water, the rapid stirring crystallization specifically refers to the stirring speed of 700-1000 revolutions per minute, the wet product with small particle size is characterized in that the site diameter D50 is less than 20 mu m, the corresponding particle size D90 is less than 30 mu m when the cumulative particle size distribution reaches 90%, and the drying specifically refers to drying under the conditions of the temperature of 40-50 ℃ and the pressure of less than or equal to 4 KPa.
The sodium creatine phosphate tetrahydrate with good fluidity disclosed by the invention is obviously different from the existing sodium creatine phosphate tetrahydrate in D90, repose angle and crystal habit, and thus shows obvious improvement in fluidity. The method for preparing the creatine phosphate tetrahydrate sodium phosphate with good fluidity supposes that the principle may be as follows: the wet product with small grain size, free water and combined water with much adsorption and secondary nucleation and crystallization in the rotary drying process are obtained by rapid stirring and crystallization, so that the creatine phosphate tetrahydrate with remarkably improved fluidity is obtained. Meanwhile, the data obtained in the preparation process shows the phenomenon that the finer the grain size of the wet product is, the larger the grain size of the finished product is, the better the flowability is.
The inventor also compares the good-fluidity creatine phosphate tetrahydrate sodium of the invention with the original traditional Chinese medicine grinding system in parallel to perform a high-temperature test according to the guiding principle of 9001 bulk drug and preparation stability test in the four-part general rules of Chinese pharmacopoeia 2015 edition, detects the moisture, related substances and contents, and has the following results:
as can be seen from the above table, the sodium creatine phosphate tetrahydrate with good flowability and a particle size D90 of 200-280 μm, an angle of repose of 20-30 degrees and a particle morphology (crystal habit) of 100 times of optical microscope magnification is consistent with the stability of the original Murill system. Further, the fluidity-improved creatine sulfate tetrahydrate disclosed in this invention has no change in stability while meeting the quality requirements. The invention is described below with the aid of the accompanying drawings
Description of the drawings:
FIG. 1: the particle size of the original grindelian system is shown.
FIG. 2: showing the particle morphology of the original grindeli system.
FIG. 3: it is shown that example 1 of the present invention discloses the particle size of creatine phosphate tetrahydrate.
FIG. 4: the particle morphology of creatine phosphate tetrahydrate is shown in example 1 of the present invention.
FIG. 5: a particle size diagram showing the small particle size wet product obtained during the preparation of creatine phosphate sodium tetrahydrate disclosed in example 1 of the present invention is shown.
The present invention is further illustrated by the following examples, and various substitutions and combinations made according to the common knowledge and conventional means in the art are included in the scope of the present invention.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1: adding 30kg of creatine phosphate tetrahydrate into 150kg of water for dissolving, starting stirring, enabling the stirring speed to be 700 rpm, adding 600kg of anti-solvent 10% ethanol (namely 90 ethanol), crystallizing at normal temperature for half an hour, and filtering to obtain 59kg of wet products with the diameters of D9028.1 micrometers and D5010.6 micrometers. The wet product is dried in a rotating way under the conditions of 40-50 ℃ and the pressure of not more than 4KPa, and 28kg of creatine phosphate tetrahydrate sodium with D90218 mu m, 30 degrees of angle of repose and good fluidity and with the particle appearance of similar cube shape is obtained.
Example 2: adding 30kg of creatine phosphate tetrahydrate into 90kg of water for dissolving, starting stirring, enabling the stirring speed to be 1000 revolutions per minute, adding 300kg of anti-solvent absolute ethyl alcohol, crystallizing at normal temperature for half an hour, and filtering to obtain 62kg of wet products with the D9020.1 mu m and the D508.6 mu m. The wet product is dried in a rotating way under the conditions of 40-50 ℃ and the pressure of not more than 4KPa, and 29kg of creatine phosphate tetrahydrate sodium with D90280 mu m, 20 degrees of angle of repose and good fluidity and with the particle appearance of similar cube shape is obtained.
Example 3: adding 30kg of creatine phosphate tetrahydrate into 120kg of water for dissolving, starting stirring, enabling the stirring speed to be 850 rpm, adding 420kg of antisolvent 95 ethanol, crystallizing for half an hour at normal temperature, and filtering to obtain 60kg of wet products with the diameters of D9025.6 micrometers and D5013.2 micrometers. The wet product is dried in a rotating way under the conditions of 40-50 ℃ and the pressure of not more than 4KPa, and 27.5kg of creatine phosphate tetrahydrate sodium with D90246 mu m, 25 degrees of angle of repose and cubic-like particle appearance and good fluidity is obtained.
Claims (6)
1. The tetrahydrate creatine phosphate sodium with good fluidity is characterized in that when the cumulative particle size distribution number reaches 90%, the corresponding particle size D90 is between 200 and 280 mu m, the angle of repose is 20-30 degrees, and the particle appearance is in a cube-like shape under the optical microscope magnification of 100 times.
2. The method for preparing the good-fluidity creatine phosphate tetrahydrate sodium as claimed in claim 1 is characterized in that the poor-fluidity creatine phosphate tetrahydrate sodium is added into 3-5 times of water for dissolving, after dissolving, 10-20 times of anti-solvent ethanol is added into the system for quickly stirring at normal temperature for crystallization and filtration to obtain a wet product with small particle size, and then the wet product is rotated and dried to obtain a large-particle-size good-fluidity creatine phosphate sodium tetrahydrate dry product.
3. The method of claim 2, wherein the anti-solvent ethanol is ethanol containing 0% -10% water.
4. The method as claimed in claim 2, wherein the rapid stirring crystallization is performed at a stirring speed of 700 and 1000 revolutions per minute.
5. The process of claim 2, wherein the wet product having a small particle size is characterized by a particle size D90 of less than 30 μm when the median diameter D50 is less than 20 μm and the cumulative number of particle size distributions is 90%.
6. The method of claim 2, wherein the drying is carried out at a temperature of 40-50 ℃ and a pressure of 4KPa or less.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911304735.2A CN112979697A (en) | 2019-12-17 | 2019-12-17 | Creatine phosphate tetrahydrate sodium with good fluidity and preparation method thereof |
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| CN201911304735.2A CN112979697A (en) | 2019-12-17 | 2019-12-17 | Creatine phosphate tetrahydrate sodium with good fluidity and preparation method thereof |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3036087A (en) * | 1958-09-26 | 1962-05-22 | Cfmc | Process for the preparation of phosphocreatine and/or phosphocreatinine |
| BE666891A (en) * | 1964-10-28 | 1965-11-03 | ||
| 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 |
| CN103304597A (en) * | 2013-06-28 | 2013-09-18 | 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 |
| CN104530120A (en) * | 2014-12-30 | 2015-04-22 | 哈尔滨莱博通药业有限公司 | Creatine phosphate sodium compound and crystal form thereof |
| CN106831858A (en) * | 2017-02-08 | 2017-06-13 | 哈尔滨莱博通药业有限公司 | A kind of preparation method of Creatine Phosphate Sodium |
| CN108017668A (en) * | 2016-11-04 | 2018-05-11 | 上海华拓医药科技发展有限公司 | A kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound and preparation method thereof and purposes |
-
2019
- 2019-12-17 CN CN201911304735.2A patent/CN112979697A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3036087A (en) * | 1958-09-26 | 1962-05-22 | Cfmc | Process for the preparation of phosphocreatine and/or phosphocreatinine |
| BE666891A (en) * | 1964-10-28 | 1965-11-03 | ||
| 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 |
| CN103304597A (en) * | 2013-06-28 | 2013-09-18 | 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 |
| CN104530120A (en) * | 2014-12-30 | 2015-04-22 | 哈尔滨莱博通药业有限公司 | Creatine phosphate sodium compound and crystal form thereof |
| CN108017668A (en) * | 2016-11-04 | 2018-05-11 | 上海华拓医药科技发展有限公司 | A kind of high four water of crystal form purity Creatine Phosphate Sodium, half compound and preparation method thereof and purposes |
| CN106831858A (en) * | 2017-02-08 | 2017-06-13 | 哈尔滨莱博通药业有限公司 | A kind of preparation method of Creatine Phosphate Sodium |
Non-Patent Citations (3)
| Title |
|---|
| WU JJ，等: "Effect of Drying Methods on Crystal Properties and Stability of Creatine Phosphate Sodium", 《LATIN AMERICAN JOURNAL OF PHARMACY》 * |
| YANG M，等: "Preparation and characterization of creatine phosphate sodium", 《LATIN AMERICAN JOURNAL OF PHARMACY》 * |
| 练美华，等: "磷酸肌酸钠的合成", 《中国医药工业杂志》 * |
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Application publication date: 20210618 |