CN108264466B - Preparation method of anhydrous potassium aspartate bulk drug and tablet thereof - Google Patents
Preparation method of anhydrous potassium aspartate bulk drug and tablet thereof Download PDFInfo
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- CN108264466B CN108264466B CN201710003687.8A CN201710003687A CN108264466B CN 108264466 B CN108264466 B CN 108264466B CN 201710003687 A CN201710003687 A CN 201710003687A CN 108264466 B CN108264466 B CN 108264466B
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- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 title claims abstract description 92
- 229940068988 potassium aspartate Drugs 0.000 title claims abstract description 92
- 239000003814 drug Substances 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 229940079593 drug Drugs 0.000 title description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 76
- 239000002994 raw material Substances 0.000 claims abstract description 73
- 238000000034 method Methods 0.000 claims abstract description 38
- 238000004090 dissolution Methods 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims description 41
- 239000008213 purified water Substances 0.000 claims description 41
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 34
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- 235000003704 aspartic acid Nutrition 0.000 claims description 29
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 29
- 238000003756 stirring Methods 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- 238000001035 drying Methods 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000005507 spraying Methods 0.000 claims description 10
- 230000001502 supplementing effect Effects 0.000 claims description 3
- 238000001694 spray drying Methods 0.000 abstract description 23
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 239000013078 crystal Substances 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 3
- 239000002245 particle Substances 0.000 description 16
- 239000000463 material Substances 0.000 description 11
- 230000008901 benefit Effects 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- 229940009098 aspartate Drugs 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000005262 decarbonization Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 238000007599 discharging Methods 0.000 description 3
- TXXVQZSTAVIHFD-DKWTVANSSA-M potassium;(2s)-2-aminobutanedioate;hydron Chemical compound [K+].[O-]C(=O)[C@@H](N)CC(O)=O TXXVQZSTAVIHFD-DKWTVANSSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 208000019025 Hypokalemia Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 208000024896 potassium deficiency disease Diseases 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a preparation method of anhydrous potassium aspartate raw material medicine and a tablet thereof. By adopting a new spray drying process, the prepared anhydrous potassium aspartate raw material medicine does not contain crystal water, and the product quality is stable and controllable. The raw material medicine prepared by the process is directly tableted to prepare the potassium aspartate tablet, the control requirement of the preparation process on the environment humidity in the tabletting process is effectively reduced, the process is reliable, the operation is simple and easy, and the obtained potassium aspartate tablet has a good in-vitro dissolution effect. The preparation method of the invention obviously improves the preparation yield, greatly reduces the production cost, solves the situation that the requirement on the humidity of the production environment of the potassium aspartate tablet is higher for a long time, and is a low-cost process which can be popularized.
Description
Technical Field
The invention relates to a preparation method for preparing anhydrous potassium aspartate raw material medicines and tablets thereof in the technical field of pharmacy, in particular to the anhydrous potassium aspartate raw material medicines prepared in a spray drying mode, and the tablets are prepared from the prepared anhydrous potassium aspartate raw material medicines in a direct tabletting mode.
Background
Aspartate is a precursor of oxaloacetate in the human body and plays an important role in the tricarboxylic acid cycle. Meanwhile, it also participates in ornithine circulation, promotes the metabolism of ammonia and carbon dioxide, and leads the ammonia and carbon dioxide to generate urea, thereby reducing the content of ammonia and carbon dioxide in blood. The aspartic acid has strong affinity with cells and can be used as a carrier of potassium ions, so that the potassium ions are returned into the cells to maintain the normal functions of the cells. Potassium aspartate is commonly used clinically to treat various hypokalemia, arrhythmia caused by digitalis intoxication, etc.
At present, the technical research reports about potassium aspartate raw material medicines are potassium aspartate semihydrate and dihydrate, and no report about the preparation process of anhydrous potassium aspartate raw material medicines exists. The potassium aspartate tablet sold in Japan is prepared by using anhydrous potassium aspartate as a raw material medicine and adding a proper amount of auxiliary materials, so that the product stability is greatly improved. Compared with the reported process, the anhydrous potassium aspartate bulk drug particles have the characteristics of good stability and high yield, particularly have outstanding advantages in the preparation of potassium aspartate tablets, reduce the sticking problem caused by moisture absorption of raw materials, greatly improve the yield, reduce the production cost, solve the situation that the requirement on the humidity of the production environment of the potassium aspartate tablets is high for a long time, and are a low-cost process capable of being popularized.
The invention has the advantages that the raw material medicine of the anhydrous potassium aspartate is prepared, and the stability and the practicability of the preparation are improved. Has outstanding advantages compared with the prior art. The granted patent CN 101675921B adopts a physical method to prepare the potassium aspartate raw material, the published patent CN 103664668A adopts a spray drying mode to prepare the potassium aspartate raw material medicine, the potassium aspartate raw material prepared by the process contains half of crystal water, and the problems of low product yield, unsafe industrial conditions and the like are solved. The invention provides a novel spray drying process for preparing the potassium aspartate, the prepared potassium aspartate does not contain crystal water, the product is stable and controllable, the preparation of a later-period preparation is facilitated, the environmental control requirement in the tabletting process is greatly reduced, the yield is improved, and the production cost is reduced.
The invention has another advantage that the raw material medicine of the anhydrous potassium aspartate is used for preparing the tablet, and has outstanding advantages compared with the prior art. The common specification of the potassium aspartate tablet is 300mg, the drug loading is large, the conventionally used potassium aspartate bulk drug containing half of crystal water has strong hygroscopicity, the requirements on environment humidity and equipment are high when the tablet is prepared, and under the humidity of a conventional laboratory, the main steps in the pharmaceutical process such as mixing, tabletting and the like are greatly influenced. Although there are patents that optimize and improve the prescription and process of potassium aspartate tablets, the results are not ideal and the cost is high. Chinese patent CN104069082A discloses a potassium aspartate and waxy material tablet, which reduces the hygroscopicity of the material and improves the compressibility; chinese patent CN103181917A discloses a method for reducing hygroscopicity and improving compressibility by tabletting potassium aspartate and increasing the dosage of silica gel micropowder; european patent BG19990103125 discloses a traditional granulating and tabletting preparation process of potassium aspartate and conventional amount of auxiliary materials. The anhydrous potassium aspartate prepared by the novel process can be used as a raw material drug of a potassium aspartate tablet, the requirement on the humidity of the environment is reduced, the process is reliable, the preparation is simple and convenient, and the in-vitro dissolution effect is good.
Disclosure of Invention
The invention aims to provide a preparation method of an anhydrous potassium aspartate raw material medicine, which is characterized in that the anhydrous potassium aspartate raw material medicine is prepared by a spray drying method, and the granularity of the anhydrous potassium aspartate raw material medicine is 60-80 meshes;
the preparation method comprises the following specific steps:
(1) adding a proper amount of purified water into the liquid preparation tank, adding potassium hydroxide for dissolving under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction;
(2) adjusting the pH value to be within the range of 6.5-8.0, adding 0.1% of activated carbon, stirring for 30 minutes, decarburizing, and supplementing purified water to a proper amount to prepare a water feed liquid;
(3) forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 240-250 ℃, the air outlet temperature to be 150-;
the preparation method is characterized in that the dosage of the purified water is 0.4-1.0 time of that of the aspartic acid, preferably 0.6-0.7 time of that of the aspartic acid;
the preparation method is characterized in that the frequency of the atomizer is adjusted to be 30-50 Hz, preferably 35-40 Hz;
the preparation method is characterized in that the pressure in the tower is kept within-3.0 to-0.1 kpa, preferably-2.5 kpa;
the anhydrous potassium aspartate raw material medicine obtained by the preparation method is white or off-white powder, odorless and hygroscopic.
The anhydrous potassium aspartate bulk drug prepared by the preparation method is used for preparing tablets, and the preparation process is characterized in that the tablets are prepared by a direct tabletting mode;
the anhydrous potassium aspartate bulk drug prepared by the preparation method is used for preparing tablets, and is characterized in that the anhydrous potassium aspartate is mixed with proper auxiliary materials, the mixture is sieved and then directly tableted to obtain tablet cores, and the tablet cores are coated with coating liquid to obtain potassium aspartate tablets;
the anhydrous potassium aspartate bulk drug prepared by the preparation method is used for preparing tablets, and has the advantages that: the hygroscopicity of the raw materials in the preparation process of the tablet is reduced, the requirement of the preparation process of the tablet on the humidity of the environment is reduced, the process is reliable, the preparation is simple and convenient, and the in-vitro dissolution effect is good.
Detailed Description
The invention aims to provide a preparation method of an anhydrous potassium aspartate raw material medicine, which is characterized in that the anhydrous potassium aspartate raw material medicine is prepared by a spray drying method, and the granularity of the anhydrous potassium aspartate raw material medicine is 60-80 meshes;
the advantage of adopting the spray drying method to prepare the anhydrous potassium aspartate bulk drug is that the spray drying technology is a widely applied technology in liquid forming and drying industries, is suitable for generating powdery and granular products from raw material liquids such as solution, emulsion and the like, and has mature technology and strong operability. In the rotary spray drying process, the water content of the finished product is related to a plurality of parameters, such as the rotating speed of an atomizer, the air inlet temperature, the air outlet temperature, the feeding concentration, the feeding speed, the air flow and the like. The anhydrous potassium aspartate raw material medicine is prepared by optimizing the air inlet and outlet temperature, the feeding concentration and amount, increasing the air flow and other process controls.
The spray drying technology is adopted to prepare the anhydrous potassium aspartate, and the specific steps are as follows:
(1) adding a proper amount of purified water into the liquid preparation tank, adding potassium hydroxide for dissolving under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction;
(2) adjusting the pH value to be within the range of 6.5-8.0, adding 0.1% of activated carbon, stirring for 30 minutes, supplementing purified water to a proper amount after decarbonization, wherein the amount of the purified water is 0.4-1.0 time, preferably 0.6-0.7 time of the amount of the aspartic acid, and preparing a water feed liquid;
(3) forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 240-250 ℃, the air outlet temperature to be 150-;
in addition, it was found in the study that: the rotating speed of the atomizer has great influence on the drying process, not only the moisture of a finished product but also the particle size of the finished product, a series of researches are intensively made on the parameters to obtain the optimal process parameters, and the granularity of the prepared raw materials is 60-80 meshes on the premise of ensuring no water, so that the preparation of potassium aspartate tablets is facilitated, the problem of moisture absorption in the process of storing and preparing the tablets is reduced, the operability of the tablet preparation is greatly improved, and the production cost and the process difficulty are reduced.
The principle is that the rotational speed of the atomizer, i.e. the corresponding circumferential rotational speed, is one of the droplet influencing parameters. When liquid is supplied to a blade disc rotating at high speed, the liquid moves over the surface in front of the blades. Due to the centrifugal force, the liquid moves outwards and spreads out as a film on the blades, wetting the blade surfaces. When the liquid comes into contact with the blade, the liquid does not slide on the blade, and the liquid drops leave from the wheel edge with relatively low radial velocity and high tangential velocity. As the rotational speed of the atomizer increases, the release rate and particle size of the droplets from the atomizer will vary. The water content and the particle size of the dried product of the fog drops are influenced by combining the factors. Practice has shown that the rotational speed of the atomizer also has an effect on the degree of wall sticking during the drying of the product.
The anhydrous potassium aspartate bulk drug prepared by adopting the spray drying method has special effects, particularly has great improvement effect on the hygroscopicity of the raw material, and lays a foundation for providing a simple and effective preparation process for preparing tablets by adopting the anhydrous potassium aspartate raw material. Unlike the granted patent CN 101675921B and the published patent CN 103664668A which adopt a spray drying mode to prepare the potassium aspartate bulk drug, the potassium aspartate prepared by the patented method contains half of crystal water, and the granularity of the raw materials is controlled to pass through a 120-mesh sieve. We optimized the spray drying process to dry the potassium aspartate material as an anhydrate with a certain particle size (60-80 mesh). Generally speaking, improve air inlet temperature and air-out temperature and can effectively reduce material moisture, raise the efficiency. Meanwhile, the frequency of the atomizer is properly reduced, the atomization speed is reduced, and the particle size of the fog drops is increased. The granularity of the prepared anhydrous potassium aspartate raw material medicine is improved, the superficial area of the raw material medicine is favorably reduced, the contact between the raw material medicine and the air is reduced, and the hygroscopicity of the anhydrous potassium aspartate raw material medicine is reduced. Therefore, the raw material medicine is favorable for storage and transportation of the raw material medicine, more stable raw material medicine is provided for preparation of the potassium aspartate tablet, the hygroscopicity of the raw material medicine in the tablet preparation process is reduced, and mixing and tabletting are facilitated, so that the environmental control requirement in the production process is reduced, the production cost is reduced, and the productivity is improved.
Similarly, the raw material medicine of the anhydrous potassium aspartate can also be prepared by adopting reduced pressure drying or other drying modes, but certain problems exist. Under the condition of high-temperature or long-time drying, the water content of the bulk drug can be reduced as much as possible, but the drying speed of the surface and the central area is different in the drying process, so that the drying time is long, the appearance of the bulk drug cannot be guaranteed, and the particle size is controlled unevenly. The powder solid is easily formed on the surface, the surface area contacting with the external environment is increased, and the hygroscopicity of the powder solid is increased. The invention adopts a spray drying mode to prepare the anhydrous potassium aspartate bulk drug, controls the granularity within a proper range, not only effectively controls the hygroscopicity of the raw material, but also is beneficial to the preparation of tablets. The optimization process has the advantages of strong operability, low energy consumption and great practical benefit.
To further illustrate the superiority of the present invention, we will describe the optimization process of the present invention in detail.
The anhydrous potassium aspartate bulk drug is prepared in a spray drying mode, and the feeding concentration is firstly inspected.
The preparation process comprises the following steps: adding a proper amount of purified water into the liquid preparation tank, adding potassium hydroxide for dissolving under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction; adjusting the pH value to be within the range of 6.5-8.0, adding 0.1% of activated carbon, stirring for 30 minutes, adding purified water to a proper amount after decarbonization, wherein the amount of the purified water is 0.4 time, 0.6 time, 0.7 time, 0.8 time and 1.0 time of the amount of the aspartic acid, and preparing a water feed liquid; forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 240-250 ℃, the air outlet temperature to be 150-;
and (3) measuring the moisture of the anhydrous potassium aspartate raw material medicine (referring to a moisture measuring method of potassium aspartate hydrate in European pharmacopoeia):
table 1: water content test result of raw material medicine for preparing anhydrous potassium aspartate by using different amounts of purified water and aspartate
| The ratio of the purified water to the amount of aspartic acid | 0.4 | 0.6 | 0.7 | 0.8 | 1.0 |
| Moisture content | 0.53% | 0.25% | 0.33% | 0.49% | 0.62% |
From the above results, it can be seen that: different feed concentrations have certain influence on the moisture of finished products, and the moisture standard is set to be less than 1.0 percent due to the hygroscopicity of the potassium aspartate raw material. The ratio of the amount of the purified water to the amount of the aspartic acid is within the range of 0.4-1.0, the water content of the anhydrous potassium aspartate raw material drug meets the specification, and the liquid medicine of the anhydrous potassium aspartate raw material is optimally controlled when the ratio of the amount of the purified water to the amount of the aspartic acid is within the range of 0.6-0.7.
The particle size determination of the potassium aspartate anhydrous raw material medicine (screening method, sampling and screening, and counting by the passing rate):
table 2: granularity result of raw material medicine for preparing anhydrous potassium aspartate by using different amounts of purified water and aspartate
| The ratio of the purified water to the amount of aspartic acid | 0.4 | 0.6 | 0.7 | 0.8 | 1.0 |
| Raw material particle size (60 mesh sieve pass rate) | 98% | 99% | 100% | 100% | 100% |
| Raw material particle size (80 mesh sieve passing rate) | 79% | 88% | 87% | 92% | 93% |
| Raw material particle size (100 mesh sieve pass rate) | 16% | 25% | 28% | 35% | 40% |
Because different feeding concentrations have certain influence on the granularity of finished products, the condition that the dosage ratio of purified water to aspartic acid is within 0.4-1.0 and the raw material medicines obtained by spray drying are sieved is investigated. The experimental results show that the anhydrous potassium aspartate raw material medicines prepared by different processes can completely pass through a 60-mesh sieve, have uniform granularity and only contain a small amount of fine powder. In order to ensure that the granularity is within a certain range and facilitate the preparation of potassium aspartate tablets, the prepared raw material medicines are respectively sieved by an 80-mesh sieve and a 100-mesh sieve, the dosage ratio of purified water to aspartate is within 0.6-1.0, 85% of anhydrous potassium aspartate raw material medicines pass through the 80-mesh sieve, and only 25% -40% of anhydrous potassium aspartate raw material medicines pass through the 100-mesh sieve. Therefore, the anhydrous potassium aspartate bulk drug prepared under the process condition has uniform granularity, the dosage ratio of the purified water to the aspartic acid is within 0.6-1.0, and the granularity of the obtained raw material is 60-80 meshes.
Preparing anhydrous potassium aspartate raw material medicine in a spray drying mode, determining the dosage ratio of purified water to aspartate to be 0.6 times, adjusting different atomizer frequencies, and investigating the influence of the atomizer frequencies on materials.
The preparation process comprises the following steps: adding a proper amount of purified water into the liquid preparation tank, adding potassium hydroxide for dissolving under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction; adjusting the pH value to be within the range of 6.5-8.0, adding 0.1% of activated carbon, stirring for 30 minutes, adding purified water to a proper amount after decarbonization, and preparing a water feed liquid with the amount of the purified water being 0.6 times of the amount of the aspartic acid; forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 240-250 ℃, the air outlet temperature to be 150-160 ℃, adjusting the frequency of the atomizer to be 30-50 Hz, and keeping the pressure in the tower at-0.2 kpa;
and (3) measuring the moisture of the anhydrous potassium aspartate raw material medicine (referring to a moisture measuring method of potassium aspartate hydrate in European pharmacopoeia):
table 3: water content test result of anhydrous potassium aspartate raw material medicine prepared by different atomizer frequencies
| Atomizer frequency (Hz) | 30 | 35 | 40 | 45 | 50 |
| Moisture content | 0.35% | 0.20% | 0.18% | 0.55% | 0.71% |
From the above results, it can be seen that: different atomizer frequencies have some effect on the moisture of the finished product, and since potassium aspartate has hygroscopicity, we set the moisture standard to less than 1.0%. The frequency of the atomizer is within the range of 30 Hz-50 Hz, the moisture of the anhydrous potassium aspartate raw material drug is checked to meet the specification, and when the frequency of the atomizer is within the range of 35 Hz-40 Hz, the moisture of the anhydrous potassium aspartate raw material is optimally controlled.
The particle size determination of the potassium aspartate anhydrous raw material medicine (screening method, sampling and screening, and counting by the passing rate):
table 4: particle size test result of anhydrous potassium aspartate bulk drug prepared by different atomizer frequencies
| Atomizer frequency (Hz) | 30 | 35 | 40 | 45 | 50 |
| Raw material particle size (60 mesh sieve pass rate) | 99% | 99% | 97% | 100% | 100% |
| Raw material particle size (80 mesh sieve passing rate) | 85% | 88% | 92% | 95% | 95% |
| Raw material particle size (100 mesh sieve pass rate) | 33% | 42% | 41% | 45% | 40% |
Because different atomizer frequencies have certain influence on the granularity of finished products, the condition that the raw material medicines obtained by spray drying are sieved when the atomizer frequency is within the range of 30 Hz-50 Hz is considered. The experimental results show that the anhydrous potassium aspartate bulk drug prepared by different processes can completely pass through a 60-mesh sieve and a 80-mesh sieve, the granularity is uniform, only a small amount of fine powder exists, the granularity is ensured to be within the range of 60-80 meshes, and the anhydrous potassium aspartate tablet is favorably prepared.
The moisture results are combined, the frequency of the atomizer is adjusted within the range of 30 Hz-50 Hz, and 35 Hz-40 Hz is preferred;
the anhydrous potassium aspartate raw material medicine is prepared in a spray drying mode, and the influence of the pressure in an atomizer tower on the material is inspected.
The preparation process comprises the following steps: adding a proper amount of purified water into the liquid preparation tank, adding potassium hydroxide for dissolving under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction; adjusting the pH value to be within the range of 6.5-8.0, adding 0.1% of activated carbon, stirring for 30 minutes, adding purified water to a proper amount after decarbonization, and preparing a water feed liquid with the amount of the purified water being 0.6 times of the amount of the aspartic acid; forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 240-250 ℃, the air outlet temperature to be 150-;
and (3) measuring the moisture of the anhydrous potassium aspartate raw material medicine (referring to a moisture measuring method of potassium aspartate hydrate in European pharmacopoeia):
table 5: water content test result of anhydrous potassium aspartate raw material medicine prepared under different tower internal pressures
| Pressure in the tower (kpa) | -3.0 | -2.5 | -2.0 | -1.5 | -1.0 |
| Moisture content | 0.17% | 0.15% | 0.35% | 0.55% | 0.70% |
From the above results, it can be seen that: different tower internal pressures have certain influence on finished product moisture, and the moisture standard is set to be less than 1.0 percent due to the hygroscopicity of potassium aspartate. The pressure in the tower is in the range of-3.0 to-0.1 kpa, the water content of the anhydrous potassium aspartate raw material drug is in accordance with the specification after inspection, the pressure in the tower is in the range of-3.0 to-2.5 kpa, the water content of the anhydrous potassium aspartate raw material is optimally controlled, but the higher the negative pressure is, the higher the requirement on equipment is, the higher the equipment loss is, and the preferable pressure in the tower is-2.5 kpa.
The advantages of the invention are further illustrated by the following examples, which are not intended to be limiting:
the first embodiment is as follows:
adding a proper amount of purified water into the liquid preparation tank, adding 80kg of potassium hydroxide for dissolution under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction; adjusting the pH value to 6.5, adding 0.1% active carbon, stirring for 30 minutes, adding purified water to 384kg after decarburizing, wherein the amount of the purified water is 0.6 times of that of the aspartic acid to prepare a water feed liquid; forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 240 ℃, the air outlet temperature to be 150 ℃, adjusting the frequency of the atomizer to be 40Hz, and keeping the pressure in the tower at-0.25 kpa; discharging after spray drying to obtain 228kg of finished product with the yield of 93.4%.
Example two:
adding a proper amount of purified water into the liquid preparation tank, adding 80kg of potassium hydroxide for dissolution under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction; adjusting the pH value to 8.0, adding 0.1% of activated carbon, stirring for 30 minutes, adding purified water to 460kg after decarburizing, wherein the amount of the purified water is 1.0 time of that of the aspartic acid to prepare a water feed liquid; forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 250 ℃, the air outlet temperature to be 160 ℃, adjusting the frequency of the atomizer to be 50Hz, and keeping the pressure in the tower at-0.1 kpa; after spray drying, the material is discharged to obtain 220kg of finished product with the yield of 90.2 percent.
Example three:
adding a proper amount of purified water into the liquid preparation tank, adding 80kg of potassium hydroxide for dissolution under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction; adjusting the pH value to 7.0, adding 0.1% of activated carbon, stirring for 30 minutes, adding purified water to 346kg after decarburizing, wherein the amount of the purified water is 0.4 times of that of the aspartic acid to prepare a water feed liquid; forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 250 ℃, the air outlet temperature to be 150 ℃, adjusting the frequency of the atomizer to be 35Hz, and keeping the pressure in the tower at-0.3 kpa; and discharging after spray drying to obtain 222kg of finished product with the yield of 91.0%.
Example four:
adding a proper amount of purified water into the liquid preparation tank, adding 80kg of potassium hydroxide for dissolution under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction; adjusting the pH value to 7.5, adding 0.1% of activated carbon, stirring for 30 minutes, adding purified water to 403kg after decarburizing, wherein the amount of the purified water is 0.7 times of that of the aspartic acid to prepare a water feed liquid; forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 255 ℃, the air outlet temperature to be 155 ℃, adjusting the frequency of the atomizer to be 30Hz, and keeping the pressure in the tower at-0.2 kpa; spray drying, discharging to obtain 224kg of finished product with the yield of 91.8%.
Example five:
the potassium aspartate anhydrous raw material medicine prepared in the first embodiment is used for preparing tablets, the tablets are mixed with proper auxiliary materials, the tablets are directly compressed after being sieved to obtain tablet cores, and the tablet cores are coated with coating liquid to obtain the potassium aspartate tablets.
Claims (4)
1. A preparation method of anhydrous potassium aspartate raw material medicine is characterized by comprising the following specific steps:
(1) adding purified water into the liquid preparation tank, adding potassium hydroxide for dissolution under stirring, and adding aspartic acid according to a molar equivalent of 1:1 for reaction;
(2) adjusting the pH value to be within the range of 6.5-8.0, adding 0.1% of activated carbon, stirring for 30 minutes, decarburizing, and supplementing purified water to a proper amount to prepare a water feed liquid;
(3) forming water feed liquid into fog drops through an atomizer, spraying the fog drops into a drying chamber, controlling the air inlet temperature to be 240-250 ℃, the air outlet temperature to be 150-;
the amount of the purified water is 0.4-1.0 time of the amount of the aspartic acid.
2. The method according to claim 1, wherein the amount of purified water is 0.6 to 0.7 times the amount of aspartic acid.
3. The method according to claim 1, wherein the atomizer frequency is adjusted to 35 to 40 Hz.
4. The process of claim 1, wherein the pressure in the column is maintained at-2.5 kpa.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2752287A1 (en) * | 1977-11-23 | 1979-05-31 | Degussa | PROCESS FOR THE EXTRACTION OF SALT OF ASPARAGIC ACID |
| CN101675921A (en) * | 2008-09-19 | 2010-03-24 | 于航 | Method for preparing potassium aspartape raw medicine by physical method and preparation thereof |
| CN103193661A (en) * | 2013-04-11 | 2013-07-10 | 吴玉柱 | Potassium aspartate crystal, and preparation method of potassium magnesium aspartate drug composition |
| CN103664668A (en) * | 2012-09-24 | 2014-03-26 | 沈阳药联科技创新有限公司 | Preparation method of potassium aspartate crude drug |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2752287A1 (en) * | 1977-11-23 | 1979-05-31 | Degussa | PROCESS FOR THE EXTRACTION OF SALT OF ASPARAGIC ACID |
| CN101675921A (en) * | 2008-09-19 | 2010-03-24 | 于航 | Method for preparing potassium aspartape raw medicine by physical method and preparation thereof |
| CN103664668A (en) * | 2012-09-24 | 2014-03-26 | 沈阳药联科技创新有限公司 | Preparation method of potassium aspartate crude drug |
| CN103193661A (en) * | 2013-04-11 | 2013-07-10 | 吴玉柱 | Potassium aspartate crystal, and preparation method of potassium magnesium aspartate drug composition |
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