CN108264466A - The preparation method of anhydrous potassium aspartate crude drug and its tablet - Google Patents
The preparation method of anhydrous potassium aspartate crude drug and its tablet Download PDFInfo
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- CN108264466A CN108264466A CN201710003687.8A CN201710003687A CN108264466A CN 108264466 A CN108264466 A CN 108264466A CN 201710003687 A CN201710003687 A CN 201710003687A CN 108264466 A CN108264466 A CN 108264466A
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- preparation
- crude drug
- prepared
- tablet
- aspartic acid
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- 239000003814 drug Substances 0.000 title claims abstract description 48
- 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 47
- 229940079593 drug Drugs 0.000 title claims abstract description 47
- 229940068988 potassium aspartate Drugs 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 73
- 238000000034 method Methods 0.000 claims abstract description 36
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 35
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 35
- 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 abstract description 35
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- 239000007788 liquid Substances 0.000 claims description 28
- 239000008213 purified water Substances 0.000 claims description 28
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 239000000463 material Substances 0.000 claims description 12
- 238000001694 spray drying Methods 0.000 claims description 12
- 238000013019 agitation Methods 0.000 claims description 10
- 239000003610 charcoal Substances 0.000 claims description 10
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 abstract description 20
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 238000001035 drying Methods 0.000 abstract description 9
- 238000002425 crystallisation Methods 0.000 abstract description 5
- 230000008025 crystallization Effects 0.000 abstract description 5
- 238000000605 extraction Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 21
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 10
- 229910052700 potassium Inorganic materials 0.000 description 10
- 239000011591 potassium Substances 0.000 description 10
- 230000008901 benefit Effects 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- LBXRPPWPQUZKBO-DKWTVANSSA-N (2s)-2-aminobutanedioic acid;hydrate Chemical compound O.OC(=O)[C@@H](N)CC(O)=O LBXRPPWPQUZKBO-DKWTVANSSA-N 0.000 description 3
- KTHUPQRVVIDEPB-RGMNGODLSA-N [K].C(CC)N[C@@H](CCO)C(=O)O Chemical compound [K].C(CC)N[C@@H](CCO)C(=O)O KTHUPQRVVIDEPB-RGMNGODLSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001033 granulometry Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000003643 water by type 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
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 150000008064 anhydrides Chemical group 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000021264 digitalis poisoning Diseases 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 238000005457 optimization Methods 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
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- 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 present invention relates to a kind of anhydrous potassium aspartate crude drug and its preparation methods of tablet.Using a kind of new drying process with atomizing, prepared anhydrous potassium aspartate crude drug does not contain the crystallization water, and product quality is stably and controllable.The bulk pharmaceutical chemicals direct tablet compressing prepared using this technique prepares aspartic acid piece, effectively reduces control requirement of the preparation process to ambient humidity in tableting processes, and process, simple to operation, the external result of extraction of gained aspartic acid piece is good.The preparation method of the invention significantly improves preparation yield, and production cost is greatly reduced, and solves the situation that aspartic acid tablet manufacturing ambient humidity is more demanding for a long time, is a kind of low cost process that can be promoted.
Description
Technical field
The present invention relates to the preparation sides that anhydrous potassium aspartate crude drug and its tablet are prepared in a kind of pharmaceutical technology
Method is specifically to prepare anhydrous potassium aspartate crude drug by the way of spray drying, by prepared anhydrous L-aminobutanedioic acid
Potassium bulk pharmaceutical chemicals prepare tablet by the way of direct tablet compressing.
Background technology
L-aminobutanedioic acid is the precursor of oxaloacetic acid in human body, is played an important role in tricarboxylic acid cycle.It is also assisted in simultaneously
Ornithine recycles, and promotes the metabolism of ammonia and carbon dioxide, is allowed to generate urea, so as to reduce containing for ammonia and carbon dioxide in blood
Amount.L-aminobutanedioic acid has very strong affinity with cell, potassium ion can be made to return into the cell, maintain it as the carrier of potassium ion
Normal function.Arrhythmia cordis etc. caused by clinically treating various hypopotassaemias, digitalis poisoning frequently with aspartic acid.
At present, it is aspartic acid semihydrate and two hydrations about the technical study of potassium aspartate crude drug report
Object, without the report of anhydrous potassium aspartate crude drug preparation process.In view of Japanese commercialized product aspartic acid piece uses nothing
Water aspartic acid is bulk pharmaceutical chemicals, and prepared by addition appropriate amount of auxiliary materials, product stability greatly improves.Our emphasis have developed no water valve
The preparation process of winter propylhomoserin potassium bulk pharmaceutical chemicals, compared with the technique reported, anhydrous potassium aspartate crude drug particle, which has, to be stablized
Property good, the characteristics of yield is high, prominent advantage is especially embodied in the preparation of L-aminobutanedioic acid potassium tablets, reduces the raw material moisture absorption
Caused sticking problem substantially increases yield, reduces production cost, solves aspartic acid tablet manufacturing ring for a long time
Humidity more demanding situation in border is a kind of low cost process that can be promoted.
Advantage of the invention is that the bulk pharmaceutical chemicals of anhydrous aspartic acid are prepared for, improve its stability and prepare preparation
Practicability.Compared with the prior art there is outstanding advantage.101675921 B of granted patent CN are using a kind of physical method system
Standby aspartic acid raw material, 103664668 A of publication CN prepare aspartic acid raw material by the way of spray drying
Medicine, the aspartic acid raw material prepared using above-mentioned technique contain the half crystallization water, solve that product yield is low, industrial item
The problems such as part is dangerous.And using the present invention provides a kind of new drying process with atomizing for preparing aspartic acid, it is prepared
Aspartic acid do not contain the crystallization water, product is stably and controllable, is conducive to the preparation of later stage preparation, substantially reduces in tableting processes
Environmental Kuznets Curves requirement, improves yield, reduces production cost.
Another advantage of the present invention is that the bulk pharmaceutical chemicals using anhydrous aspartic acid prepare tablet, compared with the prior art
With outstanding advantage.L-aminobutanedioic acid potassium tablets regular size is 300mg, and drugloading rate is larger, and it is conventional use of containing two/
The potassium aspartate crude drug of one crystallization water have it is very strong draw it is moist, when preparing the tablet to ambient humidity and equipment requirement compared with
Height, under Routine Test Lab humidity, the key step in pharmacy procedure is as mixed, and tabletting etc. is by extreme influence.Although
There is patent that the prescription and technique of L-aminobutanedioic acid potassium tablets are optimized and improved, but effect is unsatisfactory, and cost is higher.In
State patent CN104069082A discloses a kind of aspartic acid and wax material tabletting, makes the reduction of material hygroscopicity, compressibility
It improves；Chinese patent CN103181917A discloses a kind of aspartic acid and reduces moisture absorption with increasing the tabletting of superfine silica gel powder dosage
Property, compressibility improves；European patent BG19990103125 discloses the tradition system of a kind of aspartic acid and conventional amount used auxiliary material
Grain tabletting preparation process.Anhydrous aspartic acid, prepared no water valve winter are prepared using the present invention provides a kind of new processes
Propylhomoserin potassium can require to reduce, process, prepare simple side as the bulk pharmaceutical chemicals of L-aminobutanedioic acid potassium tablets to the humidity of environment
Just, In Vitro Dissolution works well.
Invention content
Present invention aims at a kind of preparation method of anhydrous potassium aspartate crude drug is provided, it is characterized in that using spraying
Dry method prepares anhydrous potassium aspartate crude drug, and granularity is in 60 ~ 80 mesh；
Above-mentioned preparation method, is as follows：
（1）Appropriate purified water is added in into Agitation Tank, potassium hydroxide dissolving is added with stirring, according to molar equivalent 1:1 adds in door
Winter propylhomoserin reacts；
（2）It adjusts pH values and stirs 30 minutes in the range of 6.5~8.0, adding in 0.1% activated carbon, purified water is added extremely after de- charcoal
In right amount, water feed liquid is prepared；
（3）Water feed liquid is formed into droplet by atomizer and is injected into hothouse, control inlet air temperature is at 240~250 DEG C, outlet air
150-160 DEG C of temperature, atomizer frequency are adjusted to 30 ~ 50Hz, and tower pressure interior force is maintained at -3.0~-0.1kpa；
Above-mentioned preparation method, it is characterised in that purifying water consumption is 0.4 ~ 1.0 times, preferably 0.6 ~ 0.7 times of L-aminobutanedioic acid dosage；
Above-mentioned preparation method, it is characterised in that adjusting atomizer frequency to 30 ~ 50Hz, preferably 35 ~ 40Hz；
Above-mentioned preparation method, it is characterised in that keep tower pressure interior force in -3.0 ~ -0.1kpa, preferably -2.5kpa；
The anhydrous potassium aspartate crude drug obtained by above-mentioned preparation method is the powder of white or off-white color, odorless, have draw it is wet
Property.
Tablet is prepared by the anhydrous potassium aspartate crude drug that above-mentioned preparation method obtains, preparation process is characterized in that
Tablet is prepared by the way of direct tablet compressing；
Tablet is prepared by the anhydrous potassium aspartate crude drug that above-mentioned preparation method obtains, it is characterised in that by anhydrous L-aminobutanedioic acid
After potassium is mixed with appropriate auxiliary material, direct tablet compressing obtains label after sieving, and aspartic acid piece is made after the coating of label coating solution；
Tablet is prepared by the anhydrous potassium aspartate crude drug that above-mentioned preparation method obtains, it is advantageous that：Raw material is reduced in piece
Drawing in agent preparation process is moist, reduces tablet manufacture to the requirement of the humidity of environment, process, prepare it is simple and convenient,
Its In Vitro Dissolution works well.
Specific embodiment
Present invention aims at a kind of preparation method of anhydrous potassium aspartate crude drug is provided, it is characterized in that using spraying
Dry method prepares anhydrous potassium aspartate crude drug, and granularity is in 60 ~ 80 mesh；
The advantage that anhydrous potassium aspartate crude drug is prepared using the method for spray drying is, spray drying technology be liquid into
Shape and the dry widely applied technique of industry, suitable for generating powdery, granular product, skill from material liquids such as solution, lotions
Art is ripe, and operability is strong.In the technique being rotatably spray-dried, the height of finished product water content is related to multiple parameters, such as
Atomizer rotating speed, inlet air temperature, leaving air temp, input concentration, charging rate, air mass flow etc..We are by optimizing air inlet/outlet
Temperature, input concentration and amount, and the technology controlling and process such as air mass flow are increased, prepare anhydrous potassium aspartate crude drug.
Anhydrous aspartic acid is prepared using spray drying technology, is as follows：
（1）Appropriate purified water is added in into Agitation Tank, potassium hydroxide dissolving is added with stirring, according to molar equivalent 1:1 adds in door
Winter propylhomoserin reacts；
（2）It adjusts pH values and stirs 30 minutes in the range of 6.5~8.0, adding in 0.1% activated carbon, purified water is added extremely after de- charcoal
In right amount, 0.4 ~ 1.0 times that water consumption is L-aminobutanedioic acid dosage is purified, preferably 0.6 ~ 0.7 times, prepares water feed liquid；
（3）Water feed liquid is formed into droplet by atomizer and is injected into hothouse, control inlet air temperature is at 240~250 DEG C, outlet air
150-160 DEG C of temperature, atomizer frequency are adjusted to 30 ~ 50Hz, and tower pressure interior force is maintained at -3.0~-0.1kpa；
In addition, it is found in research：The rotating speed of atomizer has tremendous influence for drying process, not only influences the moisture of finished product,
Also finished particle size is influenced, we have carried out a series of research to this parameter emphatically, obtain optimal processing parameter, are protecting
Demonstrate,prove it is anhydrous under the premise of, prepared raw material granularity is conducive to the preparation of L-aminobutanedioic acid potassium tablets in 60-80 mesh in this way, reduces
Sucting wet problem during tablet is preserved and prepared, substantially increases the operability of tablet preparation, reduces production cost and technique
Difficulty.
Its principle is one of droplet affecting parameters for atomizer rotating speed, that is, corresponding circumferential speed.When liquid is supplied at a high speed
When on the fan disk of rotation, surface movement of the liquid before blade.Since centrifugal force acts on, liquid is displaced outwardly and in blade
On be launched into film-form, soak blade surface.When liquid and during blade contact, liquid does not slide on blade, drop from
Wheel edge is when leaving with respect to smaller radial to speed and larger tangential velocity.With the raising of atomizer rotating speed, droplet leaves atomization
The rate of release and grain size of device will all change.In summary factor will be to the dry products water content and particle size of droplet
It has an impact.It was verified that the rotating speed of atomizer also has an impact to gluing wall degree in the drying process of product.
There is special-effect, especially drawing in raw material using potassium aspartate crude drug anhydrous made from spray drying process
The effect of having greatly improved of moist aspect, this also provides simple and effective system to prepare tablet using anhydrous aspartic acid raw material
Standby technique lays the first stone.Spray drying side is used with 103664668 A of granted patent CN 101675921 B and publication CN
Formula is prepared the aspartic acid unlike potassium aspartate crude drug, prepared using patented method and contains half crystallization
Water, and raw material granularity is controlled all to be sieved by 120 mesh.We optimize drying process with atomizing, make aspartic acid raw material with
Anhydride form is dried, and with certain granularity（60-80 mesh）.In general, improving inlet air temperature and leaving air temp can have
Effect reduces material moisture, improves efficiency.We suitably reduce the frequency of atomizer simultaneously, reduce atomization speed, make mist droplet granularity
Increase.Improve the granularity that anhydrous potassium aspartate crude drug is made, advantageously reduce the surface areas of bulk pharmaceutical chemicals, reduce bulk pharmaceutical chemicals with
It is moist to reduce drawing for anhydrous potassium aspartate crude drug for the contact of air.The storage and transport of bulk pharmaceutical chemicals are not only contributed in this way,
Also more stable bulk pharmaceutical chemicals are provided to the preparation of aspartic acid piece, it is moist to reduce drawing for bulk pharmaceutical chemicals in tablet manufacture,
Conducive to mixing and tabletting, so as to reduce the environmental Kuznets Curves requirement in production process, production cost is reduced, improves production capacity.
Equally, using being dried under reduced pressure or other drying modes can also prepare the bulk pharmaceutical chemicals of anhydrous aspartic acid, but
There are some problems.In high temperature or under conditions of dry for a long time, the water content of bulk pharmaceutical chemicals can be reduced as far as possible, but in drying
Surface is different with the rate of drying of central area in the process, causes drying time long, the appearance of bulk pharmaceutical chemicals can not ensure, i.e. granularity
It controls uneven.Pulverulent solids easily are formed on surface, increases the surface area contacted with external environment, it is made to draw moist increasing
Add.And the present invention using be spray-dried by the way of prepare anhydrous potassium aspartate crude drug, Control granularity in suitable range,
It not only effectively controls drawing for raw material moist, also helps the preparation of tablet.This optimize technique have strong operability, low energy consumption,
The advantages of actual benefit is big.
For the superiority further illustrated the present invention, we will be described in the optimization process of the present invention.
Spray dried form prepares anhydrous potassium aspartate crude drug, and input concentration is investigated first.
Preparation process：Appropriate purified water is added in into Agitation Tank, potassium hydroxide dissolving is added with stirring, according to molar equivalent
1:1 adds in L-aminobutanedioic acid reaction；It adjusts pH values and stirs 30 minutes in the range of 6.5~8.0, adding in 0.1% activated carbon, after taking off charcoal
Purified water is added to appropriate, purifying water consumption is 0.4 times of L-aminobutanedioic acid dosage, 0.6 times, 0.7 times, 0.8 times, 1.0 times, is prepared
Water feed liquid；Water feed liquid is formed into droplet by atomizer and is injected into hothouse, control inlet air temperature is at 240~250 DEG C, outlet air
150-160 DEG C of temperature, atomizer frequency are adjusted to 50Hz, and tower pressure interior force is maintained at -3.0kpa；
Anhydrous potassium aspartate crude drug determination of moisture（With reference to European Pharmacopoeia aspartic acid hydrate determination of moisture method）：
Table 1：Different purified waters prepare anhydrous potassium aspartate crude drug moisture measurement result with L-aminobutanedioic acid amount ratio
| Purified water and L-aminobutanedioic acid amount ratio | 0.4 | 0.6 | 0.7 | 0.8 | 1.0 |
| Moisture | 0.53% | 0.25% | 0.33% | 0.49% | 0.62% |
From the above results：Different feeds concentration has moisture content of finished products certain influence, draws because aspartic acid raw material has
Moist, we set moisture standards as less than 1.0%.Purified water and L-aminobutanedioic acid amount ratio are in the range of 0.4 ~ 1.0, no water valve
Winter propylhomoserin potassium bulk pharmaceutical chemicals moisture inspection meets regulation, and purified water and L-aminobutanedioic acid amount ratio are at 0.6 ~ 0.7, no water valve winter ammonia
Sour potassium bulk pharmaceutical chemicals moisture control is best.
Anhydrous potassium aspartate crude drug granulometry（Crossing sieve method takes sample to be sieved, and is counted with percent of pass）：
Table 2：Different purified waters prepare anhydrous potassium aspartate crude drug particle size results with L-aminobutanedioic acid amount ratio
| Purified water and L-aminobutanedioic acid amount ratio | 0.4 | 0.6 | 0.7 | 0.8 | 1.0 |
| Raw material granularity（60 mesh sieve percent of pass） | 98% | 99% | 100% | 100% | 100% |
| Raw material granularity（80 mesh sieve percent of pass） | 79% | 88% | 87% | 92% | 93% |
| Raw material granularity（100 mesh sieve percent of pass） | 16% | 25% | 28% | 35% | 40% |
Because different feeds concentration has product grading certain influence, we have investigated purified water and have existed with L-aminobutanedioic acid amount ratio
In the range of 0.4 ~ 1.0, the situation of the bulk pharmaceutical chemicals that are spray-dried sieving.From above-mentioned experimental result:It is made under different process
Standby anhydrous potassium aspartate crude drug can all be sieved, and epigranular by 60 mesh, and there is only minute quantity fine powders.To ensure grain
Degree in a certain range, be conducive to L-aminobutanedioic acid potassium tablets preparation, we by bulk pharmaceutical chemicals obtained above respectively cross 80 mesh sieve and
100 mesh sieve, and for purified water with L-aminobutanedioic acid amount ratio in the range of 0.6 ~ 1.0, anhydrous potassium aspartate crude drug 85% passes through 80 mesh
Sieve, and only 25% ~ 40% logical sieves with 100 mesh sieve.It follows that the anhydrous potassium aspartate crude drug granularity prepared under this process conditions
Uniformly, purified water is with L-aminobutanedioic acid amount ratio in the range of 0.6 ~ 1.0, and gained raw material granularity is in 60 ~ 80 mesh.
Spray dried form prepares anhydrous potassium aspartate crude drug, and purified water and L-aminobutanedioic acid amount ratio are determined as
0.6 times, different atomizer frequencies are adjusted, investigate influence of the atomizer frequency to material.
Preparation process：Appropriate purified water is added in into Agitation Tank, potassium hydroxide dissolving is added with stirring, according to molar equivalent
1:1 adds in L-aminobutanedioic acid reaction；It adjusts pH values and stirs 30 minutes in the range of 6.5~8.0, adding in 0.1% activated carbon, after taking off charcoal
Purified water is added to appropriate, purifying water consumption is 0.6 times of L-aminobutanedioic acid dosage and prepares water feed liquid；Water feed liquid is passed through into atomizer
It forms droplet and is injected into hothouse, control inlet air temperature is at 240~250 DEG C, 150-160 DEG C of leaving air temp, atomizer frequency
It adjusts to 30 Hz ~ 50Hz, tower pressure interior force is maintained at -0.2kpa；
Anhydrous potassium aspartate crude drug determination of moisture（With reference to European Pharmacopoeia aspartic acid hydrate determination of moisture method）：
Table 3：Different atomizer frequencies prepare anhydrous potassium aspartate crude drug moisture measurement result
| Atomizer frequency（Hz） | 30 | 35 | 40 | 45 | 50 |
| Moisture | 0.35% | 0.20% | 0.18% | 0.55% | 0.71% |
From the above results：Different atomizer frequencies have moisture content of finished products certain influence, because aspartic acid is wet with drawing
Property, we set moisture standards as less than 1.0%.For atomizer frequency in the range of 30 Hz ~ 50Hz, anhydrous aspartic acid is former
Material liquid medicine sorting, which is looked into, meets regulation, and for atomizer frequency in 35 Hz ~ 40Hz, anhydrous aspartic acid raw material moisture control is most
It is good.
Anhydrous potassium aspartate crude drug granulometry（Crossing sieve method takes sample to be sieved, and is counted with percent of pass）：
Table 4：Different atomizer frequencies prepare anhydrous potassium aspartate crude drug testing graininess result
| Atomizer frequency（Hz） | 30 | 35 | 40 | 45 | 50 |
| Raw material granularity（60 mesh sieve percent of pass） | 99% | 99% | 97% | 100% | 100% |
| Raw material granularity（80 mesh sieve percent of pass） | 85% | 88% | 92% | 95% | 95% |
| Raw material granularity（100 mesh sieve percent of pass） | 33% | 42% | 41% | 45% | 40% |
Because different atomizer frequencies have product grading certain influence, we have investigated atomizer frequency in 30 Hz ~ 50Hz
In the range of, the situation of the bulk pharmaceutical chemicals that are spray-dried sieving.From above-mentioned experimental result:The nothing prepared under different process
Water potassium aspartate crude drug can be sieved all, and epigranular by 60 mesh sieve and 80 mesh, and there is only minute quantity fine powders, ensure grain
Degree is conducive to anhydrous L-aminobutanedioic acid potassium tablets and prepares in the range of the mesh of 60 mesh ~ 80.
In summary moisture as a result, atomizer frequency adjust in the range of 30 Hz ~ 50Hz, preferably 35 Hz ~ 40Hz；
Spray dried form prepares anhydrous potassium aspartate crude drug, investigates influence of the atomizer tower pressure interior force to material.
Preparation process：Appropriate purified water is added in into Agitation Tank, potassium hydroxide dissolving is added with stirring, according to molar equivalent
1:1 adds in L-aminobutanedioic acid reaction；It adjusts pH values and stirs 30 minutes in the range of 6.5~8.0, adding in 0.1% activated carbon, after taking off charcoal
Purified water is added to appropriate, purifying water consumption is 0.6 times of L-aminobutanedioic acid dosage and prepares water feed liquid；Water feed liquid is passed through into atomizer
It forms droplet and is injected into hothouse, control inlet air temperature is at 240~250 DEG C, 150-160 DEG C of leaving air temp, atomizer frequency
It adjusts to 30 Hz, tower pressure interior force is maintained at -3.0 ~ -0.1kpa；
Anhydrous potassium aspartate crude drug determination of moisture（With reference to European Pharmacopoeia aspartic acid hydrate determination of moisture method）：
Table 5：Different tower pressure interior forces prepare anhydrous potassium aspartate crude drug moisture measurement result
| Tower pressure interior force（kpa） | -3.0 | -2.5 | -2.0 | -1.5 | -1.0 |
| Moisture | 0.17% | 0.15% | 0.35% | 0.55% | 0.70% |
From the above results：Different tower pressure interior forces have moisture content of finished products certain influence, because aspartic acid is moist with drawing,
We set moisture standards as less than 1.0%.Tower pressure interior force is in the range of -3.0 ~ -0.1kpa, anhydrous potassium aspartate crude drug
Moisture inspection meets regulation, and tower pressure interior force is in the range of -3.0 ~ -2.5kpa, and anhydrous aspartic acid raw material moisture control is most
It is good, but negative pressure is higher, and higher to equipment requirement, equipment consume is also bigger, so tower pressure interior force preferably -2.5kpa.
The superiority further illustrated the present invention by the following examples, but not as the limitation of the present invention：
Embodiment one：
Appropriate purified water is added in into Agitation Tank, the dissolving of 80kg potassium hydroxide is added with stirring, according to molar equivalent 1:1 adds in door
Winter propylhomoserin reacts；PH values are adjusted to 6.5,0.1% activated carbon of addition stirs 30 minutes, and purified water is added to 384kg after de- charcoal, pure
Change 0.6 times that water consumption is L-aminobutanedioic acid dosage and prepare water feed liquid；By water feed liquid by atomizer formed droplet be injected into it is dry
Dry room, at 240 DEG C, 150 DEG C of leaving air temp, atomizer frequency is adjusted to 40Hz control inlet air temperature, and tower pressure interior force is maintained at-
0.25kpa；It discharges after spray drying, obtains finished product 228kg, yield 93.4%.
Embodiment two：
Appropriate purified water is added in into Agitation Tank, the dissolving of 80kg potassium hydroxide is added with stirring, according to molar equivalent 1:1 adds in door
Winter propylhomoserin reacts；PH values are adjusted to 8.0,0.1% activated carbon of addition stirs 30 minutes, and purified water is added to 460kg after de- charcoal, pure
Change 1.0 times that water consumption is L-aminobutanedioic acid dosage and prepare water feed liquid；By water feed liquid by atomizer formed droplet be injected into it is dry
Dry room, at 250 DEG C, 160 DEG C of leaving air temp, atomizer frequency is adjusted to 50Hz control inlet air temperature, and tower pressure interior force is maintained at-
0.1kpa；It discharges after spray drying, obtains finished product 220kg, yield 90.2%.
Embodiment three：
Appropriate purified water is added in into Agitation Tank, the dissolving of 80kg potassium hydroxide is added with stirring, according to molar equivalent 1:1 adds in door
Winter propylhomoserin reacts；PH values are adjusted to 7.0,0.1% activated carbon of addition stirs 30 minutes, and purified water is added to 346kg after de- charcoal, pure
Change 0.4 times that water consumption is L-aminobutanedioic acid dosage and prepare water feed liquid；By water feed liquid by atomizer formed droplet be injected into it is dry
Dry room, at 250 DEG C, 150 DEG C of leaving air temp, atomizer frequency is adjusted to 35Hz control inlet air temperature, and tower pressure interior force is maintained at-
0.3kpa；It discharges after spray drying, obtains finished product 222kg, yield 91.0%.
Example IV：
Appropriate purified water is added in into Agitation Tank, the dissolving of 80kg potassium hydroxide is added with stirring, according to molar equivalent 1:1 adds in door
Winter propylhomoserin reacts；PH values are adjusted to 7.5,0.1% activated carbon of addition stirs 30 minutes, and purified water is added to 403kg after de- charcoal, pure
Change 0.7 times that water consumption is L-aminobutanedioic acid dosage and prepare water feed liquid；By water feed liquid by atomizer formed droplet be injected into it is dry
Dry room, at 255 DEG C, 155 DEG C of leaving air temp, atomizer frequency is adjusted to 30Hz control inlet air temperature, and tower pressure interior force is maintained at-
0.2kpa；It discharges after spray drying, obtains finished product 224kg, yield 91.8%.
Embodiment five：
The anhydrous potassium aspartate crude drug prepared using embodiment one prepares tablet, is mixed with appropriate auxiliary material, after sieving directly
Tabletting obtains label, and aspartic acid piece is made after the coating of label coating solution.
Claims (7)
1. a kind of preparation method of anhydrous potassium aspartate crude drug, which is characterized in that nothing is prepared using the method for spray drying
Water potassium aspartate crude drug, granularity is in 60~80 mesh.
2. preparation method described in claim 1, is as follows：
（1）Appropriate purified water is added in into Agitation Tank, potassium hydroxide dissolving is added with stirring, according to molar equivalent 1:1 adds in door
Winter propylhomoserin reacts；
（2）It adjusts pH values and stirs 30 minutes in the range of 6.5~8.0, adding in 0.1% activated carbon, purified water is added extremely after de- charcoal
In right amount, water feed liquid is prepared；
（3）Water feed liquid is formed into droplet by atomizer and is injected into hothouse, control inlet air temperature is at 240~250 DEG C, outlet air
150-160 DEG C of temperature, atomizer frequency are adjusted to 30~50Hz, and tower pressure interior force is maintained at -3.0~-0.1kpa.
3. preparation method described in claim 2, it is characterised in that purifying water consumption is 0.4~1.0 times of L-aminobutanedioic acid dosage, excellent
Select 0.6~0.7 times.
4. preparation method described in claim 2, it is characterised in that adjusting atomizer frequency to 30~50Hz, preferably 35~40Hz.
5. preparation method described in claim 2, it is characterised in that tower pressure interior force is kept in -3.0~-0.1kpa, preferably -
2.5kpa。
6. the tablet prepared as the anhydrous potassium aspartate crude drug prepared by claim 1, preparation process are characterized in that
Tablet is prepared by the way of direct tablet compressing.
7. preparation process described in claim 6, it is characterised in that after anhydrous aspartic acid is mixed with appropriate auxiliary material, after sieving
Direct tablet compressing obtains label, and aspartic acid piece is made after the coating of label coating solution.
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| CN111302964A (en) * | 2018-12-11 | 2020-06-19 | 赵紫岭 | Novel stable crystal of potassium L-aspartate and preparation method thereof |
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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2017
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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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302964A (en) * | 2018-12-11 | 2020-06-19 | 赵紫岭 | Novel stable crystal of potassium L-aspartate and preparation method thereof |
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