CN114773251B - L-tryptophan spherical crystal and preparation method and application thereof - Google Patents
L-tryptophan spherical crystal and preparation method and application thereof Download PDFInfo
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- CN114773251B CN114773251B CN202210294977.3A CN202210294977A CN114773251B CN 114773251 B CN114773251 B CN 114773251B CN 202210294977 A CN202210294977 A CN 202210294977A CN 114773251 B CN114773251 B CN 114773251B
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- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 title claims abstract description 169
- 229960004799 tryptophan Drugs 0.000 title claims abstract description 86
- 239000013078 crystal Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 99
- 239000011259 mixed solution Substances 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000007788 liquid Substances 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 8
- 230000008025 crystallization Effects 0.000 claims abstract description 8
- 239000003929 acidic solution Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims 2
- 238000004090 dissolution Methods 0.000 claims 1
- 239000012798 spherical particle Substances 0.000 abstract description 58
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 abstract description 3
- 238000007441 Spherical agglomeration method Methods 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- 238000009827 uniform distribution Methods 0.000 abstract description 2
- 239000002245 particle Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 12
- 238000010998 test method Methods 0.000 description 9
- 238000009826 distribution Methods 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 5
- 238000005054 agglomeration Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000003674 animal food additive Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004581 coalescence Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 230000006911 nucleation Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- OTTFEJLDNFEPGG-UHFFFAOYSA-N 2-amino-2-(1h-indol-2-yl)propanoic acid Chemical compound C1=CC=C2NC(C(N)(C(O)=O)C)=CC2=C1 OTTFEJLDNFEPGG-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- -1 CN 104926709A Chemical compound 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
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- 238000005286 illumination Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- 239000000932 sedative agent Substances 0.000 description 1
- 230000003860 sleep quality Effects 0.000 description 1
- 239000002438 stress hormone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000003746 surface roughness Effects 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/142—Amino acids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Polymers & Plastics (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Food Science & Technology (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
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- Nutrition Science (AREA)
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Abstract
The invention provides an L-tryptophan spherical crystal, and a preparation method and application thereof, wherein the preparation method comprises the following steps: (1) Dissolving an L-tryptophan raw material in an acidic solution at 20-50 ℃ to obtain a mixed solution; (2) Adding ethyl acetate into the mixed solution obtained in the step (1) to obtain a mixed solution in which spherical liquid drops are dispersed; (3) Adding alkali liquor into the mixed solution with the spherical liquid drops dispersed in the step (2) until the pH reaches the vicinity of the isoelectric point of the L-tryptophan, and keeping for 0.5-2.5h to obtain spherical crystals of the L-tryptophan; the L-tryptophan prepared by the method has regular shape, adjustable size, uniform distribution and good fluidity; by combining isoelectric point crystallization and spherical agglomeration technology, the good wettability of ethyl acetate to L-tryptophan is utilized, so that the L-tryptophan is crystallized and agglomerated into spherical particles. The preparation method is simple, the raw materials are easy to obtain, the price is low, and the preparation method is easy to realize.
Description
Technical Field
The invention belongs to the technical field of industrial crystallization, and relates to an L-tryptophan spherical crystal, a preparation method and application thereof.
Background
L-tryptophan is also known as alpha-aminoindolyl propionic acid, and has a molecular formula of C 11H12N2O2, white to yellowish white crystals or crystalline powder. No or little odor, and coloring after long-time illumination. Is stable to heating in the dark with acid. Is extremely easy to decompose when coexisting with other amino acids, saccharides and aldehydes. L-tryptophan is commonly found in high-protein foods, is one of essential amino acids of human bodies, and is widely applied to industries such as medicines, foods, feed additives, agricultural environment detection and the like at present. Naturally occurring tryptophan contributes to the production of serotonin, and its health benefits include: helps promote sleep, relieves anxiety and depression, improves emotional well-being, and can also help control pain tolerance. Tryptophan also has natural sedative effect, and can help to improve sleep quality and overall health.
Studies have shown that tryptophan can be converted to sedative serotonin in the brain, allowing other essential amino acids to function better. This, in turn, can help control mood and reduce the production of stress hormones. In recent years, along with rapid development of domestic feed industry and more deep research on L-tryptophan and metabolites thereof, especially along with continuous aggravation of the aging degree of China, the application of the L-tryptophan in the pharmaceutical industry is also continuously expanded, and the L-tryptophan gradually becomes a product with huge international market development potential and larger domestic market demand.
L-tryptophan obtained by the traditional crystallization mode is flaky crystal or crystalline powder with poor crystal habit, and the crystal has irregular shape, uneven size and poor fluidity, so that the processing efficiency of downstream products is affected, and the processing cost is increased. Although many patents attempt to improve the crystallization process of L-tryptophan, such as CN 104926709A, CN106986808a, the foothold is often to increase the purity and yield of the product, neglecting the important impact of the product crystal habit on subsequent processing.
Therefore, the preparation method of the spherical L-tryptophan is designed, so that the spherical L-tryptophan particles with regular shape, adjustable size, uniform distribution and good fluidity are prepared.
Disclosure of Invention
Aiming at the problems of irregular shape, uneven size, poor fluidity and the like of an L-tryptophan product, the invention aims to provide a method for preparing spherical L-tryptophan particles which are regular in shape, adjustable in size, uniform in distribution and good in fluidity. By combining isoelectric point crystallization and spherical agglomeration technology, the good wettability of ethyl acetate to L-tryptophan is utilized, so that the L-tryptophan is crystallized and agglomerated into spherical particles. The spherical particles are compact in size, adjustable in size, uniform in size distribution and good in fluidity; the preparation method has the advantages of simple process, easily available raw materials, low cost and easy realization.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
One of the purposes of the invention is to provide a preparation method of an L-tryptophan spherical crystal, which comprises the following steps:
(1) Dissolving L-tryptophan raw material in an acidic solution at 20-50deg.C (such as 20deg.C, 22deg.C, 25deg.C, 30deg.C, 33deg.C, 36deg.C, 40deg.C, 47 deg.C, 50deg.C, etc.), to obtain a mixed solution;
(2) Adding ethyl acetate into the mixed solution obtained in the step (1) to obtain a mixed solution in which spherical liquid drops are dispersed;
(3) Adding alkali liquor into the mixed solution with the spherical liquid drops dispersed in the step (2) until the pH reaches the vicinity of the isoelectric point of the L-tryptophan, and maintaining for 0.5-2.5h (such as 0.5h、0.6h、0.7h、0.8h、0.9h、1.0h、1.1h、1.2h、1.3h、1.4h、1.5h、1.6h、1.7h、1.8h、1.9h、2.0h、2.1h、2.2h、2.3h、2.4h、2.5h and the like) to obtain the spherical crystal of the L-tryptophan.
The preparation method has the advantages of simple process, easily available raw materials, low price and easy realization; the prepared spherical product has compact particles, adjustable size, uniform size distribution and good fluidity.
Preferably, the acidic solution in step (1) includes, but is not limited to, hydrochloric acid, nitric acid, formic acid, acetic acid, preferably with a concentration of 1-1.8wt% hydrochloric acid solution, e.g. 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8% by mass, etc.
Preferably, the concentration of L-tryptophan in the mixed solution in step (1) is 0.04-0.1mg/L, such as 0.04g/mL, 0.05g/mL, 0.06g/mL, 0.07g/mL, 0.08g/mL, 0.09g/mL, 0.10g/mL, etc. The concentration of the L-tryptophan is moderate, so that the L-tryptophan is favorable for keeping proper supersaturation; when the supersaturation degree is lower, the crystal precipitation is slower, and the spherical product is easily not compact; when the supersaturation degree is higher, small crystals are formed by rapid nucleation, and are more easily agglomerated into balls, but the surface roughness of the spherical product is easily caused, and the fluidity is reduced.
Preferably, the dissolving of step (1) is performed under stirring conditions at a rate of 400-600rpm (e.g., 400rpm, 420rpm, 450rpm, 480rpm, 500rpm, 520rpm, 550rpm, 580rpm, 600rpm, etc.) for a period of 10-30min (e.g., 10min, 12min, 15min, 18min, 20min, 22min, 25min, 28min, 30min, etc.).
Preferably, the ethyl acetate of step (2) is added in a volume of 0.8 to 1.3mL (e.g., 0.8mL, 0.9mL, 1mL, 1.1mL, 1.2mL, 1.3mL, etc.), preferably 0.9 to 1.2mL, based on 1mL of the added volume of the L-tryptophan feedstock; if the addition amount of ethyl acetate is small, the ethyl acetate cannot wet and coat all L-tryptophan crystals, so that the final effect of not forming balls or forming partial crystals is achieved; if ethyl acetate is added in a large amount, the excessive ethyl acetate will cause the L-tryptophan crystals to become sticky and cannot be formed into balls.
Preferably, the addition of ethyl acetate in step (2) is performed under stirring conditions at a rate of 200-600rpm (e.g., 200rpm, 210rpm, 230rpm, 250rpm, 300rpm, 360rpm, 370rpm, 400rpm, 480rpm, 490rpm, 500rpm, 550rpm, 600rpm, etc.) for a period of 5-20min (e.g., 5min, 8min, 10min, 12min, 15min, 18min, 20min, etc.). If the stirring speed is too high in the stirring process, spherical liquid drops formed by the ethyl acetate are smaller, and finally spherical particles are smaller or cannot be obtained; if the stirring rate is too low, ethyl acetate cannot be uniformly dispersed, and spherical particles cannot be finally obtained.
Preferably, the lye of step (3) includes, but is not limited to, sodium hydroxide solution or potassium hydroxide solution.
Preferably, the lye of step (3) is added at a rate of 1-3mL/min (e.g., 1.0mL/min、1.1mL/min、1.3mL/min、1.8mL/min、2.0mL/min、2.2mL/min、2.4mL/min、2.5mL/min、2.6mL/min、2.9mL/min、3.0mL/min, etc.), preferably 1.5-2.5mL/min; the dropping speed of the alkali liquor influences the duration time of the supersaturation degree, and the supersaturation degree is increased instantaneously when the dropping speed is higher, so that the crystal nucleation process is facilitated. And correspondingly the duration of supersaturation, i.e. the crystal coalescence time, is reduced, both of which lead to a reduction in the size of the final spherical product. Thus, an increased lye addition rate reduces the size of the spherical particles.
Preferably, the lye addition of step (3) is performed under stirring conditions at a stirring rate of 200-600rpm, e.g. 200rpm, 210rpm, 230rpm, 250rpm, 300rpm, 360rpm, 370rpm, 400rpm, 480rpm, 490rpm, 500rpm, 550rpm, 600rpm, etc. Stirring plays an important role in the particle size, particle size distribution and shape of the agglomerates by inducing collisions and redispersions between the particles. Stirring has two important roles, one is to fully mix the system and disperse the bridging agent into uniform droplets; another is to provide shear forces to shape the spherical product. Properly increasing the stirring speed promotes agglomerate collisions, which significantly increases agglomerate growth. However, excessive agitation can also lead to disruption of the coalescence and disruption of the agglomerates. Therefore, if the stirring time is too short, the sphericity of the product is low, and if the stirring time is too long, the spherical particles are broken.
Preferably, the isoelectric point of L-tryptophan in step (3) is 5.89 and the titration endpoint of the pH is 3-8 (e.g., 3.0, 3.2, 3.5, 4.0, 4.6, 4.8, 5.0, 5.9, 6.0, 6.3, 6.8, 7.0, 7.5, 8.0, etc.), preferably 5-6.5, wherein the solubility of L-tryptophan is minimal and crystals are most precipitated when the titration of the pH is at about 5.89.
Preferably, the step (3) further comprises sequentially performing solid-liquid separation and drying on the mixture obtained by crystallization after adding the alkali liquor.
Preferably, the solid-liquid separation is performed by filtration.
Preferably, the drying temperature is 30-50deg.C (e.g. 30deg.C, 33deg.C, 36deg.C, 40deg.C, 47deg.C, 50deg.C, etc.), and the drying time is 20-40min (e.g. 20min, 22min, 25min, 28min, 30min, 32min, 35min, 38min, 40min, etc.).
The second purpose of the invention is to prepare the spherical crystal of L-tryptophan according to the preparation method of the first purpose.
Preferably, the average particle size of the spherical crystals of L-tryptophan is 300 to 3000. Mu.m, for example 300. Mu.m, 400. Mu.m, 800. Mu.m, 1000. Mu.m, 1500. Mu.m, 1700. Mu.m, 1900. Mu.m, 2000. Mu.m, 2300. Mu.m, 2600. Mu.m, 3000. Mu.m, etc.
Preferably, the L-tryptophan spherical crystals have a purity of higher than 99.0%, such as 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, etc. Purity was determined by high performance liquid chromatography (model Waters e-2695, waters, america) and the relevant assay standard was determined according to the method of the chinese pharmacopoeia (2015).
Preferably, the sphericity of the L-tryptophan spherical crystals is 75-100%, such as 75%, 78%, 80%, 82%, 85%, 89%, 90%, 92%, 97%, 99%, etc. Sphericity was determined by a particle size and shape analyzer (Occhio Instruments-Calisto 3D 1.7, belgium).
Preferably, the angle of repose of the spherical crystal of L-tryptophan is 20-30, e.g., 20 °, 21 °, 22 °, 23 °, 24 °, 25 °, 26 °, 27 °, 28 °, 29 °,30 °, etc. The repose angle is measured by using a BT-1000 powder comprehensive property tester, and the test standard of the repose angle is GB/T11986-1989.
It is another object of the present invention to provide a spherical crystal of L-tryptophan as defined in the second object for use in the preparation of a pharmaceutical, food or feed additive.
Compared with the prior art, the invention has the following beneficial effects:
1) The L-tryptophan prepared by the method is spherical with regular shape, has high sphericity of 75-100%, has good flow property, provides better conditions for subsequent treatment (such as filtration, screening, tabletting and the like) of the L-tryptophan product, can reduce equipment investment of post-treatment, reduces cost and improves production efficiency.
2) The size of the L-tryptophan prepared by the method can be regulated and controlled, and the same batch of products are uniform in size, so that the products with proper sizes can be conveniently prepared according to the requirements.
3) The method combines crystallization and granulation in the same operation unit, and has low energy consumption, simple process and high efficiency compared with the traditional granulation process.
4) The spherical particle product obtained by the method has better filling property, compression formability and stability, and can be directly pressed into tablets, thereby greatly reducing the industrialization cost.
Drawings
Fig. 1: scanning electron microscope images of the spherical particles of L-tryptophan;
fig. 2: scanning electron microscope images of the L-tryptophan raw material;
fig. 3: XRD pattern of L-tryptophan feedstock and spherical particles;
fig. 4: a standard curve of high performance liquid chromatography of L-tryptophan;
Fig. 5: particle size distribution and roundness profile of the product of example 1.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It should be apparent to those skilled in the art that the examples are merely provided to aid in understanding the present invention and should not be construed as limiting the invention in any way.
Example 1:
(1) Preparing a mixed solution of L-tryptophan and dilute hydrochloric acid at 25 ℃, wherein the mass fraction of the dilute hydrochloric acid is 1.38%; the concentration of L-tryptophan in the mixed solution is 0.06g/mL;
(2) Stirring the mixed solution in the step (1) for 10min at 20 ℃ to fully dissolve the L-tryptophan;
(3) Adding 12mL of ethyl acetate solution into the mixed solution obtained in the step (2), and stirring for 5min at a rotation speed of 400rpm to uniformly disperse the ethyl acetate into spherical liquid drops;
(4) Maintaining the rotation speed of 400rpm, and dropwise adding sodium hydroxide solution into the mixed solution obtained in the step (3) at the speed of 2mL/min until the PH reaches 6.0; the crystals of L-tryptophan are gradually separated out, and spherical particles are formed under the action of ethyl acetate;
(5) Stirring for 1h at 400rpm to obtain compact spherical particles with good sphericity;
(6) And (3) carrying out suction filtration on the mixed solution in the step (5), drying the obtained spherical particles at 40 ℃ for 30min, and storing the spherical particles in a dark and dry environment.
The scanning electron microscope (Hitachi-TM 3000, japan) of the spherical particle product (product) of L-tryptophan is shown in FIG. 1, and the crystal morphology is greatly improved compared with the raw material of L-tryptophan (FIG. 2).
Powder X-ray diffraction (Rigaku D/max-2500, rigaku, japan) tests were performed on the raw material of L-tryptophan and the spherical particles, as shown in FIG. 3, and the XRD patterns of the raw material of L-tryptophan and the spherical particles were consistent, which showed that the L-tryptophan did not deteriorate during the preparation of the spherical particles.
The spherical particles of L-tryptophan obtained in this example were subjected to purity testing by high performance liquid chromatography (Waters e-2695, waters, america) and the standard curve is shown in FIG. 4, and the purity of the spherical particles in example 1 was calculated to be 99.672%.
The particle size distribution and sphericity distribution of the spherical particles of L-tryptophan were determined using a particle size and shape analyzer (Occhio Instruments-Calisto 3D 1.7, belgium), as shown in FIG. 5. The average particle diameter of the spherical particles in example 1 was 2564.893 μm and the average sphericity was 89.318%.
The angle of repose of spherical particles of L-tryptophan was measured using a BT-1000 type powder comprehensive property tester and was found to be 29.
Example 2:
The difference from example 1 was that the stirring rate in steps (3), (4) and (5) was 500rpm, and the other preparation methods were the same as in example 1.
The spherical particles of L-tryptophan obtained in this example were subjected to the same test method as in example 1, and it was found that the purity of the obtained spherical particles was 99.522%, the average particle diameter was 2090.971. Mu.m, the average sphericity was 88.966%, and the angle of repose was 28 °.
Example 3:
The difference from example 1 was that the stirring rate in steps (3), (4) and (5) was 600rpm, and the other preparation methods were the same as in example 1.
The spherical particles of L-tryptophan obtained in this example were subjected to the same test method as in example 1, and it was found that the purity of the obtained spherical particles was 99.572%, the average particle diameter was 1622.632. Mu.m, the average sphericity was 91.186%, and the angle of repose was 26 °.
As is evident from the comparison of examples 1 to 3, the size of the spherical particles finally obtained was gradually reduced with an increase in stirring rate at the time of agglomeration. This is because a high stirring rate provides a greater resistance to agglomeration, making agglomeration between crystals more difficult and thus smaller agglomerates.
Example 4:
(1) Preparing a mixed solution of L-tryptophan and dilute hydrochloric acid at 25 ℃, wherein the mass fraction of the dilute hydrochloric acid is 1.42%; the concentration of L-tryptophan in the mixed solution is 0.08g/mL;
(2) Stirring the mixed solution in the step (1) for 10min at 20 ℃ to fully dissolve the L-tryptophan;
(3) Adding 9mL of ethyl acetate solution into the mixed solution obtained in the step (2), and stirring for 5min at a rotating speed of 500rpm to uniformly disperse the ethyl acetate into spherical liquid drops;
(4) Maintaining the rotating speed of 500rpm, and dropwise adding sodium hydroxide solution into the mixed solution obtained in the step (3) at the speed of 2mL/min until the PH reaches 6.0; the crystals of L-tryptophan are gradually separated out, and spherical particles are formed under the action of ethyl acetate;
(5) Stirring for 1h at 500rpm to obtain compact spherical particles with good sphericity;
(6) And (3) carrying out suction filtration on the mixed solution in the step (5), drying the obtained spherical particles at 40 ℃ for 30min, and storing the spherical particles in a dark and dry environment.
The spherical particles of L-tryptophan obtained in this example were subjected to the same test method as in example 1, and it was found that the purity of the obtained spherical particles was 99.632%, the average particle diameter was 855.529. Mu.m, the average sphericity was 84.686%, and the angle of repose was 30 °.
Example 5:
the difference from example 4 was that the amount of ethyl acetate added in step (2) was 10.5mL, and the other preparation methods were the same as in example 4.
The spherical particles of L-tryptophan obtained in this example were subjected to the same test method as in example 1, and it was found that the purity of the obtained spherical particles was 99.593%, the average particle diameter was 1294.191. Mu.m, the average sphericity was 89.318%, and the angle of repose was 27 °.
Example 6:
the difference from example 4 was that the amount of ethyl acetate added in step (2) was 11mL, and the other preparation methods were the same as in example 4.
The spherical particles of L-tryptophan obtained in this example were subjected to the same test method as in example 1, and it was found that the purity of the obtained spherical particles was 99.733%, the average particle diameter was 1697.897. Mu.m, the average sphericity was 86.716%, and the angle of repose was 30 °.
As can be seen from a comparison of examples 4-6, as the amount of ethyl acetate increases, the size of the final spherical particles also increases. This is because, as ethyl acetate increases, spherical droplets of ethyl acetate are formed in a larger size, the number of crystals that can be coated is large, and finally spherical particles of a larger size can be obtained.
Example 7:
(1) Preparing a mixed solution of L-tryptophan and dilute hydrochloric acid at 25 ℃, wherein the mass fraction of the dilute hydrochloric acid is 1.68%; the concentration of L-tryptophan in the mixed solution is 0.10g/mL;
(2) Stirring the mixed solution in the step (1) for 10min at 20 ℃ to fully dissolve the L-tryptophan;
(3) Adding 10mL of ethyl acetate solution into the mixed solution obtained in the step (2), and stirring for 5min at a rotating speed of 500rpm to uniformly disperse the ethyl acetate into spherical liquid drops;
(4) Maintaining the rotating speed of 500rpm, and dropwise adding sodium hydroxide solution into the mixed solution obtained in the step (3) at the speed of 1mL/min until the PH reaches 6.0; the crystals of L-tryptophan are gradually separated out, and spherical particles are formed under the action of ethyl acetate;
(5) Stirring for 1h at 500rpm to obtain compact spherical particles with good sphericity;
(6) And (3) carrying out suction filtration on the mixed solution in the step (5), drying the obtained spherical particles at 40 ℃ for 30min, and storing the spherical particles in a dark and dry environment.
The spherical particles of L-tryptophan obtained in this example were subjected to the same test method as in example 1, and it was found that the purity of the obtained spherical particles was 99.572%, the average particle diameter was 1101.802. Mu.m, the average sphericity was 87.306%, and the angle of repose was 29 °.
Example 8:
The difference from example 7 is that the dropping rate of sodium hydroxide in step (4) was 2mL/min, and the other preparation methods were the same as in example 7.
The spherical particles of L-tryptophan obtained in this example were subjected to the same test method as in example 1, and it was found that the purity of the obtained spherical particles was 99.482%, the average particle diameter was 1062.484. Mu.m, the average sphericity was 84.954%, and the angle of repose was 28 °.
Example 9:
The difference from example 7 is that the dropping rate of sodium hydroxide in step (4) was 3mL/min, and the other preparation methods were the same as in example 7.
The spherical particles of L-tryptophan obtained in this example were subjected to the same test method as in example 1, and it was found that the purity of the obtained spherical particles was 99.658%, the average particle diameter was 1047.989. Mu.m, the average sphericity was 81.817%, and the angle of repose was 30 °.
As can be seen from a comparison of examples 7-9, the size of the final spherical particles was slightly reduced as the dropping rate of sodium hydroxide was increased. Because the increased rate of addition will allow the solution to quickly reach supersaturation and the duration of supersaturation to be reduced, i.e. the agglomeration time, will be reduced, resulting in a reduction in the size of the final product.
Comparative example 1:
The difference from example 1 was that the amount of ethyl acetate added in step (2) was 14mL, and the other preparation methods were the same as in example 1.
No spherical particles of L-tryptophan were obtained in this comparative example, and the crystals became a sticky morphology.
As is clear from comparative examples 1 and 1, the addition of ethyl acetate in an amount exceeding the range defined in the present invention resulted in the crystals being relatively viscous and forming a paste-like morphology, and not being agglomerated into spherical particles.
Comparative example 2:
the difference from example 1 was that the stirring rate in steps (3), (4) and (5) was 800rpm, and the other preparation methods were the same as in example 1.
In this comparative example, the crystals of L-tryptophan were not agglomerated to obtain crystalline powder.
As is clear from comparative examples 1 and 2, stirring rates exceeding the range defined by the present invention resulted in the formation of spherical droplets of ethyl acetate too small to achieve wetting and coating of L-tryptophan crystals, and eventually no spherical particles were obtained.
Comparative example 3:
the difference from example 1 was only that the titration end point of pH in step (4) was 8.5, and the other preparation methods were the same as in example 1.
No spherical particles of L-tryptophan were obtained in this comparative example, and the crystals became a sticky morphology.
As is clear from comparative examples 1 and 3, when the pH titration end point is out of the range defined in the present invention, the number of precipitated crystals is small, and the crystals form a paste-like morphology due to an excessive amount of ethyl acetate.
Comparative example 4:
the difference from example 1 is that the stirring time in step (5) is 5 hours, and the other preparation methods are the same as example 1.
The spherical particles of L-tryptophan obtained in this comparative example were subjected to the same test method as in example 1, and it was found that the average sphericity of the obtained spherical particles was 65.331% and the angle of repose was 48 °.
As is clear from comparative examples 1 and 4, when the stirring period exceeds the limit of the present invention, the spherical particles are broken, resulting in a decrease in average sphericity and an increase in angle of repose.
The applicant declares that the above is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that are easily conceivable within the technical scope of the present invention disclosed by the present invention fall within the scope of the present invention and the disclosure.
Claims (6)
1. A method for preparing an L-tryptophan spherical crystal, comprising the steps of:
(1) Dissolving an L-tryptophan raw material in an acidic solution at 20-50 ℃ to obtain a mixed solution;
(2) Adding ethyl acetate into the mixed solution obtained in the step (1) to obtain a mixed solution in which spherical liquid drops are dispersed;
(3) Adding alkali liquor into the mixed solution with the spherical liquid drops dispersed in the step (2) until the pH value reaches 3-8, and keeping for 0.5-2.5h to obtain L-tryptophan spherical crystals;
The adding volume of the ethyl acetate in the step (2) is 0.8-1.3mL based on the adding volume of the L-tryptophan raw material being 1 mL; the ethyl acetate is added in the step (2) under stirring, wherein the stirring speed is 200-600rpm, and the stirring time is 5-20min;
The concentration of L-tryptophan in the mixed solution in the step (1) is 0.04-0.1mg/L;
the adding rate of the alkali liquor in the step (3) is 1-3mL/min;
The alkali liquor is added in the step (3) under the stirring condition, and the stirring speed is 200-600rpm.
2. The method of claim 1, wherein the acidic solution in step (1) is hydrochloric acid, nitric acid, formic acid, or acetic acid.
3. The process according to claim 1, wherein the dissolution in step (1) is carried out under stirring conditions at a rate of 400 to 600rpm for a period of 10 to 30 minutes.
4. The method according to claim 1, wherein the alkaline solution in the step (3) is a sodium hydroxide solution or a potassium hydroxide solution.
5. The process according to claim 4, wherein the alkaline solution is added in step (3) at a rate of 1.5 to 2.5mL/min.
6. The method according to claim 1, wherein the step (3) further comprises sequentially subjecting the mixture obtained by crystallization after addition of the alkali solution to solid-liquid separation and drying;
The solid-liquid separation mode is suction filtration;
the drying temperature is 30-50deg.C, and the drying time is 20-40min.
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