WO2006001345A1 - Cristal de sel de l-lysine·acide citrique - Google Patents

Cristal de sel de l-lysine·acide citrique Download PDF

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Publication number
WO2006001345A1
WO2006001345A1 PCT/JP2005/011557 JP2005011557W WO2006001345A1 WO 2006001345 A1 WO2006001345 A1 WO 2006001345A1 JP 2005011557 W JP2005011557 W JP 2005011557W WO 2006001345 A1 WO2006001345 A1 WO 2006001345A1
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WO
WIPO (PCT)
Prior art keywords
lysine
aqueous solution
crystal
crystals
organic solvent
Prior art date
Application number
PCT/JP2005/011557
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English (en)
Japanese (ja)
Inventor
Hideki Murata
Yu Yamamoto
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to JP2006528600A priority Critical patent/JP4796493B2/ja
Publication of WO2006001345A1 publication Critical patent/WO2006001345A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid

Definitions

  • the present invention relates to crystals of L-lysine and a salt (L-lysine 'citrate) having citrate power and a method for producing the same.
  • L-Lysine is one of the essential amino acids and is widely used for nutritional supplements and pharmaceuticals. L-lysine is also used as a feed additive because it is a restricted amino acid in feed corn.
  • L-lysine is usually distributed in the form of salt such as hydrochloride (Sigma Product Catalog 2004-2005 edition).
  • L-lysine When L-lysine is used as a component such as an infusion solution for the purpose of nutrition intake, for example, if hydrochloride is used as it is, it may cause acidosis symptoms. In addition, administration of an infusion solution containing a large amount of chloride ions is preferable particularly for patients with renal diseases. Furthermore, when L-lysine is mixed with food as a nutritional supplement or used as it is orally, it is well known that, for example, hydrochloride is difficult to use due to its bitter taste.
  • Patent Document 1 Japanese Patent Laid-Open No. 62-174043
  • Patent Document 2 JP-A-55-69546
  • Patent Document 3 JP 2003-144088
  • Non-Patent Document 1 “Acta Crystallographica, Section B: Structural Crystallography and Crystal Chemistry”, 1976, p. 891, p. 891
  • An object of the present invention is to provide a crystal of L-lysine 'citrate excellent as a source of L-lysine and a method for producing the same.
  • the present invention relates to the following (1) to (11).
  • hydrophilic organic solvent is an alcohol organic solvent, an amide solvent, acetone, or acetonitrile.
  • the hydrophilic organic solvent is methanol, ethanol, propanol, isopropyl alcohol, butanol, ethylene glycol, diethylene glycol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetone, and acetone.
  • L-lysine 'citrate crystals excellent as a source of L-lysine and a method for producing the same are provided.
  • FIG. 1 shows the results of a hygroscopicity test of the L-lysine 1 ⁇ 2 citrate crystals obtained in Example 1.
  • the horizontal axis shows the number of days (days) since the start of the test, and the vertical axis shows the moisture absorption (%).
  • the crystal of L-lysine 'citrate of the present invention is preferably composed of 0.5 to 3 moles of L-lysine and 1 mole of citrate, and more preferably 2 moles of L-lysine and 1 mole of L-lysine. Consists of citrate.
  • the aqueous solution is also acidic in neutrality, and in a 5 wt% aqueous solution, ⁇ is 3 to 7, preferably 3 to 6, more preferably 4.5 to 5.5, most preferably 4.8 to 5.0. Indicates.
  • the crystal usually exists alone, but can also exist as a solvate with water or various organic solvents, and these solvates are also encompassed in the present invention.
  • hydrophilic organic solvent used in the present invention examples include alcohol-based organic solvents such as methanol, ethanol, phenol, isopropyl alcohol, butanol, ethylene glycolanol, and diethylene glycol, ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylformamide, ⁇ , ⁇ ⁇ ⁇ Organic solvents such as dimethylacetamide and ⁇ ⁇ ⁇ -methylpyrrolidone, acetonitrile, acetone and the like are preferable, and methanol, ethanol and the like are preferable, and these are used alone or in combination.
  • alcohol-based organic solvents such as methanol, ethanol, phenol, isopropyl alcohol, butanol, ethylene glycolanol, and diethylene glycol, ⁇ , ⁇ ⁇ ⁇
  • Organic solvents such as dimethylacetamide and ⁇ ⁇ ⁇ -methylpyrrolidone, acetonitrile, acetone and the like are preferable, and methanol, ethanol and
  • an aqueous solution containing free L-lysine is obtained by treating commercially available L-lysine hydrochloride or the like with a strongly acidic ion exchange resin.
  • a strongly acidic ion exchange resin for example, a strongly acidic ion exchange resin.
  • citrate for example, a strongly acidic ion exchange resin.
  • L-lysine is 0.3 to L equivalent, preferably 0. 4 to 0.6 equivalents, most preferably 0.5 equivalents
  • the resulting aqueous solution For example, 3 to 7, preferably 3 to 6, more preferably 4.5 to 5.5, and most preferably 4.9.
  • the aqueous solution is cooled to ⁇ 10 to 20 ° C.
  • seed crystals are added to the aqueous solution, or a hydrophilic organic solvent is added to the aqueous solution. It is preferable to precipitate and isolate the crystals by adding the aqueous solution to a hydrophilic organic solvent. Alternatively, crystals can also be precipitated by combining these methods.
  • a hydrophilic organic solvent is added to the aqueous solution, or when the aqueous solution is added to the hydrophilic organic solvent, crystals may partially precipitate in the aqueous solution.
  • the aqueous solution is concentrated so that the concentration of L-lysine.kenate is 30 to 70%, preferably 40 to 70%. It is preferable to use it after adjusting it.
  • the use of an aqueous solution having a concentration of 30% or more is more preferable because the amount of the hydrophilic organic solvent used for precipitating crystals can be reduced.
  • an aqueous solution having a concentration of 70% or less is used, the miscibility between the aqueous solution and the hydrophilic organic solvent becomes easy, and crystal precipitation is more easily induced. In addition, it is easy to avoid the precipitated crystals from becoming block-like lumps.
  • the hydrophilic organic solvent is usually 1 to 8 times the amount of the above-adjusted aqueous solution (water content is 50% to 11%), preferably 1.5 to 5 times (water content force S40 to 17). And is added by gradually adding or dropping it to an aqueous solution adjusted to the above concentration at 10 ° C to 60 ° C, preferably at room temperature to 50 ° C. Crystals may be precipitated just by adding a hydrophilic organic solvent, but usually the resulting mixture is at ⁇ 10 ° C. to 50 ° C., preferably at ⁇ 10 ° C. to room temperature for 5 minutes to Precipitate by stirring for 72 hours.
  • the crystal obtained in the present invention is also possible to induce crystal precipitation by separately adding the crystal obtained in the present invention as a seed crystal to the obtained mixed solution.
  • the seed is sufficient if it can induce crystallization.
  • the amount of L-lysine 'citrate contained in the mixture is 0.01. ⁇ 0.1%, preferably 0.05% is used.
  • aqueous solution When the above aqueous solution is added to a hydrophilic organic solvent to precipitate crystals, the mixture is stirred at -10 ° C to 60 ° C, preferably -10 ° C in the hydrophilic organic solvent. Crystals can be precipitated by adding dropwise an aqueous solution having the same concentration as described above at room temperature.
  • the hydrophilic organic solvent is usually used in an amount of 1 to 8 times that of the aqueous solution with the above concentration adjusted.
  • the precipitated crystals are separated by a method such as filtration, and dried to obtain L-lysine 'citrate crystals.
  • Example 1 Approximately 200mL of saturated aqueous sodium chloride solution was left in a plastic desiccator for 24 hours at 25 ° C. Adjusting the humidity to 75%). 2 g of the crystals obtained in Example 1 were weighed into a glass jar. The weighed bottle was weighed and left in the desiccator with the above humidity adjusted, and the weight change of the bottle was measured over time.
  • the hygroscopicity (hygroscopicity) was calculated using the following equation (1).
  • the weight change of the force bottle was measured until the 7th day.
  • Hygroscopicity (./.) 1 0 0 (1)
  • Example 1 The crystals of L-lysine ⁇ ckenate obtained in Example 1 did not show significant hygroscopicity. That is, it was shown that the L-lysine 'citrate of the present invention does not require special attention to moisture during storage.
  • the L-lysine 'citrate crystals of the present invention can be stored at room temperature in the atmosphere. Also, do not use corrosive chemicals such as hydrochloric acid in the manufacturing process. In addition, citrate is an excellent source of L-lysine because it is less expensive than L-malic acid.
  • L-lysine 'citrate crystals are expected to be more combined with the properties of L-lysine in addition to the inherent properties of L-lysine.
  • Quenic acid is an intermediate of the citrate cycle (TCA cycle), and its activity can be expected to promote fatty acid synthesis and recover from fatigue by eliminating accumulated lactic acid.
  • improvement of the bitterness of hydrochlorides is also expected.
  • crystals of L-lysine 'citrate are expected to be used as a better source of L-lysine in nutritional supplements, pharmaceuticals, and feeds.
  • the pH of the aqueous solution was adjusted to 4.9.
  • the resulting aqueous solution was concentrated under reduced pressure to a total volume of 38 mL, and then 57 mL of ethanol was gradually added while stirring at room temperature. After further stirring at room temperature for 8 hours, the precipitated crystals were collected by filtration and washed with ethanol. The obtained crystals were dried under reduced pressure at 20 ° C. overnight to obtain 24.8 g (yield: 93.4%) of L-lysine 1/2 queenate crystals as pale yellow needles.
  • L-lysine hydrochloride (720 g as L lysine) was dissolved in 18 L of water and passed through a column packed with 9 L of strongly acidic ion-exchanged resin (Marathon C) (H type). After washing the resin with 9 L of water, L-lysine was eluted with 18 L of 2 mol ZL aqueous ammonia. Concentrate the eluate under reduced pressure to about 5 L, and then add 474 g of cenoic acid (0.5 equivalent to L-lysine) to the resulting L-lysine aqueous solution (containing 4.93 mol of L-lysine). Was adjusted to pH 4.9.
  • the obtained aqueous solution was decolorized by adding 60 g of activated carbon and treating at 50 ° C. for 30 minutes. Activated carbon was filtered off, and the filtrate was concentrated under reduced pressure to make the total volume 2.5 L. While stirring the obtained aqueous solution at 40 ° C., 2.5 L of ethanol was added, 20 g of seed crystals were inoculated, and the mixture was stirred at 40 ° C. for 5 hours. Next, 3.3 L of ethanol was added, the reaction solution was cooled to 20 ° C., and the precipitated crystals were separated by a centrifuge.
  • the crystals of L-lysine 'citrate provided by the present invention and the production method thereof are useful as a source of L-lysine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nutrition Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Il est exposé un cristal d'un sel composé de L-lysine et d'acide citrique, un cristal d'un sel composé de L-lysine et d'acide citrique dont une solution aqueuse à 5 % en poids a un pH de 3-6, un cristal d'un sel composé de L-lysine et d'acide citrique dans lequel la proportion dans la composition (proportion molaire) de la L-lysine par rapport à l'acide citrique est de 2:1, un procédé servant à produire un cristal d'un sel composé de L-lysine et d'acide citrique lequel est caractérisé en ce qu'on dissout de la L-lysine et de l'acide citrique dans de l'eau et on sépare un cristal de la solution aqueuse ainsi obtenue et un tel procédé servant à produire un cristal d'un sel composé de L-lysine et d'acide citrique dans lequel la solution aqueuse a un pH de 3-6.
PCT/JP2005/011557 2004-06-23 2005-06-23 Cristal de sel de l-lysine·acide citrique WO2006001345A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2006528600A JP4796493B2 (ja) 2004-06-23 2005-06-23 Ｌ−リジン・クエン酸塩結晶

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JP2004184453 2004-06-23
JP2004-184453 2004-06-23

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WO2006001345A1 true WO2006001345A1 (fr) 2006-01-05

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007514642A (ja) * 2003-12-17 2007-06-07 味の素株式会社 ２ｌ−リジン硫酸塩・３水和物結晶及びその製造法
US9216946B2 (en) 2012-08-03 2015-12-22 Ajinomoto Co., Inc. Method of producing basic amino acid or basic amino acid salt
WO2020046059A3 (fr) * 2018-08-31 2020-04-23 씨제이제일제당(주) Procédé d'inhibition de la génération de poussière, composition de stabilisateur de sol et dispositif de pulvérisation le comprenant
AU2018239785B2 (en) * 2017-03-21 2020-08-20 Cj Cheiljedang Corporation Adhesive composition and method for preparing same
US20210269717A1 (en) * 2018-08-31 2021-09-02 Cj Cheiljedang Corporation Method of suppressing dust generation, soil stabilizing composition, and spray device including soil stabilizing composition
US11779596B2 (en) 2017-03-08 2023-10-10 Hope Medical Enterprises, Inc. Intradialytic use of sodium thiosulfate

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102371578B1 (ko) * 2019-12-19 2022-03-07 씨제이제일제당 (주) 사료 바인더용 조성물, 및 이를 포함하는 동물 사료용 조성물
KR102444281B1 (ko) * 2020-02-28 2022-09-15 씨제이제일제당 (주) 토양 개량용 조성물 및 그의 이용
CN111675610B (zh) * 2020-06-18 2023-08-29 湖南新绿方药业有限公司 一种制备高纯度、不结块细颗粒枸橼酸晶体的精制方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1458094A (fr) * 1964-12-24 1966-03-04 Citrate de dl. lysine et sa préparation
JPS59216551A (ja) * 1983-05-25 1984-12-06 Itochu Shiryo Kk 鶏用飼料
JPH04229184A (ja) * 1990-07-02 1992-08-18 Degussa Ag Ｌ−オルニチン塩の製造法
JP2000086482A (ja) * 1998-09-11 2000-03-28 Shiseido Co Ltd 皮膚外用剤
JP2003144088A (ja) * 2001-11-07 2003-05-20 Hikari Seika Kk 呈味改良剤
WO2003057717A2 (fr) * 2002-01-07 2003-07-17 Abbott Gmbh & Co. Kg Cristallisation d'acides amines par agitation ultrasonique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6398359A (ja) * 1986-10-14 1988-04-28 Ajinomoto Co Inc 反芻動物用飼料添加組成物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1458094A (fr) * 1964-12-24 1966-03-04 Citrate de dl. lysine et sa préparation
JPS59216551A (ja) * 1983-05-25 1984-12-06 Itochu Shiryo Kk 鶏用飼料
JPH04229184A (ja) * 1990-07-02 1992-08-18 Degussa Ag Ｌ−オルニチン塩の製造法
JP2000086482A (ja) * 1998-09-11 2000-03-28 Shiseido Co Ltd 皮膚外用剤
JP2003144088A (ja) * 2001-11-07 2003-05-20 Hikari Seika Kk 呈味改良剤
WO2003057717A2 (fr) * 2002-01-07 2003-07-17 Abbott Gmbh & Co. Kg Cristallisation d'acides amines par agitation ultrasonique

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007514642A (ja) * 2003-12-17 2007-06-07 味の素株式会社 ２ｌ−リジン硫酸塩・３水和物結晶及びその製造法
US9216946B2 (en) 2012-08-03 2015-12-22 Ajinomoto Co., Inc. Method of producing basic amino acid or basic amino acid salt
JP5835489B2 (ja) * 2012-08-03 2015-12-24 味の素株式会社 塩基性アミノ酸又は塩基性アミノ酸塩の製造方法
US11779596B2 (en) 2017-03-08 2023-10-10 Hope Medical Enterprises, Inc. Intradialytic use of sodium thiosulfate
US11254845B2 (en) 2017-03-21 2022-02-22 Cj Cheiljedang Corporation Adhesive composition and method for preparing same
AU2018239785B2 (en) * 2017-03-21 2020-08-20 Cj Cheiljedang Corporation Adhesive composition and method for preparing same
AU2018238179B2 (en) * 2017-03-21 2020-11-12 Cj Cheiljedang Corporation Adhesive composition and method for preparing same
US11292944B2 (en) 2017-03-21 2022-04-05 Cj Cheiljedang Corporation Adhesive composition and method for preparing same
CN112334564A (zh) * 2018-08-31 2021-02-05 Cj第一制糖株式会社 抑制灰尘产生的方法、土壤稳定组成物及含其的喷洒装置
RU2767058C1 (ru) * 2018-08-31 2022-03-16 СиДжей ЧеилДжеданг Корпорейшн Способ подавления образования пыли, стабилизирующая почву композиция и распылительное устройство, включающее стабилизирующую почву композицию
US20210269717A1 (en) * 2018-08-31 2021-09-02 Cj Cheiljedang Corporation Method of suppressing dust generation, soil stabilizing composition, and spray device including soil stabilizing composition
CN112334564B (zh) * 2018-08-31 2022-05-31 Cj第一制糖株式会社 抑制灰尘产生的方法、土壤稳定组成物及包含土壤稳定组成物的喷洒装置
US11624028B2 (en) 2018-08-31 2023-04-11 Cj Cheiljedang Corporation Method of suppressing dust generation, soil stabilizing composition, and spray device including soil stabilizing composition
WO2020046059A3 (fr) * 2018-08-31 2020-04-23 씨제이제일제당(주) Procédé d'inhibition de la génération de poussière, composition de stabilisateur de sol et dispositif de pulvérisation le comprenant

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JP4796493B2 (ja) 2011-10-19

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