JP2008156281A - CRYSTALLINE SALT OF alpha-LIPOIC ACID AND L-LYSINE, AND METHOD FOR PREPARING THE SAME - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a high purity crystalline salt of α-lipoic acid and L-lysine, and an industrial method for preparing the same. <P>SOLUTION: The industrial method for preparing a high purity crystalline salt of α-lipoic acid and L-lysine comprises gradually dripping an aqueous ethanol solution of L-lysine of a temperature of 0 to 10°C into an ethanol solution of α-lipoic acid of a temperature of 0 to 10°C, stirring the mixed solution at the same temperature as above, isolating precipitated crystals by a commonly known method, and drying the isolated crystals at a temperature of 40°C or lower under vacuum. Thus obtained salt of α-lipoic acid and L-lysine shows a melting temperature of 149 to 151°C and shows crystallinity by X-ray diffractometry. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to crystals of α-lipoic acid L-lysine salt and a process for producing the same.

  Α-Lipoic acid (chemical name 1,2-dithiolane-3-pentanoic acid), also called thioctic acid, is a natural substance present in animal and plant cells as the R (+) form. This is a coenzyme essential for the oxidative decarboxylation reaction of keto acid contained in the sugar metabolic pathway in the body, and since it has an antioxidant action, it is expected to prevent aging by suppressing active oxygen. Recently, α-lipoic acid chemically synthesized has been used as a medicine and a food supplement.

  Since α-lipoic acid is hardly soluble in water, solid α-lipoic acid is used in food supplements. Water-soluble α-lipoic acid salts are also known. Among these, FR4680M describes a lysine salt of α-lipoic acid as a salt with a physiologically significant organic base. EP318891 describes an injection containing α-lipoic acid lysine salt. According to FR4680M, α-lipoic acid lysine salt is a white powder with a melting point of 153 ° C. having a bitter taste and is useful for the treatment of poisoning syndrome and anorexia disorder. Although there is no description of the production method, both lysine and its α-lipoic acid salt are well soluble in water. Therefore, a theoretical amount of α-lipoic acid is added to the lysine aqueous solution, and the resulting aqueous solution of both salts is concentrated to dryness It is presumed that it was manufactured by freeze drying. This is also supported by the fact that the product obtained by the inventors of this method was a bulky amorphous white powder.

  However, it is desirable to provide α-lipoic acid lysine salt as crystals. This is because crystallization generally gives a high purity product with a uniform composition. Furthermore, the crystal has a smaller bulk density and angle of repose than the amorphous powder, which is convenient for handling.

  The present invention provides a crystalline α-lipoic acid lysine salt and a method for producing a crystalline α-lipoic acid lysine salt by a crystallization method.

  Spanish Patent No. 313056 describes that an α-lipoic acid DL-lysine salt having a melting point of 160 to 164 ° C. was obtained by reacting an equivalent amount of α-lipoic acid with a DL-lysine salt in an aqueous system.

  However, while lysine base is almost freely soluble in water, α-lipoic acid is hardly soluble in water, so the theoretical amount of α-lipoic acid is added to an aqueous lysine solution to form both salts as an aqueous solution. There was no other choice than to concentrate the product under reduced pressure or freeze-dry it and collect it as a powder.

  However, it is desirable to separate the α-lipoic acid lysine salt from the reaction solution as a crystal by crystallization. This is because crystallization generally gives a high-purity product, and crystals have a smaller bulk density and angle of repose than amorphous powders, which is convenient for handling.

  α-Lipoic acid is hardly soluble in water but soluble in ethanol. On the contrary, L-lysine (base) is almost freely soluble in water, but hardly soluble in ordinary organic solvents including ethanol. The present invention utilizes this property, and each theoretical amount of α-lipoic acid is dissolved in ethanol, L-lysine is once made into an aqueous solution, and ethanol is added thereto to produce a hydrous ethanol solution of L-lysine. The aqueous ethanol solution of L-lysine prepared as described above is gradually added dropwise to the ethanol solution of α-lipoic acid and stirred to precipitate both salts as crystals. Thereafter, the precipitated crystals are separated from the mother liquor by a conventional method, washed with ethanol, and dried under reduced pressure at a temperature of 40 ° C. or lower to produce α-lipoic acid L-lysine salt crystals. At that time, it is important to keep the temperature of all liquids, that is, ethanol solution of α-lipoic acid, aqueous ethanol solution of L-lysine, mother liquor from which crystals are precipitated, and ethanol for washing the crystals at 0 ° C. to 10 ° C. is there. This is to reduce the supersaturated solubility of the salt at the time of crystallization and to avoid the contamination of α-lipoic acid polymerized impurities.

  The α-lipoic acid L-lysine salt crystal thus obtained has a melting point of 149 to 151 ° C., which is different from the melting point of the one reported so far, indicating that there is very little contamination with impurities. Furthermore, the crystal is clearly crystallized by X-ray diffraction. Furthermore, the only solvents used in this method are physiologically harmless water and ethanol, which is essential for use as a food supplement.

The production method of α-lipoic acid L-lysine salt crystals according to the present invention will be described according to the process.
(A) dissolving α-lipoic acid in a required amount of ethanol;
(B) A step of dissolving a theoretical amount of L-lysine in α-lipoic acid in water and adding ethanol to the aqueous solution to produce L-lysine hydrous ethanol;
(C) The step of gradually dropping the L-lysine solution obtained in step (b) into the α-lipoic acid solution obtained in step (a) and stirring to precipitate crystals;
(D) a step of separating the crystals precipitated in step (c) from the mother liquor by a conventional method (for example, centrifugation) and washing with ethanol;
(E) comprising a step of drying the separated crystals under reduced pressure at a temperature of 40 ° C. or lower,
(F) Steps (a) to (d) are performed at a liquid temperature of 0 to 10 ° C.

  At this time, except for ethanol used for washing in step (d), it is more efficient to use as little ethanol and water as possible before that, and the final yield of crystals is also high. However, the mother liquor (hydrated ethanol) from which crystals are precipitated in step (c) needs to be supersaturated with salt so that most of the produced salt precipitates as crystals. Therefore, the amount of water for dissolving L-lysine is 10/90 to 3/97 by volume with respect to the total amount of alcohol added to the lysine aqueous solution and alcohol for initially dissolving α-lipoic acid. It is preferable that it exists in the range. In other words, in the step (c), the crystal is preferably precipitated from hydrous ethanol having an ethanol concentration of 90 v / v% or more. For example, α-lipoic acid is dissolved in 40 to 48 L / kg of ethanol, while equivalent lysine hydrate is dissolved in 1.8 to 2.2 L / kg of water and then 2 to 10 L / kg of ethanol is added. Then, this is dropped into an alcohol solution of α-lipoic acid. As a result, the amount of ethanol and the whole liquid can be reduced, and the crystal yield of the salt is improved to, for example, 80 to 90%, which is suitable for industrial production.

  The raw material α-lipoic acid is usually a racemate, but R (+) type isomers obtained by optical resolution can also be used. L-lysine (free base) is convenient to use because it is commercially available as a monohydrate.

  The invention is illustrated by the following non-limiting examples.

  800 L of ethanol is charged into a reaction vessel whose interior has been washed and dried in advance, and cooled to an internal temperature of 0 to 10 ° C., and 20.0 kg (96.9 mol, 1 equivalent) of α-lipoic acid is added and dissolved therein. In a similar reaction vessel washed and dried in advance, 40 L of purified water (JP) and 15.9 kg (96.9 mol, 1 equivalent) of L-lysine-hydrate are charged and dissolved. 120 L of ethanol is added to this, and it cools to internal temperature 0-10 degreeC.

  While maintaining the internal temperature at 0 to 10 ° C., the L-lysine solution is dropped into the α-lipoic acid solution over 20 to 60 minutes, and further stirred at the same temperature for 1 hour or more. While maintaining the internal temperature at 0 to 10 ° C., the slurry containing the precipitated crystals is centrifuged, and the separated crystals are washed with 40 L of ethanol maintained at 0 to 10 ° C. The washed wet crystals are transferred to a vacuum dryer and dried at 40 ° C. or lower (warm water set temperature 40 ° C.) until the loss on drying is 5% or lower. 27.4-30.8 kg of crystals of α-lipoic acid L-lysine salt are obtained. Yield 80-90%

  The obtained crystal had a melting point of 149 to 151 ° C., and was clearly a crystal as shown in the X-ray analysis chart of FIG.

2 is an X-ray diffraction chart of α-lipoic acid L-lysine salt of the present invention.

Claims (4)

  An L-lysine hydrous ethanol solution having a liquid temperature of 0 to 10 ° C. is gradually added dropwise to an α-lipoic acid ethanol solution having a liquid temperature of 0 to 10 ° C., and the mixed solution is stirred at the same temperature, whereby crystals precipitated from the mother liquor are removed. A method for producing α-lipoic acid L-lysine salt crystals, which is separated and dried under reduced pressure at a temperature of 40 ° C. or lower.   The method according to claim 1, further comprising the step of washing with 0 to 10 ° C cold ethanol before drying the crystals separated from the mother liquor under reduced pressure. (A) a step of dissolving α-lipoic acid in a required amount of ethanol;
(B) a step of dissolving a theoretical amount of L-lysine in α-lipoic acid in hydrous ethanol;
(C) The step of gradually dropping the L-lysine solution obtained in step (b) into the α-lipoic acid solution obtained in step (a) and stirring to precipitate crystals;
(D) a step of separating the crystals precipitated in step (c) from the mother liquor by a conventional method and washing with ethanol;
(E) a step of drying the separated crystals under reduced pressure at a temperature of 40 ° C. or lower;
(F) Steps (a) to (d) are performed at a liquid temperature of 0 to 10 ° C;
(G) The amount of alcohol and water used in steps (a) and (b) is such that the ethanol concentration of the mother liquor in which crystals precipitate in step (c) is 90 v / v% or higher;
A process for producing an α-lipoic acid L-lysine salt crystal characterized by the above.   Α-Lipoic acid L-lysine salt crystals having a melting point of 149 to 151 ° C.

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