JP2011068563A - Carnitine fumarate, and method of producing the same - Google Patents

Abstract

【Task】
A simple operation is to efficiently produce carnitine fumarate with suppressed hygroscopicity, a specific tap density, and reduced impurities.
[Solution]
A method for producing carnitine fumarate, comprising adding carnitine to a lower alkyl alcohol containing fumaric acid. Furthermore, the step of adding carnitine and the step of adding fumaric acid to the lower alkyl alcohol containing fumaric acid can be sequentially repeated one or more times. In this way, carnitine fumarate with suppressed hygroscopicity, a specific tap density, and reduced impurities can be efficiently produced.
[Selection figure] None

Description

The present invention relates to carnitine fumarate and a method for producing the same.

  Carnitine is one of the essential ingredients for fat burning, and is currently added to various foods, mainly fat metabolism promoting foods. However, due to its high hygroscopicity, it may be modified or swelled to become a paste and sticky. In addition, since the stability is insufficient, a trace amount of trimethylamine is released, which may give an unpleasant fish odor.

  As such, carnitine has many problems in storage and processing. In order to solve such problems, carnitine fumarate has been developed as a highly stable non-hygroscopic salt. As a method for producing carnitine fumarate, for example, methods described in Patent Documents 1 to 4 are known.

  In Patent Documents 1 and 4, both carnitine and fumaric acid are dissolved in water or ethanol, the solvent is distilled off, a dry solid is obtained, and then recrystallized using ethanol or isopropanol to obtain carnitine fumarate. A method is disclosed. On the other hand, recently, in order to improve production efficiency, as described in Patent Documents 2 and 3, carnitine and fumaric acid are mixed in a small amount of water, treated at high temperature, and crushed after cooling or drying. A method for obtaining carnitine fumarate has been proposed.

  However, in the methods of Patent Documents 1 and 4, the dried product obtained is recrystallized with alcohol to obtain carnitine fumarate. However, the operation is complicated and some impurities are caused by this operation. Was found to increase. The carnitine fumaric acid obtained by the methods described in Patent Documents 2 and 3 is not sufficiently suppressed in hygroscopicity, and solidification or coloring considered to be caused by moisture absorption is observed, and it has been found that the desired properties cannot be exhibited. did.

JP-A-60-158152 Special Table 2002-540094 JP-T-2001-513096 Japanese Patent Publication No. 38-19995

  Accordingly, an object of the present invention is to provide a method for producing carnitine fumarate having high purity (impurities are sufficiently reduced) and hygroscopicity sufficiently suppressed by a simple operation.

  As a result of intensive studies in view of the problems of the prior art, the present inventors have found that the above object can be achieved by adding carnitine to a lower alkyl alcohol in which fumaric acid is dissolved in advance. It came to be completed.

  That is, this invention relates to the manufacturing method of a carnitine fumarate salt which includes adding a carnitine to the lower alkyl alcohol containing a fumaric acid.

  According to the present invention, carnitine fumarate in which impurities are sufficiently reduced can be obtained by a simple operation. Moreover, the carnitine fumarate obtained by the present invention has a low moisture absorption rate and a low tap density.

FIG. 1 is a graph showing the respective moisture absorption rates of the carnitine fumarate crystals obtained in Example 1 and Comparative Example 3.

(1) Carnitine Carnitine used in the present invention (for example, represented by the following general formula (1))

は、電気的に中性であっても、正電荷を帯びていて、負電荷を帯びていてもいずれでもよい。これらの中でも、4級アミノ基の正電荷とカルボキシル基の負電荷により分子内で電気的に中性となっているもの（以下、「カルニチン分子内塩」ということがある。）が好ましい。フマル酸と塩を形成しやすいからである。

May be electrically neutral, positively charged, or negatively charged. Among these, those that are electrically neutral in the molecule due to the positive charge of the quaternary amino group and the negative charge of the carboxyl group (hereinafter sometimes referred to as “carnitine inner salt”) are preferable. It is because it is easy to form a salt with fumaric acid.

  In the present invention, not only the above carnitine but also a carnitine derivative can be used. The type of the derivative is not limited, and examples thereof include those in which a carboxyl group forms an ester, and those in which a hydroxyl group forms an ester. Among these, acetylcarnitine, propionylcarnitine and the like are preferable.

As the carnitine used in the present invention, a commercially available one can be used, and carnitine produced by a known or novel method can also be used. As a known method, for example, the following production method is known.
(I) L-carnitine obtained by subjecting dichloropropanol to cyanation and amidation by enzymatic reaction (halohydrin epoxidase and nitrile hydratase), followed by quaternary amination, hydrolysis and the like;
(B) L-carnitine obtained by sequentially subjecting epichlorohydrin to quaternary amination, cyanation, amidation, optical resolution, etc .;
(C) L-carnitine obtained by subjecting butyrolactone to ring-opening, quaternary amination, reaction with microorganisms, etc .;
(D) L-carnitine obtained by subjecting ethyl chloroacetoacetate to asymmetric reduction, quaternary amination, hydrolysis and the like.

  Among these, carnitine obtained in (i) can be used preferably (see pamphlet of WO 2008/056827). This is because according to the method, carnitine with high yield and suppressed impurities can be used.

(2) Fumaric acid As the fumaric acid used in the present invention, a commercially available one can be used, or it can be produced by a known method.

(3) Alcohol In the present invention, when producing carnitine fumarate, a lower alkyl alcohol (hereinafter sometimes referred to as “alcohol”) is used as a solvent. The lower alkyl alcohol is preferably one that is compatible with water and that can dissolve fumaric acid or carnitine.

  Examples of such lower alkyl alcohols include alkyl alcohols having 1 to 4 carbon atoms. Preferably it is C1-C3, More preferably, it is C2-C3 alkyl alcohol. These alcohols may have a substituent such as a halide. More specifically, methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol and the like can be mentioned. Of these, ethanol is particularly preferable.

The lower alkyl alcohol used in the present invention may contain water. In that case, the density | concentration of a lower alkyl alcohol is 60-95 mass%, for example, Preferably it is 70-95 mass%, More preferably, it is 85-95 mass%. Although water will not be specifically limited if it is normally used by manufacture in this field | area, For example, purified water, distilled water, distilled purified water, etc. are mentioned.
As the alcohol, a single alcohol can be used alone, or a plurality of alcohols can be mixed and used. When mixing and using several alcohol, the mixing ratio is not limited and can be selected suitably.

(4) Production of carnitine fumarate
(4-1) Preparation of lower alkyl alcohol containing fumaric acid In the present invention, first, a lower alkyl alcohol containing fumaric acid is prepared. The method for adjusting the alcohol is not limited, and fumaric acid may be added to the alcohol and stirred as necessary. The temperature of the alcohol when adding fumaric acid is not limited. For example, what is necessary is just to be about 0-40 degreeC.

  The total amount of fumaric acid is not necessarily dissolved in alcohol. Therefore, the amount of fumaric acid added to the alcohol is 0.27 to 3 times, preferably 0.27 to 2 times, more preferably 0.27 to 1.5 times the solubility in the alcohol.

  The reason why fumaric acid having a solubility in alcohol of 0.27 or more is added is that carnitine fumarate can be sufficiently formed when carnitine is added. The reason why it is 3 times or less is that the generation efficiency of carnitine fumarate does not increase even if fumaric acid is further added.

  Taking ethanol as an example of the lower alkyl alcohol, the concentration of a saturated solution of fumaric acid is about 5.5 mass when 90 mass% ethanol (the remaining 10 mass% is water) is used at 20 ° C. %. Accordingly, when 90% by mass of ethanol is used, it may be 1.5 to 16.5% by mass, preferably 1.5 to 11.0% by mass, more preferably 1.5 to 8.5% by mass. %.

(4-2) Addition of carnitine Next, carnitine is added to the lower alkyl alcohol containing fumaric acid obtained above. The amount of carnitine added is not limited as long as a uniform carnitine fumarate with reduced impurity content is obtained. For example, the amount is 0.8 to 1.2 times, preferably 0.9 to 1.1 times, and more preferably about 1 times the number of moles of fumaric acid contained in the alcohol.

  Although the addition method is not limited, it is preferable to add while stirring from the viewpoint of efficiency. The whole amount may be added at once, or may be added divided into a plurality of times.

  The temperature of the solution (alcohol) when forming carnitine fumarate is, for example, 0 to 40 ° C. Preferably it is 10-35 degreeC, More preferably, it is 10-30 degreeC. The reason why the temperature is 0 ° C. or higher is that carnitine fumarate can be obtained efficiently. Moreover, it is 40 degrees C or less because production of a by-product can be suppressed. The stirring time after the addition of carnitine is not limited and can be appropriately selected by those skilled in the art. For example, it may be 1 minute to 24 hours, preferably 2 minutes to 20 hours, more preferably 3 minutes to 10 hours.

  Thus, carnitine fumarate can be obtained by reacting fumaric acid and carnitine in alcohol. The obtained carnitine fumarate can also be recovered by a known method such as filtration or centrifugation. In order to obtain more carnitine fumarate, it is possible to proceed to the next operation without recovering the carnitine fumarate.

(4-3) Repeated operation In the present invention, carnitine fumarate can be obtained in high yield by alternately adding carnitine and fumaric acid to alcohol containing fumaric acid. The amount of carnitine added at this time is also 0.8 to 1.2 times, preferably 0.9 to 1.1 times the amount of fumaric acid contained in the alcohol as described above. About 1 time is preferable.

  When carnitine is added in an equimolar amount with fumaric acid, it may be started from the step of adding fumaric acid to alcohol after forming carnitine fumarate. On the other hand, when carnitine in an amount exceeding 1 times the number of moles of fumaric acid in the alcohol is added, after forming carnitine fumarate, the alcohol contains carnitine in addition to the salt. It will be. Carnitine fumarate can be further formed by adding fumaric acid there (alcohol containing carnitine fumarate and carnitine). When the number of moles of fumaric acid added at this time exceeds 1 times the number of moles of carnitine contained in the alcohol just before that, carnitine fumarate is produced by adding carnitine there again. be able to.

  In this way, the carnitine fumarate can be obtained in a high yield with the impurity content kept low by repeating the operation.

  At this time, the conditions for adding carnitine and fumaric acid to produce carnitine fumarate are as described above. The addition of carnitine and fumaric acid may be repeated any number of times. The number of repetitions can be appropriately selected according to the amount of carnitine fumarate required.

  After the carnitine fumarate is formed, the carnitine fumarate can be recovered by a known method such as filtration or centrifugation as necessary. The timing for recovering the carnitine fumarate is not limited and may be performed at any stage. Each time carnitine or fumaric acid is added to form carnitine fumarate, the salt can be recovered, or can be recovered when a certain amount of carnitine fumarate is formed.

(4-4) Recycling of the solvent Furthermore, in the present invention, the alcohol (solvent or supernatant) after recovering the carnitine fumarate as described above can be reused. If carnitine or fumaric acid is not present or hardly present in the alcohol, start by adding fumaric acid to the alcohol to prepare a lower alkyl alcohol containing fumaric acid. That's fine.

  On the other hand, when fumaric acid is excessively contained in the alcohol, carnitine may be added thereto to form carnitine fumarate. In addition, when carnitine is excessively contained in the alcohol, carnitine fumarate may be formed by adding fumaric acid thereto. Even in this case, the carnitine fumarate can be formed in a high yield by alternately adding carnitine or fumaric acid as described above. The addition amount of carnitine or fumaric acid and other conditions are as described above.

  By performing such an operation, the alcohol (solvent) can be recycled, and carnitine fumarate with sufficiently reduced impurities can be obtained in high yield.

  The carnitine fumarate obtained in the present invention can be further purified or dried as necessary.

(5) Carnitine fumarate of the present invention The carnitine fumarate of the present invention obtained as described above has the following characteristics.

(5-1) Impurity (ethyl fumarate)
The carnitine fumarate obtained in the present invention is a white crystal composed of carnitine and fumaric acid in a composition ratio of substantially 1: 1, and impurities are sufficiently reduced. The concentration of by-products such as ethyl fumarate is 50 ppm or less, preferably 30 ppm or less, more preferably 25 ppm or less, with respect to the total amount of carnitine fumarate and by-products.
Ethyl fumarate can be detected (measured) by a known method such as HPLC.

(5-2) Hygroscopicity In the present invention, the hygroscopic property refers to a mass increase rate when the carnitine fumarate is left under a predetermined condition. The method of measuring the moisture absorption rate is not limited. For example, after about 3 g of carnitine fumarate crystals are precisely weighed, they are spread over a petri dish having a diameter of 9 cm and a height of 2 cm and left to stand at a predetermined temperature and humidity of 70% ± 5%. It can be obtained by measuring the mass change after a certain time.

The moisture absorption rate can be calculated from the following formula;
Moisture absorption (%) = ((mass after 24 hours−mass after 0 hours) / mass after 0 hours) × 100.

  The carnitine fumarate obtained in the present invention has a sufficiently low moisture absorption (shows a very small moisture absorption). For example, the moisture absorption when left for 24 hours under conditions of a temperature of 22 ° C. ± 3 ° C. and a humidity of 70% ± 5% is 0.3% or less, preferably 0.2% or less. Further, the moisture absorption when left for 3 hours under conditions of a temperature of 40 ° C. ± 3 ° C. and a humidity of 70% ± 5% is 6% or less, preferably 4% or less.

  Since the carnitine fumarate obtained in the present invention has a very low moisture absorption rate as described above, it has excellent storage stability and is excellent in handling.

(5-3) Tap Density In the present invention, the tap density refers to the bulk density when the carnitine fumarate is put into a container and then struck and packed as much as possible. The method for measuring the tap density is not limited. For example, an appropriate amount of carnitine fumarate is placed in a graduated cylinder, precisely weighed, and dropped from a height of around 15 mm onto a plate at a frequency of 180-200 times / minute,
The volume of carnitine fumarate after the first 500 drops and the volume of carnitine fumarate after the next 200 drops (total 700 times) are measured, and when the volume change becomes less than 2%, the final volume is obtained. It can be determined by dividing the mass of carnitine fumarate used in the measurement by the final volume.

  The tap density of the carnitine fumarate obtained in the present invention is 0.2 to 0.4 g / mL, preferably 0.25 to 0.4 g / mL, more preferably 0.3 to 0.4 g / mL. . Since the tap density is small as described above, there is an advantage that air transportation in the pipe is smoothly performed and problems such as blockage can be avoided.

(5-4) in the average particle diameter of the present invention, the average particle diameter, JIS Z 8801 Sieve test: using (mesh 300μm, 250μm, 180μm, 125μm, 90μm, 45μm, 32μm) and, JIS Z 0069 Chemistry The value obtained by the measurement method based on the product screening test method. More specifically, the mass fraction of carnitine fumarate remaining in each aperture is calculated, and the particle size with an integrated percentage of 50% is the average particle size.

  The average particle size of the carnitine fumarate obtained in the present invention is 40 to 150 μm, preferably 50 to 120 μm, more preferably 60 to 90 μm.

  The carnitine fumarate of the present invention has a rapid solubility because it is fine, and when mixed with other compounds, it exhibits good mixing properties, and furthermore, it is a fine crystal, so that it is compressed into tablets. It has the feature that the property is also good. Although it is such an excellent fine crystal, the problem of hygroscopicity due to the fine particle size is not recognized.

Example 1
Fumaric acid (3.75 g, 0.0323 mol) was dissolved in 90 g ethanol 90 g at room temperature (21 ° C.). Next, carnitine inner salt (5.21 g, 0.0324 mol) was added and stirred for 30 minutes.

  After separating the solid and liquid by suction filtration, carnitine fumarate was obtained in a yield of 77% by vacuum drying (50 ° C.). The obtained carnitine fumarate was a uniform salt (carnitine and fumaric acid formed a salt). The formation of a uniform salt was confirmed by the fact that the melting point was sharp and that the composition ratio of fumaric acid and carnitine was 1: 1 using liquid chromatography.

  The concentration of ethyl fumarate as a by-product was 16 ppm in the reaction system. Moreover, melting | fusing point was sharp and showed 137.8-138.9 degreeC.

Example 2
Fumaric acid (8.40 g, 0.0724 mol) was mixed with 100 g of 90 mass% ethanol at room temperature (23 ° C.). Next, carnitine inner salt (11.68 g, 0.0725 mol) was added and stirred for 3.5 hours. Thereafter, in the same manner as in Example 1, carnitine fumarate was obtained in a yield of 79%. The obtained carnitine fumarate was a uniform salt. The concentration of ethyl fumarate as a by-product was 22 ppm in the reaction system.

Example 3
Fumaric acid (16.5 g, 0.142 mol) was dissolved in 330 g of 90 mass% ethanol at room temperature (23 ° C.). Next, carnitine inner salt (22.9 g, 0.142 mol) was added and stirred for 30 minutes. Thereafter, in the same manner as in Example 1, carnitine fumarate was obtained in a yield of 81%. The obtained carnitine fumarate was a uniform salt. The concentration of ethyl fumarate as a by-product was 13 ppm in the reaction system.

Example 4
Fumaric acid (29.8 kg, 0.257 kmol) was added to 650 kg of 95% by mass ethanol at 20 ° C. and stirred for 15 minutes. Next, carnitine inner salt (20.7 kg, 0.128 kmol) was added and stirred for 10 minutes, and carnitine inner salt (20.7 kg, 0.128 kmol) was added and then stirred for 10 minutes (carnitine inner salt was added). Added in two portions).

  Next, fumaric acid (29.8 kg, 0.257 kmol) was added to the solution thus obtained and stirred for 15 minutes, and then carnitine inner salt (20.7 kg, 0.128 kmol) was added. Then, carnitine inner salt (20.7 kg, 0.128 kmol) was added and stirred for 10 minutes (carnitine inner salt was added in two portions).

  Subsequently, fumaric acid (29.8 kg, 0.257 kmol) was added thereto and stirred for 15 minutes, then carnitine inner salt (20.7 kg, 0.128 kmol) was added and stirred for 10 minutes, and further Carnitine inner salt (20.7 kg, 0.128 kmol) was added and stirred for 10 minutes (carnitine inner salt was added in two portions).

  Thereafter, solid-liquid separation is performed by centrifugation, and vacuum drying (60 ° C.) is performed, so that the yield of carnitine fumarate is 93% (the ratio of the mass of the acquired salt to the total mass of fumaric acid and carnitine added as raw materials) ). The obtained carnitine fumarate was a uniform salt. The concentration of ethyl fumarate as a by-product was 3.6 ppm in the reaction system. The melting point was sharp, showing 138.1-139.0 ° C.

  In addition, as described below, excellent results for storage stability were confirmed. A solution prepared by dissolving the carnitine fumarate obtained above in an aqueous solution adjusted to pH = 1, 3, 7, 8 (concentration is 1000 ppm) is heated at 80, 100, 121 ° C. for 1-3 hours, respectively. The presence or absence of changes was confirmed. As a result, chemical and physical changes represented by the content (purity of carnitine fumarate), coloring, and odor were not recognized. Moreover, although the obtained crystal | crystallization was stored at 60 degreeC for 3 days, the change was not recognized similarly.

Example 5
Fumaric acid (46.5 g, 0.401 mol) was added to 1000 g of 90 mass% ethanol at 22 ° C. and stirred for 40 minutes. Next, carnitine inner salt (64.6 g, 0.401 mol) was added and stirred for 77 minutes.

Next, after adding fumaric acid (16.0 g, 0.138 mol), the mixture was stirred for 33 minutes, and after adding carnitine inner salt (22.3 g, 0.139 mol), the mixture was stirred for 27 minutes.
Subsequently, fumaric acid (17.2 g, 0.148 mol) was added and stirred for 28 minutes, and carnitine inner salt (23.9 g, 0.148 mol) was added and stirred for 26 minutes.
Subsequently, fumaric acid (18.5 g, 0.159 mol) was added and stirred for 33 minutes, and carnitine inner salt (25.6 g, 0.159 mol) was added and stirred for 40 minutes.
Subsequently, fumaric acid (19.9 g, 0.171 mol) was added and stirred for 40 minutes, and carnitine inner salt (10.8 g, 0.172 mol) was added and stirred for 37 minutes.
Furthermore, after adding fumaric acid (19.9 g, 0.093 mol), the mixture was stirred for 37 minutes, and after adding carnitine inner salt (15.0 g, 0.093 mol), the mixture was stirred for 40 minutes.

  The solution thus obtained was subjected to solid-liquid separation by pressure filtration, and carnitine fumarate was obtained in a yield of 86% by vacuum drying (50 ° C.). The obtained carnitine fumarate was a uniform salt. The concentration of ethyl fumarate as a by-product was 24.5 ppm in the reaction system. The melting point was sharp and showed 137.4 to 139.5 ° C.

Example 6
In Example 4, fumaric acid (16.0 g, 0.138 mol) was added to 350 g (20 ° C.) of the supernatant (solvent) after performing solid-liquid separation and filtering (recovering) carnitine fumarate for 15 minutes. Stir.

Subsequently, after adding carnitine inner salt (11.1 g, 0.069 mol), it stirred for 10 minutes, and after adding carnitine inner salt (11.1 g, 0.069 mol), it stirred for 10 minutes.
Subsequently, fumaric acid (16.0 g, 0.138 mol) was added and stirred for 15 minutes, then carnitine inner salt (11.1 g, 0.069 mol) was added and stirred for 10 minutes.
Subsequently, after adding carnitine inner salt (11.1 g, 0.069 mol) and stirring for 10 minutes, fumaric acid (16.0 g, 0.138 kmol) was added and stirred for 15 minutes.
Furthermore, carnitine inner salt (11.1 g, 0.069 mol) was added and stirred for 10 minutes, and carnitine inner salt (11.1 g, 0.069 mol) was added and stirred for 10 minutes.

  Thereafter, solid-liquid separation was performed by centrifugation, and carnitine fumarate was obtained in a yield of 99% by vacuum drying (60 ° C.). The obtained carnitine fumarate was a uniform salt. The concentration of ethyl fumarate as a by-product was 7.6 ppm in the reaction system. The melting point was sharp, showing 138.2-139.3 ° C.

Comparative Example 1
Carnitine inner salt (7.10 g, 0.0612 mol) and fumaric acid (9.86 g, 0.0612 mol) were simultaneously added to 100 g of 90 mass% ethanol and dissolved by heating at 50 ° C. After cooling to room temperature (23 ° C.), carnitine fumarate was obtained in 79% yield as in Example 1. The obtained carnitine fumarate was a uniform salt, but the concentration of ethyl fumarate as a by-product was as high as 180 ppm in the reaction system.

Comparative Example 2
Carnitine inner salt (12.55 g, 0.078 mol) was dissolved in 100 g of 90 mass% ethanol at room temperature (20 ° C.). Subsequently, about 0.5 g of fumaric acid was added every 5 minutes, and a total (9.05 g, 0.078 mol) was added. After stirring for about 6 hours and separating the solid and liquid by suction filtration, the residue was vacuum dried (50 ° C.).

  Since 17.3 g of the obtained crystals had a molar ratio of carnitine inner salt to fumaric acid = 1.00 / 1.05, some fumaric acid existed alone without forming a salt. That is, it was suggested that normal salt formation was not performed, and the obtained crystal was not carnitine fumarate but a mixture of carnitine fumarate and fumaric acid.

Comparative Example 3 (method described in JP 2002-540094 A)
Carnitine inner salt (9.66 g, 0.06 mol) and fumaric acid (6.96 g, 0.06 mol) are simultaneously added to a flask containing water (1.43 g) and added at 110-120 ° C. for about 5 minutes. Stirring to obtain a translucent liquid. The mixture was allowed to cool at room temperature for 2 hours, and the resulting opaque white solid was pulverized and dried at 60 ° C. for 4 hours under vacuum. A flowable granule was obtained. Melting point was broad, showing 122.6-127.3 ° C.

Test Example 1 (Measurement of moisture absorption rate)
After about 3 g of carnitine fumarate crystals obtained in Example 1 and Comparative Example 3 were precisely weighed, they were spread over a petri dish having a diameter of 9 cm and a height of 2 cm, and the temperature was 22 ° C. ± 3 ° C. and the humidity was 70% ± 5%. The change in moisture absorption rate of each was measured. The result is shown in FIG. In FIG. 1, -O- represents the moisture absorption rate of the carnitine fumarate obtained in Example 1, and-♦-represents the moisture absorption rate of the carnitine fumarate obtained in Comparative Example 3.

  The moisture absorption after 24 hours was 0.14% for the carnitine fumarate obtained in Example 1. On the other hand, the carnitine fumarate obtained in Comparative Example 3 was 0.52%, and powder consolidation was observed. The moisture absorption rate of the carnitine fumarate obtained in Examples 4 to 6 was also measured in the same manner, and the results are shown in Table 1.

  In addition, after about 3 g of carnitine fumarate crystals obtained in Example 4 were precisely weighed, they were spread over a petri dish having a diameter of 9 cm and a height of 2 cm and left to stand at a temperature of 40 ° C. and a humidity of 75%. Was 1.85% after 30 minutes and 3.60% after 89 minutes, with little change thereafter.

Test Example 2 (Measurement of tap density)
30 g of carnitine fumarate obtained in Examples 1, 4 to 6 and Comparative Example 1 was put in a 100 mL graduated cylinder and dropped onto a plate from a height of around 15 mm at a fall frequency of 180 to 200 times / minute. The change in the volume of carnitine fumarate after the first 500 drops and the volume of carnitine fumarate after the next 200 drops (total 700 times) were less than 2%. The tap density was determined by dividing by the final volume. The results are shown in Table 1.

Test Example 3 (Measurement of particle diameter)
3 g of carnitine fumarate obtained in Examples 1, 4 to 6 and Comparative Example 1 was used in accordance with JIS Z 8801 test sieves (mesh openings: 300 μ, 250 μ, 180 μ, 125 μ, 90 μ, 45 μ, 32 μ). Measured according to the screening test method for chemical products. The results are shown in Table 1.

  The mass percentages of carnitine fumarate obtained in Example 1 were 25.7%, 6.7%, 17.3%, 25.9%, 21.2%, 3.0%, 0.2%, respectively. The average particle size was about 150 μm.

  The mass percentages of carnitine fumarate obtained in Example 4 were 12.2%, 3.1%, 7.7%, 12.0%, 13.7%, 44.3%, 6.5%, respectively. The average particle size was about 65 μm.

  The mass percentages of carnitine fumarate obtained in Example 5 were 22.3%, 11.3%, 19.0%, 20.4%, 15.8%, 10.8%, 0.5%, respectively. The average particle size was about 150 μm.

  The mass percentages of carnitine fumarate obtained in Example 6 were 21.1%, 9.4%, 10.6%, 25.7%, 19.3%, 13.6%, 0.4%, respectively. The average particle size was about 120 μm.

  The mass percentages of carnitine fumarate obtained in Comparative Example 1 are 23.8%, 8.8%, 14.7%, 16.6%, 13.0%, 18.2%, 3.6%, respectively. The average particle size was about 140 μm.

Claims (7)

  A method for producing carnitine fumarate, comprising a step of forming carnitine fumarate by adding carnitine to a lower alkyl alcohol containing fumaric acid.   The method of claim 1, further comprising adding fumaric acid.   The method according to claim 1, further comprising the step of repeating the step of adding fumaric acid and the step of adding carnitine one or more times sequentially. The method according to any one of claims 1 to 3, further comprising a step of recovering the carnitine fumarate after adding carnitine or fumaric acid to form a carnitine fumarate.   The method according to claim 4, further comprising the step of forming carnitine fumarate by adding carnitine or fumaric acid to the alcohol after recovering the carnitine fumarate.   Carnitine fumarate by repeating the step of adding fumaric acid and the step of adding carnitine or the step of adding carnitine and the step of adding fumaric acid to the alcohol solution after recovering carnitine fumarate one or more times in sequence. The method of claim 4, further comprising the step of forming a salt. Carnitine fumarate having at least one of the following properties (i) to (iii):
(I) The moisture absorption rate after 24 hours when measured under conditions of a temperature of 22 ° C. ± 3 ° C. and a humidity of 70% ± 5% is 0.3% or less. (Ii) The tap density is 0.2 to 0.4 g. / ML
(Iii) The content of ethyl fumarate is 50 ppm or less

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