ES2773495T3 - Astaxanthin purification procedure - Google Patents

Abstract

A process for the manufacture of food grade synthetic astaxanthin, comprising the following steps: a) providing synthetic astaxanthin crystals containing dichloromethane; and b) adding methanol to the synthetic astaxanthin crystals in an amount to obtain a suspension of synthetic astaxanthin in methanol, whereby the amount of synthetic astaxanthin in said suspension is in the range of 5 to 70% by weight, based on the weight. total suspension; and c) heating the suspension obtained in step b) to a temperature in the range of 80 to 140 ° C in a closed reactor; and d) maintaining the suspension at a temperature in the range as given for step c) until the content of dichloromethane in the synthetic astaxanthin is <= 250 ppm; and e) cooling the methanolic suspension of synthetic astaxanthin, whereby its dichloromethane content is <= 250 ppm, to a temperature in the range of 10 to 35 ° C; and f) filtering out the synthetic astaxanthin crystals and optionally drying them; with which a synthetic astaxanthin of food grade is obtained.

Description

DESCRIPTION

Procedure for the purification of astaxanthin

The object of the invention is to provide a synthetic food grade astaxanthin (AXN) which is hitherto unknown. "Food grade" within the present invention means "suitable for human consumption". A synthetic food grade AXN thus meets all regulatory requirements for purity and can be used in the commercial production of food and dietary supplements.

AXN can be manufactured by chemical synthesis (see EP-A 908449, WO 2005/087720, EP-A 733 619), can be produced by fermentation (see EP-A 543023) and isolated from natural sources such as waste shells (see JP-A 11-049 972) or Haematococcus pluvialis algae (see GB-A 2,301,587), in which the isolated esters would have to be cleaved to AXN itself.

AXN isolated from natural sources is already used in products for human consumption: see, p. eg, US 2009/0297492, where AXN is described to improve cognitive performance; US 2009/0018210, which describes that AXN promotes fat degradation; EP-A 1867 327, where AXN is described to prevent neurodegenerative disease, to name just a few. Until now, however, synthetic AXN has not been used in products for human consumption.

Synthetic AXN is of standardized quality compared to AXN from natural sources, as it is much easier to use a standardized procedure for its chemical synthesis and purification than to depend on the variable quality of natural AXN that results from using natural sources than they also vary in their composition. Therefore, in the context of the present invention, the term "AXN" means "synthetic AXN".

Chemical processes for the manufacture of AXN are often carried out in halogenated hydrocarbons such as dichloromethane (see, for example, WO 2011/095571), since AXN and its precursors have a high solubility in these solvents, although there were intentions in the past to avoid the use of solvents of this type (see, for example, EP-A 908 449 and WO 2005/087720). There are also purification methods using chloroform (see JP-A 07118226). The AXN obtained in this way often crystallizes from lower alkanols, since it is hardly soluble in these types of solvents.

Procedures for the purification of astaxanthin already exist: In example 11 of WO 2007/072529 the synthesis of astaxanthin is carried out in isopropanol. The product obtained is recrystallized in three successive rounds: one with methylene chloride, another with methanol and another with heptane. In this way, all of the astaxanthin dissolves. According to WO 2007/128574 (see page 9, line 25) the astaxanthin filter cake is washed with methanol. According to EP-A 633258 (see Example 2) the astaxanthin crystals have been washed with heptane.

Therefore, it was an object of the present invention to provide a synthetic AXN which is of reliable quality, easy to obtain also on an industrial scale and suitable for human consumption.

Therefore, it was an object of the present invention to provide a food grade synthetic AXN.

This object is achieved by the process of the present invention which provides a XNA with extremely low levels of solvent, preferably with extremely low levels of dichloromethane, thus making this AXN suitable for human consumption.

Therefore, the present invention is especially directed to the synthesis of a synthetic AXN with a content of dichloromethane <250 ppm, preferably with a content of dichloromethane <200 ppm, more preferably with a content of dichloromethane <100 ppm, even more preferably with a dichloromethane content <50 ppm, <35 ppm, <30 ppm, <25 ppm, <20 ppm, most preferably with a dichloromethane content <10 ppm.

In an especially preferred embodiment of the present invention, synthetic AXN has a dichloromethane content in the range of 0 to 100 ppm, preferably in the range of 10 to 100 ppm.

Preferably, the synthetic AXN prepared according to the present invention has a methanol content <500 ppm, preferably it has a methanol content <350 ppm, more preferably it has a methanol content <250 ppm, even more preferably it has a methanol content <150 ppm, <100 ppm, most preferably it has a methanol content <50 ppm, <20 ppm, <10 ppm, <5 ppm.

In an especially preferred embodiment of the present invention, the synthetic AXN has a methanol content in the range of 0 to 50 ppm, preferably in the range of 0 to 20 ppm, more preferably in the range of 0 to 10 ppm, most preferably in the range of 0 to 5 ppm.

In a further preferred embodiment, the synthetic AXN has a dichloromethane content <50 ppm and a methanol content <100 ppm.

The synthetic AXN prepared according to the present invention can be used especially in dietary supplements. For these purposes, it is often provided in the form of an oily suspension or a powdered formulation such as a microsphere, thereby protecting food grade synthetic AXN from degradation.

Since it is possible with the processes of the present invention to significantly reduce the content of halogenated organic solvents such as dichloromethane, there is no longer a need to use a chemical synthesis, where the use of this type of solvents is avoided.

Procedures

Such an AXN can be obtained by one of the following procedures, which are the objects of the present invention.

Procedure A

A process for the manufacture of synthetic astaxanthin, suitable for human consumption, comprising the following steps:

a) provide synthetic astaxanthin crystals containing dichloromethane: and

b) adding methanol to the synthetic astaxanthin crystals in an amount to obtain a suspension of synthetic astaxanthin in methanol, whereby the amount of synthetic astaxanthin in said suspension is in the range of 5 to 70% by weight, based on weight total suspension: and

c) heating the suspension obtained in step b) to a temperature in the range of 80 to 140 ° C in a closed reactor: and

d) maintaining the suspension at a temperature in the range as given for step c) until the content of dichloromethane in the synthetic astaxanthin is <250 ppm; and e) cooling the synthetic astaxanthin methanolic suspension, whereby its dichloromethane content is <250 ppm, to a temperature in the range of 10 to 35 ° C; and

f) separating the synthetic astaxanthin crystals by filtration and, optionally, drying them;

with which a synthetic astaxanthin suitable for human consumption is obtained.

Procedure B

A process for the manufacture of synthetic astaxanthin suitable for human consumption (starting material: solution of synthetic astaxanthin in dichloromethane) comprising the following steps:

a1) providing a solution of synthetic astaxanthin in dichloromethane; and

a2) optionally, add methanol to the synthetic astaxanthin solution from step a1); and a3) distilling off dichloromethane and, optionally, methanol; and

b1) adding methanol to the synthetic astaxanthin solution in an amount to obtain a synthetic astaxanthin suspension, whereby the amount of synthetic astaxanthin in said suspension is in the range of 5 to 70% by weight, based on the total weight of the suspension; and c1) heating the suspension obtained in step b1) to a temperature in the range of 80 to 140 ° C in a closed reactor; and

d1) keeping the suspension at a temperature in the range as given for step c1) until the content of dichloromethane in synthetic astaxanthin is <250 ppm; and e1) cooling the synthetic astaxanthin methanolic suspension, whereby its dichloromethane content is <250 ppm, to a temperature in the range of 10 to 35 ° C; and f1) separating the synthetic astaxanthin crystals by filtration and, optionally, drying them;

with which a synthetic astaxanthin suitable for human consumption is obtained.

These procedures will now be described in more detail. They are inexpensive and can be done on an industrial scale. During the processes according to the present invention, the total amount of synthetic astaxanthin is not completely dissolved in the methanol. This is in contrast to a crystallization process in which the total amount of astaxanthin dissolves completely on heating and recrystallizes when the temperature drops again.

Since Procedure steps A and B differ only with respect to starting material, they are the same and are therefore described together.

Stage a) / stage a1)

Synthetic AXN crystals (see procedure A - step a)) or a solution of synthetic AXN in dichloromethane (see procedure B - step a1)) can be used as starting material.

Procedure A: Synthetic AXN crystals are as obtained from any of the chemical syntheses after removal of the solvent, wherein the synthesis has been performed such as, e.g. eg, preferably in dichloromethane. The dichloromethane may have been removed by distillation or by solvent exchange. Preferably, the dichloromethane has been removed by solvent exchange with methanol. In this case, the mixture of astaxanthin and dichloromethane is heated to a temperature of 38 to 40 ° C at atmospheric pressure and the dichloromethane is distilled off. Methanol is added simultaneously, so that the volume of the mixture remains constant. Then the solvent (dichloromethane methanol) is distilled off until the internal temperature has risen to 64 ° C (boiling point of methanol), which means that only methanol is distilled off, but no longer dichloromethane.

These synthetic AXN crystals still contain dichloromethane which cannot be removed simply by prolonging the drying time of these synthetic AXN crystals, even if the temperature and / or vacuum is increased. Typical amounts of dichloromethane remaining in synthetic AXN crystals are 0.2 to 0.3% by weight, based on the total weight of synthetic AXN crystals.

Process B: Since the process of the present invention is very efficient in removing dichloromethane, it is also possible to directly use a solution of synthetic AXN in dichloromethane. In this case, it is advantageous to first reduce the amount of dichloromethane in the solution by distillation. Preferably, this is done by simultaneously adding methanol.

Therefore, if procedure B is carried out, advantageously also steps a2) and a3) are carried out.

a2) adding methanol to the synthetic astaxanthin solution from step a1);

a3) Separate dichloromethane and methanol by distillation.

Stage b) / stage b1)

Preferably, step b) / step b1) is carried out in a closed reactor.

Preferably, methanol is added to the crystals of synthetic astaxanthin (step b) - Procedure A) or to the solution of synthetic AXN in dichloromethane (step b1) - Procedure B) in an amount to obtain a suspension of synthetic astaxanthin in methanol, with which the amount of synthetic astaxanthin in said suspension is in the range of 20 to 60% by weight, more preferably in the range of 30 to 50% by weight. Preferably this is done under nitrogen.

Stage c) / stage c1)

Preferably, the suspension obtained in step b) / step b1) is heated to a temperature, that is, it is brought to a temperature in the range of 80 to 140 ° C, more preferably to a temperature in the range of 90 to 125 ° C, even more preferably at a temperature in the range of 100 to 120 ° C, most preferably at a temperature in the range of 105 to 115 ° C, in a closed reactor. With this, the pressure increases.

Stage d) / stage d1)

The temperature is kept constant at the desired value - the same temperature as in step c) / c1) - until the content of dichloromethane in the synthetic astaxanthin is <250 ppm, preferably <200 ppm, more preferably <100 ppm, even more preferably <50 ppm, <35 ppm, <30 ppm, <25 ppm, <20 ppm, most preferably <10 ppm.

Stage e) / stage e1)

Preferably, the synthetic astaxanthin methanolic suspension, whereby its dichloromethane content is <250 ppm, is cooled to a temperature in the range of 15-30 ° C, more preferably to a temperature in the range of 20 to 25 ° C .

Stage f) / stage f1)

The synthetic astaxanthin crystals are filtered off and optionally dried.

The drying of the synthetic AXN crystals obtained is generally carried out at a temperature below 140 ° C, preferably at a temperature in the range of 40 to 140 ° C, and under vacuum. The vacuum is preferably in a range between 0 and 20 mbara.

In one embodiment of the present invention, drying of synthetic AXN crystals is carried out at a temperature of 80 ° C and at 20 mbar. In a further embodiment of the present invention, the drying of synthetic AXN crystals is carried out at a temperature in the range of 55 to 70 ° C and at a pressure below 20 mbar.

One embodiment of the present invention is a process in which steps a) to f) and a1) to f1) respectively, are carried out twice, which means that the astaxanthin obtained in step f) or in the step f1) respectively, is used as starting material for step a) and step a1) respectively.

Especially preferred embodiments of the present invention are those processes in which one or more of the preferred conditions given above are carried out. The most preferred processes of the present invention are those in which all of the preferred conditions given above are carried out.

The invention is now further illustrated in the following non-limiting example.

Examples

Example 1: Procedures to obtain food grade synthetic astaxanthin

120 g of astaxanthin (97%) containing 2000 mg / kg of dichloromethane are introduced into a 1000 ml steel autoclave under inert conditions with 280 ml of methanol. The autoclave is closed, the mixture is stirred at 350 rpm (rotations per minute) and heated to 105 ° C (internal temperature). Once the internal temperature (105 ° C) has been reached, the mixture is constantly kept at this temperature for 7 hours with stirring. After 7 hours of this treatment, the mixture is cooled to 25 ° C and diluted with 50 ml of methanol. The crystals are filtered off, washed with 150 ml of methanol and dried in a drying oven for 16 hours at 80 ° C under 20 mbara. Dry astaxanthin is obtained containing 45 mg / kg of dichloromethane.

In principle it is possible to carry out Example 1 as described above also at any other temperature in the range from 80 to 140 ° C instead of 105 ° C. These other temperatures are, e.g. e.g. 80 ° C, 85 ° C, 90 ° C, 95 ° C, 100 ° C, 110 ° C, 115 ° C, 120 ° C, 125 ° C, 130 ° C, 135 ° C, 140 ° C and any other temperature in between. Example 1 can be repeated especially at a temperature of 110 ° C and 115 ° C, respectively.

Claims (6)

1. A process for the manufacture of food grade synthetic astaxanthin, comprising the following steps: a) providing synthetic astaxanthin crystals containing dichloromethane; and b) adding methanol to the synthetic astaxanthin crystals in an amount to obtain a suspension of synthetic astaxanthin in methanol, whereby the amount of synthetic astaxanthin in said suspension is in the range of 5 to 70% by weight, based on weight total suspension; and c) heating the suspension obtained in step b) to a temperature in the range of 80 to 140 ° C in a closed reactor; and d) maintaining the suspension at a temperature in the range as given for step c) until the content of dichloromethane in the synthetic astaxanthin is <250 ppm; and e) cooling the methanolic suspension of synthetic astaxanthin, whereby its dichloromethane content is <250 ppm, to a temperature in the range of 10 to 35 ° C; and f) separating the synthetic astaxanthin crystals by filtration and, optionally, drying them; with which a synthetic astaxanthin of food grade is obtained. 2. A process for the manufacture of food grade synthetic astaxanthin, comprising the following steps: a1) providing a solution of synthetic astaxanthin in dichloromethane; and a2) optionally, add methanol to the synthetic astaxanthin solution from step a1); and a3) distilling off methanol, if present, and dichloromethane; and b1) adding methanol to the synthetic astaxanthin solution in an amount to obtain a synthetic astaxanthin suspension, whereby the amount of synthetic astaxanthin in said suspension is in the range of 5 to 70% by weight, based on the total weight of the suspension; and c1) heating the suspension obtained in step b1) to a temperature in the range of 80 to 140 ° C in a closed reactor; and d1) keeping the suspension at a temperature in the range as given for step c1) until the content of dichloromethane in synthetic astaxanthin is <250 ppm; and e1) cooling the methanolic suspension of synthetic astaxanthin, whereby its dichloromethane content is <250 ppm, to a temperature in the range of 10 to 35 ° C; and f1) separating the synthetic astaxanthin crystals by filtration and, optionally, drying them; with which a synthetic astaxanthin of food grade is obtained. The method according to claim 1 or 2, wherein steps b) and e) or steps b1) and e1), respectively, are carried out simultaneously. The method according to claim 1 or 2, wherein in step b) or in step b1) the amount of synthetic astaxanthin in said suspension is in the range of 20 to 60% by weight, preferably the amount of synthetic astaxanthin in said suspension is in the range of 30 to 50% by weight, based on the total weight of the suspension. The process according to claim 1 or 2 or 4, wherein in step c) or in step c1) the suspension is brought to a temperature in the range of 90 to 125 ° C, preferably at a temperature in the range of 100 to 120 ° C, more preferably at a temperature in the range of 105 to 115 ° C; and in stage d) or in stage d1), the suspension is kept at said temperature. 6. The process according to claim 1 or 2 or 4 or 5, wherein in step e) or in step e1) the methanolic suspension of synthetic AXN is cooled to a temperature in the range of 15 to 30 ° C, preferably at a temperature in the range of 20 to 25 ° C.