TECHNICAL FIELD

The present invention relates to a reduced coenzyme Q10 crystal excellent in stability and a method for producing reduced coenzyme Q10 containing large quantities of the aforementioned crystals.

BACKGROUND ART

Coenzyme Q is an essential component widely distributed in living organisms from bacteria to mammals, and is known as a member of mitochondrial electron transfer system in cells in the living organisms. Coenzyme Q engages in electron transfer in the electron transfer system by the repetition of oxidation and reduction in mitochondria. Further, reduced coenzyme Q is known to have antioxidant activity. The major component in humans is coenzyme Q10 which is one having 10 repeating structures in the side chain of coenzyme Q, and usually, about 40% to 90% thereof is present in the living body as the reduced form. The physiological activity of coenzyme Q includes activation of energy production by mitochondrial activation, activation of cardiac function, an effect of stabilizing cell membranes, and an effect of protecting cells by antioxidant activity.

While coenzyme Q10 currently produced and sold is, in large part, oxidized coenzyme Q10, reduced coenzyme Q10 which exhibits higher oral absorbability than that of oxidized coenzyme Q10 has also been commercially available and has come to be used in recent years.

A common method for obtaining reduced coenzyme Q10 has already been disclosed (Patent Literature 1). Furthermore, several methods for obtaining reduced coenzyme Q10 as a crystal have also been known. For example, a method of crystallizing reduced coenzyme Q10 in an alcohol solution and/or a ketone solution to produce a crystal (Patent Literature 2), a method of adding a high concentration liquid phase of reduced coenzyme Q10 into a poor solvent for crystallization (Patent Literature 3), and the like have been reported.

On the other hand, Patent Literature 4 reports that crystal polymorphism is found in reduced coenzyme Q10. It reports that a newly found crystal form (this crystal is hereinafter referred to as a “reduced coenzyme Q10 Form II crystal”) is much more stable and more excellent in other physical properties than the conventional reduced coenzyme Q10 (this crystal is hereinafter referred to as a “reduced coenzyme Q10 Form I crystal”).

CITATION LIST

Patent Literature

Patent Literature 1: JP Patent Publication No. 10-109933 A (1998)

Patent Literature 2: WO2003-006409

Patent Literature 3: JP Patent Publication No. 2003-089669 A (2003)

Patent Literature 4: WO2012-176842

SUMMARY OF INVENTION

Technical Problem

Patent Literature 4 discloses a method for obtaining a reduced coenzyme Q10 Form II crystal, in which crystallization is carried out under specific conditions. However, there is a case where it takes a long period of time and further, the recovered amount is small. Thus, the method is not necessarily industrially optimal. Moreover, Patent Literature 4 also discloses a method of using a reduced coenzyme Q10 Form II crystal as a seed crystal upon crystallization. The present inventors have examined this method. As a result, it has been found that there is a case where the yield of the reduced coenzyme Q10 Form II crystal is low or such a reduced coenzyme Q10 Form II crystal cannot be obtained depending on crystallization conditions. Hence, the present inventors have found that conducting further studies, for example, regarding reproducibility is necessary in order to efficiently produce a reduced coenzyme Q10 Form II crystal.

Accordingly, it is an object of the present invention to provide an efficient method for producing a reduced coenzyme Q10 Form II crystal, which is a stable crystal form, the method being suitable for industrial scale production.

Solution to Problem

As a result of intensive studies directed towards achieving the aforementioned object, the present inventors have found that a reduced coenzyme Q10 Form II crystal can be produced with good reproducibility and high efficiency by a crystal precipitation method in which a reduced coenzyme Q10 Form II crystal is used as a seed crystal, a specific solvent is used and the seed crystal is added to the specific solvent in a specific temperature range. Based on this finding, the present inventors have completed the present invention.

Specifically, the method for producing a reduced coenzyme Q10 Form II crystal of the present invention is characterized in that it comprises:

adding a reduced coenzyme Q10 Form II crystal as a seed crystal to a solution with a temperature of 32° C. to 43° C., containing at least one organic solvent selected from the group consisting of an alcohol, a hydrocarbon, an aliphatic acid ester and a nitrogen compound, and reduced coenzyme Q10, to prepare a mixture, and

precipitating a reduced coenzyme Q10 Form II crystal in the mixture.

In one or more preferred aspects of the present invention, the amount of the seed crystal added is 0.5% to 20% by weight, based on the weight of the reduced coenzyme Q10 in the solution before the addition of the seed crystal.

In one or more other preferred aspects of the present invention, the organic solvent comprises 0.5% to 34% by weight of water.

In one or more other preferred aspects of the present invention, the organic solvent is a monohydric alcohol having 1 to 5 carbon atoms. Further, the above-described alcohol is preferably ethanol. Further, the ethanol preferably comprises 8% by weight or less of water or does not comprise water.

One or more other preferred aspects of the present invention further comprise, before the preparation of the mixture,

heating a raw material mixture containing the organic solvent and the reduced coenzyme Q10 to 42° C. or higher, so that the reduced coenzyme Q10 is dissolved therein, and

cooling the solution after the heating to a temperature that is lower than the heating temperature and in the range of 32° C. to 43° C., to prepare a supersaturated solution of the reduced coenzyme Q10.

In one or more other preferred aspects of the present invention, the precipitating the crystal comprises maintaining the temperature of the mixture at 32° C. or higher for 1 hour or more after the adding the seed crystal.

In one or more other preferred aspects of the present invention, the precipitating the crystal comprises decreasing over time the temperature of the mixture.

In one or more other preferred aspects of the present invention, the precipitating the crystal comprises:

maintaining the temperature of the mixture at 32° C. or higher for 1 hour or more after the adding the seed crystal, and then,

decreasing the temperature of the mixture to a temperature of 25° C. or lower at a rate in which a temperature decrease amount per hour is 15° C. or lower.

In one or more other preferred aspects of the present invention, the precipitating the crystal is carried out, while forced-flowing the mixture with a power required for stirring of 0.03 kw/m3or more per unit volume.

In one or more other preferred aspects of the present invention, the solution contains 1% by weight or more and 70% by weight or less of reduced coenzyme Q10.

One or more other preferred aspects of the present invention further comprise solid-liquid separating the precipitated crystal and then drying the precipitated crystal at a temperature of 46° C. or higher.

In one or more other preferred aspects of the present invention, each step is carried out under a deoxygenated atmosphere.

The present description encompasses the specification and/or drawings in JP Patent Application No. 2018-161790 which serves as the basis of the priority of the present application.

Advantageous Effects of Invention

According to the production method of the present invention, a reduced coenzyme Q10 Form II crystal that is more stable than the conventional reduced coenzyme Q10 crystal can be produced by an efficient and industrially suitable method.

