Method for producing Form II reduced coenzyme Q10 crystals or crystalline solids thereof and crystallizer

Abstract

The purpose of the present invention is to provide a method which is for producing form-II type reduced coenzyme Q10 crystals or a crystalline solid thereof, and which enables stable production of form-II type reduced coenzyme Q10 crystals or a crystalline solid thereof.　A method for producing form-II type reduced coenzyme Q10 crystals or a crystalline solid thereof according to an embodiment of the present invention uses a crystallizing apparatus provided with a crystallization part, a turbidity detection part capable of detecting the turbidity in the crystallization part, and a temperature adjustment part capable of adjusting the temperature inside the crystallization part, the method comprising: housing a mixture solution containing an alcohol and reduced coenzyme Q10 in the crystallization part; adding, to the mixture solution, form-II type reduced coenzyme Q10 crystals as seed crystals; and precipitating form-II type reduced coenzyme Q10 crystals in the mixture solution after the seed crystals have been added. The precipitating includes controlling the temperature by the temperature adjustment part on the basis of the rate of change in the turbidity obtained by the turbidity detection part.

Description

[Technical Field]

[0001] The present disclosure relates to a method for producing reduced coenzyme Q10 crystals of Form II type or a crystalline solid thereof, and a crystallizer. [Background technology]

[0002] Coenzyme Q is an essential component found in a wide range of living organisms, from bacteria to mammals, and is known as a component of the mitochondrial electron transport chain in living cells. Coenzyme Q functions as a transport component in the electron transport chain by repeatedly undergoing oxidation and reduction within mitochondria. Reduced coenzyme Q is also known to have antioxidant properties. In humans, the main component is coenzyme Q10, which has 10 repeating side chains of coenzyme Q, and approximately 40-90% of coenzyme Q exists in the body as a reduced form. The physiological effects of coenzyme Q include mitochondrial activation, which stimulates energy production, cardiac function, stabilization of cell membranes, and cell protection through its antioxidant properties.

[0003] Most of the coenzyme Q10 currently manufactured and sold is oxidized coenzyme Q10, but in recent years, reduced coenzyme Q10, which shows higher oral absorption than oxidized coenzyme Q10, has also appeared on the market and is becoming more widely used.

[0004] A general method for obtaining reduced coenzyme Q10 has already been disclosed (Patent Document 1). Furthermore, several methods for obtaining reduced coenzyme Q10 as crystals are also known. For example, a method for producing crystals by crystallizing reduced coenzyme Q10 in an alcohol solution and / or a ketone solution (Patent Document 2) and a method for crystallizing reduced coenzyme Q10 by adding a highly concentrated liquid phase of reduced coenzyme Q10 to a poor solvent (Patent Document 3) have been reported.

[0005] Meanwhile, Patent Document 4 describes the phenomenon of crystalline polymorphism in reduced coenzyme Q10, and reports that the newly emerged crystalline form (hereinafter referred to as Form II reduced coenzyme Q10 crystal or Form II crystal) is significantly more stable than conventional reduced coenzyme Q10 (hereinafter referred to as Form I reduced coenzyme Q10 crystal or Form I crystal), and also has other superior physical properties. Patent Document 5 also describes a method for producing Form II reduced coenzyme Q10 crystal. Patent Document 5 discloses, in claim 1, a method for producing Form II reduced coenzyme Q10 crystal, comprising adding Form II reduced coenzyme Q10 crystal as seed crystals to a solution containing reduced coenzyme Q10 and at least one organic solvent selected from the group consisting of alcohols, hydrocarbons, fatty acid esters, and nitrogen compounds, and reduced coenzyme Q10, at a temperature of 32 to 43°C, to prepare a mixed solution, and precipitating Form II reduced coenzyme Q10 crystals in the mixed solution. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 10-109933 [Patent Document 2] International Publication No. 2003 / 006409 [Patent Document 3] Japanese Patent Application Laid-Open No. 2003-089669 [Patent Document 4] International Publication No. 2012 / 176842 [Patent Document 5] International Publication No. 2020 / 045571 Summary of the Invention [Problem to be solved by the invention]

[0007] Patent Document 4 describes a method for obtaining Form II reduced coenzyme Q10 crystals by crystallization under specific conditions, but this method requires a long time and the recovery amount may be small, so it is not necessarily the most suitable method for industrial use.The method disclosed in Patent Document 5 aims to provide an efficient production method suitable for industrial-scale production of Form II reduced coenzyme Q10 crystals, and the method disclosed focuses mainly on temperature.

[0008] While the inventors have been conducting extensive research into methods for producing Form II reduced coenzyme Q10 crystals or their crystalline solids, they have found that when the precipitation of Form II reduced coenzyme Q10 crystals is controlled solely based on temperature, there is a large difference in the oxidation stability between lots of the resulting Form II reduced coenzyme Q10 crystals or their crystalline solids, even when Form II reduced coenzyme Q10 crystals are repeatedly produced under the same temperature conditions.

[0009] While investigating methods for producing Form II reduced coenzyme Q10 crystals or their crystalline solids, focusing on factors other than temperature, the present inventors discovered that Form II reduced coenzyme Q10 crystals or their crystalline solids can be stably produced by controlling the temperature based on the turbidity change rate. Therefore, an object of the present disclosure is to provide a method for producing Form II reduced coenzyme Q10 crystals or their crystalline solids, which enables the stable production of Form II reduced coenzyme Q10 crystals or their crystalline solids. Another object is to provide a crystallizer that can be used in carrying out the method for producing Form II reduced coenzyme Q10 crystals or their crystalline solids. [Means for solving the problem]

[0010] When Form II reduced coenzyme Q10 crystals are precipitated in a mixture containing alcohol and reduced coenzyme Q10, the amount of Form II reduced coenzyme Q10 crystals in the mixture increases as the precipitation proceeds, resulting in an increase in turbidity. The present inventors have found that by controlling the temperature based on the rate of change in turbidity, Form II reduced coenzyme Q10 crystals or their crystalline solids with high oxidation stability can be stably produced.

[0011] An example aspect of this embodiment is described as follows. (1) A crystallization apparatus is provided with a crystallization section, a turbidity detection section capable of detecting the turbidity in the crystallization section, and a temperature control section capable of controlling the temperature in the crystallization section, placing a mixed solution containing alcohol and reduced coenzyme Q10 in a crystallization section; Adding reduced coenzyme Q10 crystals of Form II type as seed crystals to the mixture; and precipitating Form II reduced coenzyme Q10 crystals in the mixture after the addition of the seed crystals, The precipitation includes controlling the temperature by the temperature adjustment unit based on the turbidity change rate obtained from the turbidity detection unit. A method for producing Form II reduced coenzyme Q10 crystals or crystalline solids thereof. (2) The manufacturing method described in (1), wherein the control is a control that changes at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid based on a predetermined range of the turbidity change rate and the measured value of the turbidity change rate. (3) The predetermined range is determined based on a formazin turbidity (FTU) change rate, The manufacturing method according to (2), wherein the predetermined range is set within a range of 2 to 45 FTU / min during the period in which the FTU reaches from 1,000 to 10,000. (4) The method according to any one of (1) to (3), wherein the alcohol is a monohydric alcohol having 1 to 5 carbon atoms. (5) The method according to (4), wherein the monohydric alcohol having 1 to 5 carbon atoms is ethanol. (6) The method according to any one of (1) to (5), wherein the alcohol is 95% by weight or more of alcohol based on the total amount of water and alcohol. (7) a crystallization unit capable of accommodating a mixed solution containing alcohol and reduced coenzyme Q10; a turbidity detection unit that detects a rate of change in turbidity of the mixed liquid contained in the crystallization unit; a temperature control unit capable of controlling the temperature in the crystallization unit; and a control unit that controls the temperature adjustment by the temperature adjustment unit based on the turbidity change rate of the mixed liquid obtained from the turbidity detection unit; A crystallizer for producing reduced coenzyme Q10 crystals of Form II type, including: (8) The crystallization apparatus according to (7), wherein the control is a control that changes at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid based on a predetermined range of the turbidity change rate and a measured value of the turbidity change rate. (9) The predetermined range is determined based on a formazin turbidity (FTU) change rate, The crystallizer according to (8), wherein the predetermined range is set within a range of 2 to 45 FTU / min during the period in which the FTU reaches from 1,000 to 10,000. This specification includes the disclosure of Japanese Patent Application No. 2021-053784, from which this application claims priority. [Effects of the Invention]

[0012] According to the disclosed method for producing reduced coenzyme Q10 crystals of Form II or a crystalline solid thereof, reduced coenzyme Q10 crystals of Form II or a crystalline solid thereof can be stably produced. Furthermore, the disclosed crystallization apparatus can be used in carrying out the production method. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is a schematic diagram of one aspect of the crystallization apparatus of this embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention will be described in detail below.

[0015] <Reduced coenzyme Q10> As used herein, "reduced coenzyme Q10" refers to reduced coenzyme Q10 as the main component, and may also contain oxidized coenzyme Q10 as a part of it. Here, "main component" means, for example, 50% by weight or more, usually 60% by weight or more, preferably 70% by weight or more, more preferably 80% by weight or more, even more preferably 90% by weight or more, particularly preferably 95% by weight or more, and especially preferably 98% by weight or more. The aforementioned percentage refers to the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10.

[0016] As mentioned above, reduced coenzyme Q10 exists in two types of crystalline polymorphism: the conventionally known Form I and the recently discovered Form II. Specifically, Form I is a crystalline form of reduced coenzyme Q10 with a melting point of around 48°C and characteristic peaks at diffraction angles (2θ±0.2°) of 3.1°, 18.7°, 19.0°, 20.2°, and 23.0° in powder X-ray (Cu-Kα) diffraction. Form II is a crystalline form of reduced coenzyme Q10 with a melting point of around 52°C and characteristic peaks at diffraction angles (2θ±0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3° in powder X-ray (Cu-Kα) diffraction. In this specification, a "crystal of Form II reduced coenzyme Q10" refers to a crystal of reduced coenzyme Q10 that satisfies any one of the following conditions: a differential scanning calorimetry (DSC) measurement shows an endothermic peak at 54±2°C when heated at a rate of 5°C / min, a similar measurement shows an endothermic peak at 52±2°C when heated at a rate of 1°C / min, or a powder X-ray (Cu-Kα) diffraction measurement shows characteristic peaks at diffraction angles (2θ±0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3°. Of course, it is also acceptable for the crystal to satisfy all of these conditions.

[0017] Furthermore, the term "crystalline solid" as used herein refers to a solid that contains both a portion having a crystalline structure and an amorphous component that does not have a crystalline structure. That is, the term "crystalline solid thereof" in "reduced coenzyme Q10 crystal of Form II or a crystalline solid thereof" refers to a solid that contains both a portion having the crystalline structure of reduced coenzyme Q10 crystal of Form II and an amorphous component that does not have a crystalline structure.

[0018] <Alcohol> The present inventors have found that, since the saturation concentration of Form II crystals in alcohol is lower than that of Form I crystals, it is possible to efficiently precipitate Form II reduced coenzyme Q10 crystals by using alcohol as a solvent for reduced coenzyme Q10.

[0019] The alcohol is preferably a monohydric alcohol having 1 to 5 carbon atoms. Examples of the monohydric alcohol having 1 to 5 carbon atoms include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and n-pentanol. As the alcohol, ethanol is particularly preferred because the saturation concentration of Form II crystals is sufficiently lower than that of Form I crystals and is easy to handle. The alcohols exemplified above may be used alone or in combination of two or more.

[0020] The alcohol in this specification may be any solvent containing alcohol as a main component, and may also be a hydrous alcohol containing water. The lower the water content of the alcohol, the easier it is to selectively precipitate Form II crystals. Therefore, the alcohol concentration relative to the total amount of water and alcohol is, for example, 80% by weight or more, usually 90% by weight or more, preferably 95% by weight or more, more preferably 97% by weight or more, even more preferably 99% by weight or more, and particularly preferably 99.5% by weight or more. Note that alcohol with an alcohol concentration of 99.5% by weight or more means absolute alcohol. The upper limit of the alcohol concentration is 100% by weight or less.

[0021] As the alcohol, hydrous ethanol or anhydrous ethanol is particularly preferred. As the ethanol, based on the total amount of water and ethanol, the ethanol concentration is, for example, 80% by weight or more, usually 90% by weight or more, preferably 95% by weight or more, more preferably 97% by weight or more, still more preferably 99% by weight or more, particularly preferably 99.5% by weight or more. Also, the upper limit of the ethanol concentration is 100% by weight or less.

[0022] <Method for Producing Form II Reduced Coenzyme Q10 Crystal or Crystalline Solid Thereof> The method for producing a Form II reduced coenzyme Q10 crystal or a crystalline solid thereof according to the present embodiment uses a crystallization apparatus provided with a crystallization section, a turbidity detection section capable of detecting the turbidity in the crystallization section, and a temperature adjustment section capable of adjusting the temperature in the crystallization section. The method includes accommodating a mixed solution containing alcohol and reduced coenzyme Q10 in the crystallization section, adding a Form II reduced coenzyme Q10 crystal as a seed crystal to the mixed solution, and precipitating a Form II reduced coenzyme Q10 crystal in the mixed solution after the addition of the seed crystal. The precipitation includes controlling the temperature by the temperature adjustment section based on the rate of change of turbidity obtained from the turbidity detection section. It is a method for producing a Form II reduced coenzyme Q10 crystal or a crystalline solid thereof.

[0023] In the following description, the step of adding a Form II reduced coenzyme Q10 crystal as a seed crystal may be referred to as the "seed crystal addition step", and the step of precipitating a Form II reduced coenzyme Q10 crystal may be referred to as the "crystal precipitation step".

[0024] The method for producing Form II reduced coenzyme Q10 crystals according to this embodiment uses a crystallizer equipped with a crystallization section, a turbidity detection section capable of detecting turbidity within the crystallization section, and a temperature control section capable of controlling the temperature within the crystallization section. A schematic diagram of one embodiment of the crystallization section is shown in FIG. 1. The crystallization section 1 shown in FIG. 1 is shown with a mixed solution 3 containing alcohol and reduced coenzyme Q10 contained therein. The crystallization section 1 is equipped with a turbidity detection section 5 (e.g., a turbidity meter), and preferably a temperature detection section 7 (e.g., a thermometer). In the crystallization section shown in FIG. 1, the temperature of the crystallization section 1 can be controlled by a temperature control section composed of a constant-temperature water bath 9 and a heat medium 11 (e.g., water). In the crystallization section shown in FIG. 1, the turbidity detection section 5 includes a turbidity sensor 5a and a converter 5b that converts the signal detected by the turbidity sensor 5a into turbidity, such as an FTU value. The crystallizer also has a control unit 13 for controlling the temperature adjustment by the temperature adjustment unit based on the change in turbidity of the mixed solution obtained by the turbidity detection unit 5. The crystallizer shown in Fig. 1 also preferably has a stirring blade 15 for stirring the inside of the crystallization unit 1. The crystallizer shown in Fig. 1 is one embodiment of a crystallizer for Form II reduced coenzyme Q10 crystals according to this embodiment, which will be described later.

[0025] The control unit 13 is a control mechanism that controls the temperature adjustment by the temperature adjustment unit, and may also be a central control mechanism that controls other conditions (e.g., stirring conditions) in addition. The control unit 13 can be configured, for example, by software programs for implementing various processes, a CPU that executes the software programs, and various hardware controlled by the CPU. In one aspect, the control unit 13 is a computer that includes a CPU and input / output circuits. In this embodiment, the programs, data, and control parameters required for the operation of the control unit 13 can be stored in a memory unit (not shown). Note that there is no particular limitation on where these programs, data, etc. are stored. These programs, data, etc. may be stored in a separate, dedicated storage device such as a disk or flash memory. They may also be stored in an external server, memory unit, etc. that is connected for communication.

[0026] The mixed liquid containing alcohol and reduced coenzyme Q10 contained in the crystallization section is not particularly limited as long as it contains alcohol and reduced coenzyme Q10, and may be a homogeneous solution in which reduced coenzyme Q10 is dissolved in alcohol, or a slurry in which reduced coenzyme Q10 is partly dissolved in alcohol and partly undissolved and suspended, but is preferably a homogeneous solution in which reduced coenzyme Q10 is dissolved in alcohol.

[0027] The reduced coenzyme Q10 used in the mixture containing alcohol and reduced coenzyme Q10 may be crystalline or amorphous, and any crystalline polymorph may be used. Therefore, the conventionally known Form I reduced coenzyme Q10 can also be used. Furthermore, since its purity can be increased by crystal precipitation, reduced coenzyme Q10 containing impurities or unpurified or crudely purified reduced coenzyme Q10 may also be used. Furthermore, extracts of reduced coenzyme Q10 obtained by conventionally known methods, or reaction solutions containing reduced coenzyme Q10 obtained from oxidized coenzyme Q10 by known reduction methods, can be used as the mixture, either directly or after purification and / or solvent replacement as necessary.

[0028] The mixture containing alcohol and reduced coenzyme Q10 may further contain organic solvents other than alcohol (including hydrous alcohol), but the alcohol content (alcohol purity) based on the total amount of solvent components is preferably 95% by weight or more, 97% by weight or more, or 99% by weight or more, with the upper limit being preferably 100% by weight or less. The alcohol purity is most preferably 99.5% by weight or more. Examples of other organic solvents include at least one selected from the group consisting of hydrocarbons, fatty acid esters, and nitrogen compounds.

[0029] The dissolved concentration of reduced coenzyme Q10 in the mixed solution containing alcohol and reduced coenzyme Q10 before the addition of seed crystals is, for example, 2% by weight or more, preferably 3% by weight or more, more preferably 5% by weight or more, even more preferably 7% by weight or more, and particularly preferably 9% by weight or more. The dissolved concentration of reduced coenzyme Q10 before the addition of seed crystals is, for example, 50% by weight or less, preferably 45% by weight or less, more preferably 30% by weight or less, even more preferably 20% by weight or less, and particularly preferably 15% by weight or less.

[0030] The mixed solution containing alcohol and reduced coenzyme Q10 can be obtained by heating a raw material mixture containing alcohol and reduced coenzyme Q10 to a temperature of, for example, 42° C. or higher to dissolve reduced coenzyme Q10. The temperature is preferably 70° C. or lower, more preferably 55° C. or lower. After dissolving reduced coenzyme Q10, and before adding seed crystals, the mixed solution containing alcohol and reduced coenzyme Q10 is preferably cooled to the temperature at which seed crystals will be added, as described below.

[0031] The amount of Form II reduced coenzyme Q10 crystals added as seed crystals (seed crystal addition amount) is not particularly limited, but is preferably 0.1 wt% or more, more preferably 0.5 wt% or more, even more preferably 0.8 wt% or more, and particularly preferably 1 wt% or more, based on the amount of reduced coenzyme Q10 in the mixture before seed crystal addition (100 wt%). The upper limit is not particularly limited, but is preferably 20 wt% or less, more preferably 4 wt% or less, and even more preferably 2.2 wt% or less, based on the amount of reduced coenzyme Q10 in the mixture before seed crystal addition (100 wt%). The reduced coenzyme Q10 crystals used as seed crystals may contain Form I reduced coenzyme Q10 crystals or amorphous forms, as long as they contain Form II reduced coenzyme Q10 crystals. However, the purity of Form II reduced coenzyme Q10 crystals is preferred. The seed crystals to be used should be, for example, 50% by weight or more, preferably 75% by weight or more, more preferably 80% by weight or more, and even more preferably 90% by weight or more of Form II reduced coenzyme Q10 crystals.

[0032] The temperature of the mixture at the time of adding the seed crystals is preferably 30 to 43° C. The temperature of the mixture at the time of adding the seed crystals is more preferably 32° C. or higher, particularly preferably 34° C. or higher, and more preferably 40° C. or lower. Within this range, selective precipitation of Form II reduced coenzyme Q10 crystals is facilitated.

[0033] The crystal precipitation process includes controlling the temperature using a temperature control unit based on the turbidity change rate obtained from the turbidity detection unit. In the crystal precipitation process, an increase in turbidity indicates the precipitation of crystals, and the turbidity change rate (the amount of turbidity change per unit time) is an indicator of the crystal precipitation rate. Examples of control include changing at least one of the temperature of the mixed solution and the cooling rate of the mixed solution based on a predetermined range of the turbidity change rate and the measured value of the turbidity change rate. For example, if the measured turbidity change rate is greater than a predetermined range, it is determined that the crystal precipitation rate is fast, and the temperature of the mixed solution can be increased or the cooling rate can be decreased. As another example, if the measured turbidity change rate is smaller than a predetermined range, it is determined that the crystal precipitation rate is slow, and the temperature of the mixed solution can be decreased or the cooling rate can be increased. While control is preferably performed based on the predetermined range of the turbidity change rate and the measured value of the turbidity change rate, it is not necessary to always change at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid when the measured value falls outside the predetermined range. If it is expected that the measured value of the turbidity change rate will quickly return to the predetermined range, it is not necessary to change the temperature of the mixed liquid and the cooling rate of the mixed liquid. For example, if the temperature of the mixed liquid is maintained constant, as crystal precipitation progresses, the crystal precipitation rate slows and the turbidity change rate also decreases. Therefore, even if the turbidity change rate temporarily exceeds the predetermined range, it is expected that it will quickly fall within the predetermined range. Furthermore, control may be performed by changing at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid each time based on the turbidity change rate, or by setting a temperature program in advance and changing at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid when an abnormality occurs in the turbidity change rate.

[0034] The turbidity may be based on any index, such as kaolin turbidity or formazin turbidity (FTU), with formazin turbidity being preferred from the viewpoint of versatility.

[0035] The rate of change in turbidity can be calculated, for example, by dividing the difference between the turbidity measured at a certain point in time and the turbidity measured immediately before that point by the measurement interval.

[0036] For example, the rate of change in turbidity at a certain point in time (T) can be calculated using the following formula: Turbidity change rate T (Turbidity / min) = (Turbidity measurement value T -Turbidity measurements T-X ) / X(min) (In the above formula, the turbidity change rate T means the rate of change of turbidity at time point (T), and the turbidity measurement value T means the turbidity measurement value at time point (T), and the turbidity measurement value T-X means the turbidity measurement value X minutes before time T.)

[0037] Furthermore, when the turbidity to be measured is formazin turbidity (FTU), the rate of change in FTU at a certain point in time (T) can be calculated by the following formula. FTU change rate T (FTU / min) = (Turbidity measurement value T (FTU) - Turbidity measurement T-X (FTU) / X(min) (In the above formula, the FTU change rate T means the rate of change of FTU at time point (T), and is the turbidity measurement value T (FTU) means the FTU measurement value at time point (T), and the turbidity measurement value T-X (FTU) means the FTU measured X minutes before time T.)

[0038] There is no particular limitation on the frequency at which the turbidity change rate is determined, but if the turbidity change rate is measured too frequently, it may become unstable due to measurement errors or differences in concentration in the mixed solution, and if the turbidity change rate is measured too infrequently, it may become difficult to adequately control the crystal precipitation rate. From this perspective, the turbidity change rate is preferably determined, for example, every 3 to 180 minutes, more preferably every 5 to 30 minutes, and even more preferably every 10 to 30 minutes. The measurement interval may be constant or not, and is not particularly limited.

[0039] In one preferred embodiment, when the turbidity measured is formazin turbidity (FTU) and the turbidity change rate is a range determined based on the formazin turbidity (FTU) change rate, the predetermined range is set within a range of 2 to 45 FTU / min for the period from 1,000 to 10,000 FTU. The predetermined range is more preferably set within a range of 2 to 43 FTU / min, and even more preferably within a range of 2 to 35 FTU / min, for the period from 1,000 to 10,000 FTU. As crystal precipitation progresses, turbidity (e.g., FTU) increases. However, particularly immediately after the addition of seed crystals, FTU tends to increase rapidly and measurement error tends to increase. Therefore, maintaining a constant FTU change rate from the time of seed crystal addition is not necessarily practical. In this embodiment, the predetermined range is set within the period from 1,000 to 10,000 FTU. Setting such a predetermined range enables a method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof to be carried out with good reproducibility.

[0040] At the time of adding the seed crystals, the mixed solution is preferably a homogeneous solution in which reduced coenzyme Q10 is dissolved in alcohol. When the turbidity to be measured is FTU, the FTU of the mixed solution at the time of adding the seed crystals is usually 0 to 250, preferably 0 to 230, and more preferably 0 to 200. This range is preferred because Form II reduced coenzyme Q10 crystals are preferentially precipitated.

[0041] When the turbidity to be measured is FTU, the temperature of the mixed liquid during the period in which the FTU changes from 1,000 to 10,000 is preferably 30° C. or higher and 43° C. or lower, more preferably 30.5° C. or higher and 42° C. or lower, and particularly preferably 31° C. or higher and 41° C. or lower. Within the above range, it is easy to maintain the FTU change rate within the above range, which is preferable.

[0042] When the turbidity measured is in FTU, the temperature of the mixed liquid at the time when the FTU reaches 10,000 is preferably 29°C or higher and 38°C or lower, more preferably 30°C or higher and 37°C or lower, and particularly preferably 31°C or higher and 36°C or lower.

[0043] In the crystallization step, the temperature of the mixed solution may be constant, or may be decreased stepwise or continuously. Alternatively, the temperature of the mixed solution may be maintained at a constant temperature for a certain period of time and then decreased stepwise or continuously. In a preferred embodiment, the temperature of the mixed solution at the time of adding the seed crystals is 34°C or higher and 38°C or lower, and the temperature of the mixed solution at the time of FTU reaching 10,000 is 30°C or higher and 37°C or lower, and it is preferred that the temperature at the time of FTU reaching 10,000 is 0.4°C or higher and 8°C or lower than the temperature at the time of adding the seed crystals. Maintaining a constant temperature preferably means maintaining the temperature at a predetermined temperature (set temperature) ±3°C, more preferably maintaining the temperature at a predetermined temperature (set temperature) ±1°C.

[0044] The cooling rate when lowering the temperature of the mixed solution is preferably 0.05°C / hr or more and 20°C / hr or less, and more preferably 0.1°C / hr or more and 15°C / hr or less. Varying the cooling rate over time is also a preferred embodiment. For example, after adding seed crystals, the temperature is maintained for a certain period of time, for example, 0.5 to 8 hours, and then the cooling rate is changed to 0.05°C / hr or more and less than 0.5°C / hr for 3 to 20 hours, and then the cooling rate is changed to 0.5°C / hr or more and 15°C / hr or less; or after adding seed crystals, the cooling rate is changed to 0.05°C / hr or more and less than 0.5°C / hr for 3 to 20 hours, and then the cooling rate is changed to 0.5°C / hr or more and 15°C / hr or less.

[0045] In the crystallization step, when the turbidity measured is FTU, it is preferable to continue lowering the temperature of the mixed solution to precipitate crystals even after the FTU reaches the upper measurement limit of 10,000. The cooling rate at this time can be set, for example, based on the range described above. Furthermore, since most of the reduced coenzyme Q10 contained in the mixed solution has already precipitated by the time the temperature of the mixed solution reaches 23 to 34°C, it is also possible to increase the cooling rate, for example, to between 1°C / hr and 20°C / hr after the temperature reaches 23 to 34°C.

[0046] The temperature at which the crystallization step is completed, i.e., the end point temperature, is preferably 25° C. or lower, more preferably 20° C. or lower, more preferably 10° C. or lower, more preferably 7° C. or lower, and more preferably 5° C. or lower. The lower limit of the end point temperature is the solidification temperature of the mixed liquid system, and is preferably 0° C. or higher.

[0047] It is preferable to carry out crystal precipitation while forcibly flowing the mixed liquid. From the viewpoint of suppressing the formation of supersaturation and smoothly carrying out nucleation and crystal growth, or from the viewpoint of high quality, the required stirring power per unit volume is usually 0.003 kW / m 3 or more, preferably 0.004 kW / m 3 More than 0.005kW / m 3 More preferably, 0.006 kW / m 3 It is desirable to give the above flow to the mixed liquid. The required stirring power is usually 0.1 kW / m 3 Less than or equal to 0.03 kW / m 3 The following flow is preferably imparted to the mixed liquid: The above-mentioned forced flow is usually imparted by rotation of an agitator blade, but it is not always necessary to use an agitator blade as long as the above-mentioned flow can be obtained, and for example, a method of circulating the mixed liquid may also be used.

[0048] The Form II reduced coenzyme Q10 crystals obtained by the above method are recovered through solid-liquid separation and drying steps by conventionally known methods such as those described in Patent Documents 2 and 3. For example, pressure filtration, centrifugal filtration, etc. can be used for solid-liquid separation. Furthermore, the dried crystals or crystalline solids can be recovered by pulverizing and classifying (sieving) as necessary.

[0049] In one preferred embodiment of this embodiment, the content of Form II reduced coenzyme Q10 crystals can be improved by drying the Form II reduced coenzyme Q10 crystals after the solid-liquid separation under heating. For this purpose, the drying temperature is preferably 46°C or higher, more preferably 47°C or higher, and even more preferably 49°C or higher. The upper limit is usually 52°C or lower, preferably 51°C or lower. If the temperature is lower than 46°C, drying will proceed, but the content of Form II reduced coenzyme Q10 crystals will hardly improve. If the temperature is higher than 52°C, the reduced coenzyme Q10 crystals may melt during drying.

[0050] However, if the desired content of Form II reduced coenzyme Q10 crystals has already been achieved in the crystal precipitation process, the above does not apply, and drying can be carried out, for example, at 25°C or higher, preferably 30°C or higher, and more preferably 35°C or higher.

[0051] The heating time for drying is not particularly limited, but is preferably 4 hours or more, more preferably 10 hours or more, and more preferably 20 hours or more. There is no particular upper limit to the heating time, but it is usually 72 hours or less, preferably 48 hours or less, and more preferably 36 hours or less.

[0052] In addition, each step in the method of the present embodiment, specifically, the step of accommodating the above-described mixed solution in the crystallization section, the seed crystal addition step, the crystal precipitation step, and the recovery steps such as solid-liquid separation and drying, and other subsequent treatment steps are preferably carried out under a deoxygenated atmosphere. The deoxygenated atmosphere can be achieved by substituting the atmosphere with an inert gas, reducing the pressure, boiling, or combining these. At least, substitution of the atmosphere with an inert gas, that is, using an inert gas atmosphere is preferable. Examples of the inert gas include nitrogen gas, helium gas, argon gas, hydrogen gas, carbon dioxide gas, etc., and nitrogen gas is preferably used.

[0053] Whether the obtained reduced coenzyme Q10 crystals or its crystalline solid contains Form II type reduced coenzyme Q10 crystals and the content ratio thereof can be determined, for example, by measuring with a differential scanning calorimeter (DSC).

[0054] As described above, when the Form II type reduced coenzyme Q10 crystals are measured by DSC at a heating rate of 1 °C / min, an endothermic peak appears around 52 ± 2 °C, and the Form I type reduced coenzyme Q10 crystals show an endothermic peak around 48 ± 1 °C under the same conditions. Even when the Form II type reduced coenzyme Q10 crystals are mixed with the conventional Form I type reduced coenzyme Q10 crystals or its crystalline solid, the presence or absence of the Form II type reduced coenzyme Q10 crystals and the content ratio thereof can be determined by the presence or absence of the peak around 52 ± 2 °C, the height of the endothermic peak, and the ratio of the endothermic amount. According to the present invention, high-purity Form II type reduced coenzyme Q10 crystals or its crystalline solid can be efficiently obtained. According to the present embodiment, Form II type reduced coenzyme Q10 crystals can be obtained by the crystal precipitation step, but due to melting of some crystals during the subsequent drying step or the like, a crystalline solid may be obtained. Therefore, the present embodiment includes the case where crystals are obtained and the case where a crystalline solid is obtained.

[0055] <Crystallization Apparatus for Form II Type Reduced Coenzyme Q10 Crystals> The crystallization apparatus for Form II reduced coenzyme Q10 crystals of this embodiment is a crystallization apparatus for Form II reduced coenzyme Q10 crystals, comprising a crystallization section capable of accommodating a mixed solution containing alcohol and reduced coenzyme Q10, a turbidity detection section that detects the turbidity change rate of the mixed solution accommodated in the crystallization section, a temperature adjustment section that can adjust the temperature within the crystallization section, and a control section that controls the temperature adjustment by the temperature adjustment section based on the turbidity change rate of the mixed solution obtained from the turbidity detection section.

[0056] The crystallization apparatus according to this embodiment is an apparatus capable of carrying out the method for producing the above-mentioned Form II reduced coenzyme Q10 crystals or a crystalline solid thereof.

[0057] A schematic diagram illustrating one embodiment of the crystallization apparatus according to this embodiment is the crystallization apparatus shown in FIG. 1. A turbidity sensor 5a is installed in the crystallization section 1. More specifically, in FIG. 1, the turbidity sensor 5a is installed inside the crystallization section 1. In another embodiment, all or part of the crystallization section may be made of a light-transmitting material such as glass, and the turbidity sensor 5a may be installed outside the crystallization section. In FIG. 1, the temperature control section is arranged outside the crystallization section 1 as the constant-temperature water bath 9 and the heat medium 11, but in another embodiment, it may be installed inside the crystallization section 1. For example, the temperature control section may be provided by installing a heater or the like inside the crystallization section 1.

[0058] The control performed by the control unit is preferably a control that changes at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid based on a predetermined range of the turbidity change rate and a measured value of the turbidity change rate. The control unit, for example, executes a program stored in a memory unit to compare the measured value of the turbidity change rate with a predetermined range of the turbidity change rate stored in the memory unit, thereby determining whether or not it is necessary to change at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid, and then controls the temperature in response to the result of the determination. In one preferred embodiment, when the turbidity is formazin turbidity (FTU), the predetermined range of the turbidity change rate is a range determined based on the formazin turbidity (FTU) change rate, and the range is set within a range of 2 to 45 FTU / min for the period from 1,000 to 10,000 FTU. The predetermined range is more preferably set within a range of 2 to 43 FTU / min, and even more preferably within a range of 2 to 35 FTU / min, during the period from 1,000 to 10,000 FTU. [Example]

[0059] The present embodiment will be described below with reference to examples, but the present disclosure is not limited to these examples.

[0060] <Proportion of Form II crystals in reduced coenzyme Q10 crystals> The ratio of Form II crystals in the reduced coenzyme Q10 crystals obtained in the examples was calculated based on the following formula from the height of the endothermic peak (Y difference) of the obtained Form I crystals (hereinafter referred to as the Y difference of Form I) and the height of the endothermic peak (Y difference) of the Form II crystals (hereinafter referred to as the Y difference of Form II) by analyzing the crystals by DSC measurement under the conditions below. Form II ratio (%) = Y difference of Form II / (Y difference of Form I + Y difference of Form II) × 100

[0061] (DSC measurement conditions) Equipment: DSC6220 (SII Nanotechnology) Sample container: Aluminum pan & cover (SSC000C008) Heating rate: 1 °C / min Sample amount: 5 ± 2 mg

[0062] <Measurement method of FTU change rate> The FTU change rate in the examples was measured with a turbidimeter for the formazin turbidity (FTU) of the mixed solution of ethanol and reduced coenzyme Q10. The FTU change rate at time point (T) was calculated by the following formula. In addition, the turbidimeter used in this embodiment was calibrated with a turbidity (FTU) of 9,999 FTU when crystals of reduced coenzyme Q10 were present in the mixed solution at a concentration of 40,000 mg / L. FTU change rate T (FTU / min) = (Measured turbidity value T (FTU) - Measured turbidity value T-X (FTU)) / X (min) (In the above formula, the FTU change rate T means the FTU change rate at time point (T), and the measured turbidity value T (FTU) means the measured value of FTU at time point (T), and the measured turbidity value T-X (FTU) means the measured value of FTU X minutes before time point T.) Turbidimeter: Backscattered light type turbidity sensor (InPro8200, METTLER TOLEDO Co., Ltd.) Measurement range: 0 - 10,000 FTU

[0063] The measurement of FTU was carried out from immediately after the addition of seed crystals until FTU reached the measurement upper limit of 10,000, and the FTU change rate was calculated. The FTU change rate at a certain time point T was obtained by calculating the increase amount of FTU at time point T from the FTU at time point (T - X min) X minutes before, and dividing by X minutes. In the examples, the FTU change rate was calculated from the measured FTU, the FTU measured one time before, and the measurement interval.

[0064] <Evaluation method of oxidation stability (relative QH ratio)> The oxidation stability of the reduced coenzyme Q10 crystals obtained in the examples was evaluated by the following method.

[0065] The reduced coenzyme Q10 crystals obtained in the examples were stored in an open system in a thermostatic chamber set at 40°C, 75% RH (relative humidity) and 25°C, 60% RH for one month, and then the content ratio of reduced coenzyme Q10 (QH) and oxidized coenzyme Q10 was calculated using high-performance liquid chromatography.

[0066] The oxidative stability of reduced coenzyme Q10 crystals was calculated as the relative QH ratio using the following formula, relative to the content ratio of reduced coenzyme Q10 in the initial reduced coenzyme Q10 crystals before storage in a constant temperature bath, i.e., the content ratio of reduced coenzyme Q10 measured immediately after obtaining the crystals using the crystals obtained in the examples, taken as 100. Relative QH ratio (%) = reduced coenzyme Q10 ratio after storage / initial reduced coenzyme Q10 ratio × 100

[0067] The conditions for high performance liquid chromatography used to measure reduced coenzyme Q10 and oxidized coenzyme Q10 concentrations are shown below. (HPLC conditions) Column: SYMMETRY C18 (Waters), 250 mm (length), 4.6 mm (inner diameter) Mobile phase: C2H5OH:CH3OH=4:3(v:v) Detection wavelength: 210 nm Flow rate: 1ml / min

[0068] [Example 1] After replacing the nitrogen gas in a 3 L separable flask, 160 g of reduced coenzyme Q10 and 1,440 g of ethanol with a purity of 99.5 wt% or higher were added (reduced coenzyme Q10 concentration: 10 wt%) and stirred with a stirring blade (stirring power required: 0.03 kW / m 3 ) and heated to 50°C to obtain a homogeneous reduced coenzyme Q10 solution (QH solution) (1600g, 2800ml).

[0069] The QH solution at 50°C was stirred with a stirring blade (required stirring power: 0.03 kW / m 3) and cooled to 36.0°C. 3.2 g (2.0 wt%) of reduced coenzyme Q10 Form II crystals were added as seed crystals to the QH solution (FTU18) cooled to 36.0°C, and precipitation (crystallization) of reduced coenzyme Q10 crystals was initiated. Hereinafter, the QH solution with added seed crystals is referred to as the "crystallization mixture."

[0070] After the seed crystal addition, the formazin turbidity (FTU) of the mixed solution was measured periodically until it reached 10,000, and the cooling rate and cooling temperature were controlled so that the FTU change rate was around 20.8 FTU / min from 1,000 to 10,000. After the formazin turbidity of the mixed solution reached 10,000 FTU, it was cooled to 25°C at 1°C / hr, and then from 25°C to 1°C at 10°C / hr.

[0071] After cooling to 1°C, the slurry was subjected to solid-liquid separation by filtration, and the obtained crystals were dried under reduced pressure at 40°C for 24 hours to obtain Form II reduced coenzyme Q10 crystals.

[0072] The reduced coenzyme Q10 crystals obtained contained 100% Form II crystals, with no Form I reduced coenzyme Q10 crystals. The relative QH ratio of the obtained reduced coenzyme Q10 crystals after 1 month at 25°C and 60% RH was 91.8%, and the relative QH ratio after 1 month at 40°C and 75% RH was 88.1%.

[0073] Table 1 shows the elapsed time, turbidity, set temperature, and FTU change rate when the time when the FTU in Example 1 reached approximately 1,000 (942) was taken as 0 min.

[0074] [Table 1]

[0075] [Example 2] After replacing the air in a 500 mL four-neck flask with nitrogen, 32.8 g of reduced coenzyme Q10 and 295.2 g of ethanol with a purity of 99.5 wt% or higher were added (reduced coenzyme Q10 concentration: 10 wt%) and stirred with a stirring blade (stirring power required: 0.007 kW / m 3 ) and heated to 50°C to give 328 g (410 mL) of a homogeneous reduced coenzyme Q10 solution (QH solution).

[0076] The QH solution at 50°C was stirred with a stirring blade (required stirring power: 0.007 kw / m 3 ) and cooled to 34.0°C. 0.65 g (2.0 wt%) of reduced coenzyme Q10 Form II crystals were added as seed crystals to the QH solution cooled to 34.0°C, and precipitation (crystallization) of reduced coenzyme Q10 crystals was initiated.

[0077] After seed crystal addition, the formazin turbidity (FTU) of the mixture was measured periodically until it reached 10,000 FTU. The cooling rate and temperature were controlled so that the FTU change rate remained near 55.6 FTU / min from 1,000 to 10,000 FTU. If the FTU change rate of the mixture clearly deviated from 55.6 FTU / min, the crystallization rate (crystal precipitation rate) was adjusted by heating the mixture or maintaining the temperature for a certain period of time. After the formazin turbidity of the mixture reached 10,000 FTU, the mixture was cooled to 25°C at 1°C / hr, and then from 25°C to 1°C at 10°C / hr.

[0078] After cooling to 1°C, the slurry was subjected to solid-liquid separation by filtration, and the obtained crystals were dried under reduced pressure at 40°C for 24 hours to obtain Form II reduced coenzyme Q10 crystals.

[0079] The relative QH ratio of the obtained Form II reduced coenzyme Q10 crystals at 25°C and 60% RH for one month was 85.1%, and the relative QH ratio at 40°C and 75% RH for one month was 81.4%.

[0080] Table 2 shows the elapsed time, turbidity, set temperature, and FTU change rate when the time when the FTU in Example 2 reached approximately 1,000 (870) was set as 0 min.

[0081] [Table 2]

[0082] [Example 3] After replacing the air in a 500 mL separable flask with nitrogen, 32.8 g of reduced coenzyme Q10 and 295.2 g of ethanol with a purity of 99.5 wt% or higher were added (reduced coenzyme Q10 concentration: 10 wt%) and stirred with a stirring blade (required stirring power: 0.007 kW / m 3 ) and heated to 50°C to give 328 g (410 mL) of a homogeneous reduced coenzyme Q10 solution (QH solution).

[0083] The QH solution at 50°C was stirred with a stirring blade (required stirring power: 0.007 kw / m 3 ) and cooled to 34.5°C. 0.65 g (2.0 wt%) of reduced coenzyme Q10 Form II crystals were added as seed crystals to the QH solution cooled to 34.5°C, and precipitation (crystallization) of reduced coenzyme Q10 crystals was initiated.

[0084] After seed crystal addition, the formazin turbidity (FTU) of the mixture was measured periodically until it reached 10,000 FTU. The cooling rate and temperature were controlled so that the FTU change rate remained near 33.3 FTU / min from 1,000 to 10,000 FTU. If the FTU change rate of the mixture clearly deviated from 33.3 FTU / min, the crystallization rate (crystal precipitation rate) was adjusted by heating the mixture or maintaining the temperature for a certain period of time. After the formazin turbidity of the mixture reached 10,000 FTU, the mixture was cooled to 25°C at 1°C / hr, and then from 25°C to 1°C at 10°C / hr.

[0085] After cooling to 1°C, the slurry was subjected to solid-liquid separation by filtration, and the obtained crystals were dried under reduced pressure at 40°C for 24 hours to obtain Form II reduced coenzyme Q10 crystals.

[0086] The relative QH ratio of the obtained Form II reduced coenzyme Q10 crystals after 1 month at 25°C and 60% RH was 89.4%, and the relative QH ratio after 1 month at 40°C and 75% RH was 87.3%.

[0087] Table 3 shows the elapsed time, turbidity, set temperature, and FTU change rate when the time when the FTU in Example 3 reached approximately 1,000 (877) was taken as 0 min.

[0088] [Table 3]

[0089] [Example 4] After replacing the air in a 500 mL separable flask with nitrogen, 27.8 g of reduced coenzyme Q10 and 250.2 g of ethanol with a purity of 99.5 wt% or higher were added (reduced coenzyme Q10 concentration: 10 wt%) and stirred with a stirring blade (stirring power required: 0.007 kW / m 3 ) and heated to 50°C to obtain 278 g (347 mL) of a homogeneous reduced coenzyme Q10 solution (QH solution).

[0090] The QH solution at 50°C was stirred with a stirring blade (required stirring power: 0.007 kw / m 3 ) and cooled to 36.8°C. 0.56 g (2.0 wt%) of reduced coenzyme Q10 Form II crystals were added as seed crystals to the QH solution (FTU683) cooled to 36.8°C, and precipitation (crystallization) of reduced coenzyme Q10 crystals was initiated.

[0091] After seed crystal addition, the formazin turbidity (FTU) of the mixture was measured periodically until it reached 10,000 FTU. The cooling rate and temperature were controlled so that the FTU change rate remained around 6.9 FTU / min from 1,000 to 10,000 FTU. If the FTU change rate of the mixture clearly deviated from 6.9 FTU / min, the crystallization rate (crystal precipitation rate) was adjusted by heating the mixture or maintaining the temperature for a certain period of time. After the formazin turbidity of the mixture reached 10,000 FTU, the mixture was cooled to 25°C at 1°C / hr, and then cooled from 25°C to 1°C at 10°C / hr.

[0092] After cooling to 1°C, the slurry was subjected to solid-liquid separation by filtration, and the obtained crystals were dried under reduced pressure at 40°C for 24 hours to obtain Form II reduced coenzyme Q10 crystals.

[0093] The Form II crystal ratio of the obtained reduced coenzyme Q10 crystals was 100%. The relative QH ratio of the obtained Form II reduced coenzyme Q10 crystals after 1 month at 25°C and 60% RH was 92.2%, and the relative QH ratio after 1 month at 40°C and 75% RH was 90.1%.

[0094] Tables 4 and 5 show the elapsed time, turbidity, set temperature, and FTU change rate when the time when the FTU in Example 4 reached approximately 1,000 (933) was taken as 0 min.

[0095] [Table 4]

[0096] [Table 5]

[0097] Table 6 shows the proportion of Form II crystals (Form II ratio) and relative QH ratio of reduced coenzyme Q10 crystals obtained in the examples.

[0098] [Table 6]

[0099] The Form II reduced coenzyme Q10 crystals obtained in the examples have excellent oxidation stability, and it can be seen that the method for producing Form II reduced coenzyme Q10 crystals or their crystalline solids of this embodiment makes it possible to stably produce Form II reduced coenzyme Q10 crystals or their crystalline solids.

[0100] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0101] The upper and / or lower limit values ​​of the numerical ranges described herein can be arbitrarily combined to define a preferred range. For example, the upper and lower limit values ​​of the numerical ranges can be arbitrarily combined to define a preferred range, the upper limit values ​​of the numerical ranges can be arbitrarily combined to define a preferred range, and the lower limit values ​​of the numerical ranges can be arbitrarily combined to define a preferred range.

[0102] Throughout this specification, singular terms should be understood to include the plural concept unless otherwise stated. Thus, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise stated.

[0103] Although the present embodiment has been described in detail above, the specific configuration is not limited to this embodiment, and even if there are design changes within the scope that do not deviate from the gist of this disclosure, they are included in this disclosure. [Explanation of symbols]

[0104] 1. Crystallization section 3...Mixed liquid 5. Turbidity detection unit 5a Turbidity sensor 5b Converter 7 Temperature detection section 9. Constant temperature water bath 11...Heating medium 13 Control section 15...Agitation blade

Claims

1. A crystallization apparatus is provided with a crystallization section, a turbidity detection section capable of detecting the turbidity in the crystallization section, and a temperature control section capable of controlling the temperature in the crystallization section, placing a mixed solution containing alcohol and reduced coenzyme Q10 in a crystallization section; Adding Form II reduced coenzyme Q10 crystals as seed crystals to the mixture; and precipitating Form II reduced coenzyme Q10 crystals in the mixture after the addition of the seed crystals, the precipitation includes controlling a temperature by the temperature adjusting unit based on a turbidity change rate obtained by the turbidity detecting unit, the control changes at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid based on a predetermined range of the turbidity change rate and the measured value of the turbidity change rate. A method for producing Form II reduced coenzyme Q10 crystals or crystalline solids thereof.

2. the predetermined range is determined based on a formazin turbidity (FTU) change rate, 2. The manufacturing method according to claim 1, wherein the predetermined range is set within a range of 2 to 45 FTU / min for a period from 1,000 to 10,000 FTU.

3. The method according to claim 1 or 2, wherein the alcohol is a monohydric alcohol having 1 to 5 carbon atoms.

4. The method according to claim 3, wherein the monohydric alcohol having 1 to 5 carbon atoms is ethanol.

5. The method according to any one of claims 1 to 4, wherein the alcohol is 95% by weight or more of alcohol based on the total amount of water and alcohol.

6. a crystallization section capable of accommodating a mixed solution containing alcohol and reduced coenzyme Q10; a turbidity detection unit that detects a rate of change in turbidity of the mixed liquid contained in the crystallization unit; a temperature control unit capable of controlling the temperature in the crystallization unit; and a control unit that controls the temperature adjustment by the temperature adjustment unit based on the turbidity change rate of the mixed liquid obtained from the turbidity detection unit; Including, the control changes at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid based on a predetermined range of the turbidity change rate and the measured value of the turbidity change rate. Crystallizer for Form II reduced coenzyme Q10 crystals.

7. the predetermined range is determined based on a formazin turbidity (FTU) change rate, 7. The crystallizer according to claim 6, wherein the predetermined range is set within a range of 2 to 45 FTU / min for a period from 1,000 to 10,000 FTU.

Images