Method and crystallization apparatus for manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids thereof

Abstract

The purpose of this disclosure is to provide a method for stably manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids thereof. This embodiment is a method for manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids thereof. This method uses a crystallization apparatus equipped with a crystallization section, a turbidity detection section capable of detecting turbidity within the crystallization section, and a temperature control section capable of adjusting the temperature within the crystallization section. The method includes: placing a mixture containing alcohol and reduced coenzyme Q10 in the crystallization section; adding Form II type reduced coenzyme Q10 crystals as seed crystals to the mixture; and causing the Form II type reduced coenzyme Q10 crystals to precipitate in the mixture after the addition of the seed crystals. The precipitation includes controlling the temperature using the temperature control section based on the turbidity change rate obtained by the turbidity detection section.

Description

Technical Field

[0001] This disclosure relates to a method and apparatus for manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids thereof. Background Technology

[0002] Coenzyme Q is an essential component widely distributed in organisms from bacteria to mammals, and is well-known as a constituent of the electron transport chain in mitochondria within cells. Coenzyme Q functions as a transport component in the electron transport system through repeated oxidation and reduction within mitochondria, and the reduced form of coenzyme Q also possesses antioxidant properties. In humans, coenzyme Q10, with its 10 repeating side chains, is the main component, and in vivo, approximately 40-90% exists in its reduced form. The physiological functions of coenzyme Q include: activation of energy production through mitochondrial activation, activation of cardiac function, stabilization of cell membranes, and cellular protection through antioxidant effects.

[0003] Most of the coenzyme Q10 currently manufactured / sold is oxidized coenzyme Q10. However, in recent years, reduced coenzyme Q10, which shows higher oral absorption than oxidized coenzyme Q10, has also been launched and is gradually being used more widely.

[0004] A common method for obtaining reduced coenzyme Q10 has been disclosed (Patent Document 1). Furthermore, several methods for obtaining reduced coenzyme Q10 in crystalline form are known. For example, methods for producing crystals by crystallizing reduced coenzyme Q10 in alcoholic and / or ketone solutions have been reported (Patent Document 2), and methods for crystallization by adding a high-concentration liquid phase of reduced coenzyme Q10 to a poor solvent have been reported (Patent Document 3), etc.

[0005] On the other hand, Patent Document 4 describes the observation of polymorphism in reduced coenzyme Q10 and reports that the re-emerging crystalline form (hereinafter referred to as Form II type reduced coenzyme Q10 crystals or Form II type crystals) is much more stable than the existing reduced coenzyme Q10 (hereinafter referred to as Form I type reduced coenzyme Q10 crystals or Form I type crystals), and its other physical properties are also superior. Furthermore, Patent Document 5 describes a method for manufacturing Form II type reduced coenzyme Q10 crystals. Claim 1 of Patent Document 5 discloses a method for manufacturing Form II type reduced coenzyme Q10 crystals, the method comprising: adding Form II type reduced coenzyme Q10 crystals as seed crystals to a solution containing at least one organic solvent selected from alcohols, hydrocarbons, fatty acid esters, and nitrogen compounds, and reduced coenzyme Q10, at a temperature of 32–43°C, to prepare a mixture; and precipitating the Form II type reduced coenzyme Q10 crystals in the mixture.

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: Japanese Patent Application Publication No. 10-109933

[0009] Patent Document 2: International Publication No. 2003 / 006409

[0010] Patent Document 3: Japanese Patent Application Publication No. 2003-089669

[0011] Patent Document 4: International Publication No. 2012 / 176842

[0012] Patent Document 5: International Publication No. 2020 / 045571 Summary of the Invention

[0013] The problem that the invention aims to solve

[0014] Patent Document 4 describes a method for obtaining Form II type reduced coenzyme Q10 crystals, which involves crystallization under specific conditions. However, this method is sometimes time-consuming and yields low recovery rates, making it potentially unsuitable for industrial applications. Patent Document 5 aims to provide an efficient manufacturing method suitable for industrial-scale production of Form II type reduced coenzyme Q10 crystals, focusing primarily on temperature.

[0015] In their in-depth research on the manufacturing method of Form II reduced coenzyme Q10 crystals or its crystalline solids, the inventors discovered that when the precipitation of Form II reduced coenzyme Q10 crystals is controlled solely by temperature, even when Form II reduced coenzyme Q10 crystals are repeatedly manufactured under the same temperature conditions, the batch-to-batch variation in the oxidative stability of the obtained Form II reduced coenzyme Q10 crystals or its crystalline solids is significant.

[0016] The inventors, focusing on factors other than temperature, discovered in their research on methods for manufacturing Form II reduced coenzyme Q10 crystals or crystalline solids thereof that by controlling the temperature based on the turbidity change rate, Form II reduced coenzyme Q10 crystals or crystalline solids thereof can be stably manufactured. Therefore, an object of this disclosure is to provide a method for manufacturing Form II reduced coenzyme Q10 crystals or crystalline solids thereof that can stably manufacture Form II reduced coenzyme Q10 crystals or crystalline solids thereof. Another object is to provide a crystallization apparatus that can be used in implementing the method for manufacturing Form II reduced coenzyme Q10 crystals or crystalline solids thereof.

[0017] Technical solutions for solving the problem

[0018] 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 precipitation proceeds, resulting in an increase in turbidity. The inventors have discovered that by controlling the temperature based on the rate of change in turbidity, it is possible to stably produce Form II reduced coenzyme Q10 crystals or crystalline solids with high oxidative stability.

[0019] Examples of this implementation method are described below.

[0020] (1) A method for manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids thereof, the method using a crystallization apparatus having a crystallization section, a turbidity detection section capable of detecting the turbidity within the crystallization section, and a temperature control section capable of adjusting the temperature within the crystallization section.

[0021] Furthermore, the method includes:

[0022] The mixture containing alcohol and reduced coenzyme Q10 is collected in the crystallization section;

[0023] Form II type reduced coenzyme Q10 crystals were added as seed crystals to the mixture;

[0024] Form II type reduced coenzyme Q10 crystals are precipitated in the mixture after the seed crystals are added.

[0025] The precipitation includes controlling the temperature by means of the temperature regulating unit based on the turbidity change rate obtained by the turbidity detection unit.

[0026] (2) According to the manufacturing method described in (1), wherein,

[0027] The control is based on a given range of turbidity change rate and a measured value of turbidity change rate, and controls at least one of the temperature of the mixture and the cooling rate of the mixture to change.

[0028] (3) According to the manufacturing method described in (2), wherein,

[0029] The given range is determined based on the rate of change of formalin turbidity (FTU).

[0030] The given range is set within the range of 2 to 45 FTU / min during the period when FTU is 1,000 to 10,000.

[0031] (4) According to any one of the manufacturing methods described in (1) to (3), wherein,

[0032] The alcohol is a monohydric alcohol with 1 to 5 carbon atoms.

[0033] (5) According to the manufacturing method described in (4), wherein,

[0034] The monohydric alcohol with 1 to 5 carbon atoms is ethanol.

[0035] (6) The manufacturing method described in any one of (1) to (5), wherein,

[0036] The alcohol is an alcohol that accounts for more than 95% by weight of the total amount of water and alcohol.

[0037] (7) A Form II type crystallization apparatus for reducing coenzyme Q10 crystallization, comprising:

[0038] The crystallization section is capable of holding a mixture containing alcohol and reduced coenzyme Q10;

[0039] A turbidity detection unit detects the rate of change in turbidity of the mixture contained in the crystallization unit;

[0040] A temperature regulating unit is configured to regulate the temperature within the crystallization section; and

[0041] The control unit controls the temperature regulation performed by the temperature regulation unit based on the turbidity change rate of the mixture obtained by the turbidity detection unit.

[0042] (8) According to the crystallization apparatus described in (7), wherein,

[0043] The control is based on a given range of turbidity change rate and a measured value of turbidity change rate, and controls at least one of the temperature of the mixture and the cooling rate of the mixture to change.

[0044] (9) According to the crystallization apparatus described in (8), wherein,

[0045] The given range is determined based on the rate of change of formalin turbidity (FTU).

[0046] The given range is set within the range of 2 to 45 FTU / min during the period when FTU is 1,000 to 10,000.

[0047] This specification contains the disclosure of Japanese Patent Application No. 2021-053784, which forms the basis of the priority of this application.

[0048] The effects of the invention

[0049] According to the method for manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids thereof disclosed herein, Form II type reduced coenzyme Q10 crystals or crystalline solids thereof can be stably manufactured. Furthermore, the crystallization apparatus of this disclosure can be used when carrying out the manufacturing method. Attached Figure Description

[0050] Figure 1 This is a schematic diagram of one aspect of the crystallization apparatus of this embodiment.

[0051] Explanation of reference numerals in the attached figures

[0052] 1···Crystallization Department

[0053] 3··· Mixture

[0054] 5. Turbidity Detection Department

[0055] 5a···Turbidity sensor

[0056] 5b converter

[0057] 7. Temperature Detection Department

[0058] 9···Constant temperature water tank

[0059] 11···Heat medium

[0060] 13··· Control Department

[0061] 15. Stirring blades Detailed Implementation

[0062] The present invention will now be described in detail.

[0063] Reduced Coenzyme Q10

[0064] The "reduced coenzyme Q10" in this specification refers to a product that uses reduced coenzyme Q10 as its main component, and may contain oxidized coenzyme Q10 in a portion thereof. It should be noted that, here, "main component" refers to a product containing, for example, 50% or more by weight, typically 60% or more by weight, preferably 70% or more by weight, more preferably 80% or more by weight, further preferably 90% or more by weight, particularly preferably 95% or more by weight, and especially preferably 98% or more by weight. Here, the above proportions refer to the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10.

[0065] It should be noted that, as mentioned above, there are two polymorphs of reduced coenzyme Q10: the currently known Form I and the recently discovered Form II. Specifically, the reduced coenzyme Q10 with 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 at a melting point around 48°C is of the Form I type. The reduced coenzyme Q10 with 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 at a melting point around 52°C is of the Form II type. In this specification, even crystals of reduced coenzyme Q10 that meet only one of the following criteria are referred to as "crystals of Form II reduced coenzyme Q10": an endothermic peak at 54±2℃ when heated at a rate of 5℃ / min according to differential scanning calorimetry (DSC); an endothermic peak at 52±2℃ when heated at a rate of 1℃ / min; 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. Of course, all conditions may be met.

[0066] Furthermore, in this specification, "crystalline solid" refers to a solid that contains a portion having a crystalline structure and an amorphous component that does not have a crystalline structure. That is, in "Form II type reduced coenzyme Q10 crystals or their crystalline solids", "their crystalline solids" refers to "a solid that contains a portion having a crystalline structure of Form II type reduced coenzyme Q10 crystals and an amorphous component that does not have a crystalline structure".

[0067] <alcohol>

[0068] The inventors have discovered that the saturation concentration of Form II crystals in alcohol is lower than that of Form I crystals. Therefore, by using alcohol as a solvent for reduced coenzyme Q10, Form II reduced coenzyme Q10 crystals can be precipitated efficiently.

[0069] As an alcohol, a monohydric alcohol with 1 to 5 carbon atoms is preferred. Examples of monohydric alcohols with 1 to 5 carbon atoms include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and n-pentanol. Ethanol, which has a sufficiently low saturation concentration of Form II crystals compared to Form I crystals and is easy to handle, is particularly preferred. It should be noted that the alcohols mentioned above can be used alone or in mixtures of two or more.

[0070] The alcohol used in this specification can be any solvent with alcohol as its main component, or it can be an aqueous alcohol containing water. The lower the water content of the alcohol, the easier it is for Form II crystals to selectively precipitate. Therefore, the alcohol concentration relative to the total amount of water and alcohol is, for example, 80% by weight or more, typically 90% by weight or more, preferably 95% by weight or more, more preferably 97% by weight or more, further preferably 99% by weight or more, and particularly preferably 99.5% by weight or more. It should be noted that an alcohol concentration of 99.5% by weight or more refers to anhydrous alcohols. Furthermore, the upper limit for alcohol concentration is 100% by weight or less.

[0071] As the alcohol, aqueous ethanol or anhydrous ethanol is particularly preferred. As the ethanol, the ethanol concentration relative to the total amount of water and ethanol 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, further preferably 99% by weight or more, and particularly preferably 99.5% by weight or more. In addition, the upper limit of the ethanol concentration is 100% by weight or less.

[0072] <Method for manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids>

[0073] The method for manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids of the present embodiment uses a crystallization apparatus equipped with a crystallization section, a turbidity detection section capable of detecting turbidity within the crystallization section, and a temperature control section capable of adjusting the temperature within the crystallization section. The method includes: placing a mixture containing alcohol and reduced coenzyme Q10 into the crystallization section; adding Form II type reduced coenzyme Q10 crystals as seed crystals to the mixture; and causing the Form II type reduced coenzyme Q10 crystals to precipitate in the mixture after the addition of the seed crystals. The precipitation includes controlling the temperature using the temperature control section based on the turbidity change rate obtained by the turbidity detection section.

[0074] In the following description, the process of adding Form II type reduced coenzyme Q10 crystals as seed crystals is sometimes referred to as the "seed crystal addition process", and the process of causing Form II type reduced coenzyme Q10 crystals to precipitate is referred to as the "crystallization precipitation process".

[0075] In the Form II type reduced coenzyme Q10 crystal manufacturing method of this embodiment, a crystallization device is used, which is 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. Figure 1 A schematic diagram showing one embodiment of a crystallization apparatus. Figure 1 The crystallization apparatus shown depicts a state where a mixture 3 containing alcohol and reduced coenzyme Q10 is contained inside the crystallization section 1. A turbidity detection unit 5 (e.g., a turbidimeter) is provided in the crystallization section 1, and preferably a temperature detection unit 7 (e.g., a thermometer). Figure 1 In the crystallization apparatus shown, the temperature of the crystallization section 1 can be adjusted using a temperature regulating unit consisting of a constant-temperature water bath 9 and a heat transfer medium 11 (e.g., water). Figure 1 In the crystallization apparatus shown, the turbidity detection unit 5 includes a turbidity sensor 5a and a converter 5b that converts the signal detected by the turbidity sensor 5a into turbidity values ​​such as FTU values. Additionally, a control unit 13 is included, which controls the temperature adjustment performed by the temperature control unit based on the turbidity change of the mixture obtained by the turbidity detection unit 5. Figure 1 The crystallization apparatus shown preferably has stirring blades 15 for stirring within the crystallization section 1. It should be noted that... Figure 1 The crystallization apparatus shown is one embodiment of the Form II type crystallization apparatus for reducing coenzyme Q10 crystallization described later in this embodiment.

[0076] The control unit 13 is a control mechanism that controls temperature regulation performed by the temperature regulating unit, and may also be a central control mechanism that controls other conditions (such as stirring conditions). The control unit 13 can be composed of, for example, software programs for implementing various processes, a CPU executing the software program, and various hardware controlled by the CPU. In one embodiment, the control unit 13 is a computer that includes and has 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 storage unit (not shown). It should be noted that the location for storing these programs and data is not particularly limited. These programs and data can also be stored in a separately dedicated storage device such as a hard disk or flash memory. Alternatively, they can be stored in an external server or storage unit that can be communicated with.

[0077] The mixture containing alcohol and reduced coenzyme Q10 stored in the crystallization section is not particularly limited as long as it contains alcohol and reduced coenzyme Q10. It can be a homogeneous solution obtained by dissolving reduced coenzyme Q10 in alcohol, or a slurry in which part of the reduced coenzyme Q10 is dissolved in alcohol but part of it is suspended. However, it is preferred to be a homogeneous solution obtained by dissolving reduced coenzyme Q10 in alcohol.

[0078] The reduced coenzyme Q10 used in the mixture containing alcohol and reduced coenzyme Q10 is not limited to crystalline, amorphous, or polymorphic states. Therefore, the currently known Form I type reduced coenzyme Q10 can also be used. Furthermore, since its purity can be improved during crystallization, it can also be reduced coenzyme Q10 with impurities or unrefined / crudely refined reduced coenzyme Q10. Moreover, the above-mentioned mixture can also be used directly or as needed, either as an extract of reduced coenzyme Q10 obtained by currently known methods, or as a reaction solution containing reduced coenzyme Q10 obtained from oxidized coenzyme Q10 by known reduction methods, after purification and / or solvent replacement.

[0079] The mixture containing alcohol and reduced coenzyme Q10 may also contain other organic solvents besides alcohol (including hydrous alcohol), but the alcohol content (alcohol purity) corresponding to the total amount of solvent components is preferably 95% by weight or more, 97% by weight or more, or 99% by weight or more, and preferably 100% by weight or less as an upper limit. The alcohol purity is most preferably 99.5% by weight or more. Examples of other organic solvents include at least one selected from hydrocarbons, fatty acid esters, and nitrogen compounds.

[0080] The concentration of reduced coenzyme Q10 in the mixture 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, further preferably 7% by weight or more, and particularly preferably 9% by weight or more. The 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, further preferably 20% by weight or less, and particularly preferably 15% by weight or less.

[0081] The mixture containing alcohol and reduced coenzyme Q10 is obtained by heating the raw material mixture containing alcohol and reduced coenzyme Q10 to a temperature of, for example, 42°C or higher, to dissolve the reduced coenzyme Q10. Preferably, this temperature is 70°C or lower, more preferably 55°C or lower. After dissolving the reduced coenzyme Q10 and before adding the seed crystals, the mixture containing alcohol and reduced coenzyme Q10 is preferably cooled to the temperature described later for adding the seed crystals.

[0082] The amount of Form II reduced coenzyme Q10 crystals added as seed crystals (seed crystal addition amount) is not particularly limited, but it is preferably 0.1% by weight or more, more preferably 0.5% by weight or more, further preferably 0.8% by weight or more, and particularly preferably 1% by weight or more, relative to the amount of reduced coenzyme Q10 (100% by weight) in the above mixture before adding the seed crystals. There is no particular upper limit, but it is preferably 20% by weight or less, more preferably 4% by weight or less, and further preferably 2.2% by weight or less, relative to the amount of reduced coenzyme Q10 (100% by weight) in the above mixture before adding the seed crystals. It should be noted that the reduced coenzyme Q10 crystals used in the seed crystals only need to include Form II reduced coenzyme Q10 crystals, but may also include Form I reduced coenzyme Q10 crystals or amorphous crystals, but the higher the purity of the Form II reduced coenzyme Q10 crystals, the better. As seed crystals, Form II type reduced coenzyme Q10 crystals can be, for example, 50% or more by weight, preferably 75% or more by weight, more preferably 80% or more by weight, and more preferably 90% or more by weight.

[0083] The temperature of the above-mentioned mixture at the point when the seed crystals are added is preferably 30–43°C. More preferably, the temperature of the mixture at the point when the seed crystals are added is 32°C or higher, particularly preferably 34°C or higher, and even more preferably 40°C or lower. Within this range, Form II type reduced coenzyme Q10 crystals are easily and selectively precipitated.

[0084] The crystallization precipitation process includes temperature control via a temperature regulating unit based on the turbidity change rate obtained from the turbidity detection unit. In the crystallization precipitation process, an increase in turbidity indicates crystal precipitation, and the turbidity change rate (the amount of turbidity change per unit time) serves as an indicator of the crystallization precipitation rate. As a control measure, one can consider controlling at least one of the temperature of the mixture and the cooling rate of the mixture based on a given 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 given range, it is determined that the crystallization precipitation rate is fast, and the temperature of the mixture can be increased or the cooling rate decreased. Conversely, if the measured turbidity change rate is less than a given range, it is determined that the crystallization precipitation rate is slow, and the temperature of the mixture can be decreased or the cooling rate increased. It should be noted that, as control, it is preferable to perform control based on a given range of turbidity change rate and the measured value of turbidity change rate. However, if the measured value deviates from the given range, it is not necessary to frequently change at least one of the temperature and cooling rate of the mixture. If the measured value of turbidity change rate is predicted to quickly return to the given range, it is also possible not to change the temperature and cooling rate of the mixture. For example, when the temperature of the mixture is kept constant, as crystallization proceeds, the crystallization rate slows down, and the turbidity change rate also decreases. Therefore, even if the turbidity change rate temporarily exceeds the given range, it is not necessary to change the temperature and cooling rate of the mixture if it is believed that it can be quickly reduced to the given range. Alternatively, as control, it can be performed by changing at least one of the temperature and cooling rate of the mixture each time based on the turbidity change rate, or it can be performed by changing at least one of the temperature and cooling rate of the mixture when an abnormality occurs in the turbidity change rate after a pre-set temperature program.

[0085] The turbidity can be based on any index, such as kaolin turbidity and formalin turbidity (FTU). From a general point of view, formalin turbidity is preferred.

[0086] The rate of change of turbidity can be calculated by dividing the difference between the turbidity at a certain point in time and the previously measured turbidity by the measurement interval.

[0087] For example, the rate of change of turbidity at a certain time point (T) can be calculated using the following formula.

[0088] Turbidity change rate T (turbidity / min) = (turbidity measurement value) T - Turbidity measurement value T-X ) / X(min)

[0089] (In the above formula, the turbidity change rate) T This refers to the rate of change of turbidity at a point in time (T), the measured value of turbidity.T This refers to the measured value of turbidity at a specific time point (T). T-X This refers to the turbidity measurement value X minutes prior to time point T.

[0090] Furthermore, when the measured turbidity is formalin turbidity (FTU), the rate of change of FTU at a certain time point (T) can be calculated using the following formula.

[0091] FTU rate of change T (FTU / min) = (Turbidity measurement value) T (FTU) - Turbidity Measurement Value T-X (FTU)) / X(min)

[0092] (In the above formula, the rate of change of FTU) T This refers to the rate of change of FTU at a time point (T), the turbidity measurement value. T (FTU) refers to the measured FTU value at time point (T), which is the turbidity measurement value. T-X (FTU) refers to the FTU measurement value X minutes before time point T.

[0093] There is no particular limitation on the frequency of measuring the turbidity change rate. However, when the turbidity change rate is measured too frequently, it may be affected by measurement errors or concentration differences in the mixed solution, resulting in an unstable turbidity change rate. Conversely, if the turbidity change rate is measured too infrequently, the precipitation rate of crystals may not be adequately controlled. From this perspective, it is preferable to measure the turbidity change rate every 3 to 180 minutes, more preferably every 5 to 30 minutes, and even more preferably every 10 to 30 minutes. It should be noted that the measurement interval can be constant or variable, and there is no particular limitation.

[0094] When the turbidity being measured is formalin turbidity (FTU), and the range of turbidity change rate can be determined based on the change rate of formalin turbidity (FTU), setting a given range within the range of 2 to 45 FTU / min during the period of FTU from 1,000 to 10,000 is one preferred approach. More preferably, setting a given range within the range of 2 to 43 FTU / min during the period of FTU from 1,000 to 10,000 is another preferred approach, and even more preferably, setting a given range within the range of 2 to 35 FTU / min is yet another preferred approach. As crystallization proceeds, turbidity, such as FTU, increases, especially after the addition of seed crystals, where there is a tendency for FTU to increase rapidly or for measurement errors to increase. Therefore, maintaining a constant rate of change of FTU from the time of addition of seed crystals may not be feasible. In the above approach, a given range is set during the period of FTU from 1,000 to 10,000. By setting the given range in this way, the method for producing Form II type reduced coenzyme Q10 crystals or its crystalline solids can be implemented with good reproducibility.

[0095] The mixture at the time point of seed crystal addition is preferably a homogeneous solution obtained by dissolving reduced coenzyme Q10 in alcohol. When the measured turbidity is FTU, the FTU of the mixture at the time point of seed crystal addition is typically 0–250, preferably 0–230, and more preferably 0–200. Within this range, Form II type reduced coenzyme Q10 crystals preferentially precipitate, and are therefore preferred.

[0096] When the measured turbidity is FTU, the temperature of the mixture during the period when the FTU is between 1,000 and 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, and therefore it is preferred.

[0097] When the turbidity is measured as FTU, the temperature of the mixture at the time point when FTU is 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.

[0098] In the crystallization precipitation process, the temperature of the mixture can be constant, or it can be decreased in stages or continuously. Alternatively, the temperature of the mixture can be maintained at a constant temperature for a certain period and then decreased in stages or continuously. In a preferred embodiment, the temperature of the mixture at the time point when the seed crystal is added is 34°C to 38°C, and the temperature of the mixture at the time point when the FTU is 10,000 is 30°C to 37°C. Preferably, the temperature at the time point when the FTU is 10,000 is 0.4°C to 8°C lower than the temperature at the time point when the seed crystal is added. It should be noted that maintaining a constant temperature preferably means maintaining it at a given temperature (set temperature) ±3°C, and more preferably, it means maintaining it at a given temperature (set temperature) ±1°C.

[0099] The cooling rate for lowering the temperature of the mixture is preferably 0.05°C / hr to 20°C / hr, more preferably 0.1°C / hr to 15°C / hr. Varying the cooling rate over time is also preferred. Examples include maintaining the temperature for a certain period, such as 0.5 to 8 hours after adding the seed crystal, then setting the cooling rate to 0.05°C / hr or higher and lower than 0.5°C / hr for 3 to 20 hours, and then setting the cooling rate to 0.5°C / hr or higher and lower than 15°C / hr; or setting the cooling rate to 0.05°C / hr or higher and lower than 0.5°C / hr for 3 to 20 hours after adding the seed crystal, and then setting the cooling rate to 0.5°C / hr or higher and lower than 15°C / hr.

[0100] In the crystallization precipitation process, when the measured turbidity is FTU, it is preferable to lower the temperature of the mixture after the FTU reaches 10,000, which is the upper limit of the measurement, so that crystallization can proceed. The cooling rate at this time can be set, for example, based on the range described above. Furthermore, when the temperature of the mixture reaches 23–34°C, most of the reduced coenzyme Q10 contained in the mixture has already precipitated; therefore, after the temperature reaches 23–34°C, the cooling rate can be increased to, for example, 1°C / hr or more and 20°C / hr or less.

[0101] The temperature at which the crystallization precipitation process ends, i.e., the endpoint temperature, is preferably below 25°C, more preferably below 20°C, even more preferably below 10°C, even more preferably below 7°C, and even more preferably below 5°C. The lower limit of the above endpoint temperature is the curing temperature of the above-mentioned mixture system, but it is preferably above 0°C.

[0102] The precipitation of crystals is preferably carried out while the mixture is forced to flow. From the viewpoint of suppressing the formation of supersaturation, ensuring smooth nucleation and crystal growth, or achieving high quality, the stirring power required per unit volume can typically be 0.003 kW / m³ for the above mixture. 3 The above, preferably 0.004kW / m 3 The above, and more preferably, is 0.005kW / m 3 The above, further optimized, is 0.006kW / m 3 The above flow. Additionally, as the power required for stirring, a flow rate of 0.1 kW / m² can typically be applied to the above mixture. 3 The following is a preferred option: 0.03kW / m 3 The following flow. The forced flow described above is usually achieved by rotating the stirring blades, but if the above flow is obtained, it is not necessarily necessary to use stirring blades. For example, the circulation of the mixture can also be used.

[0103] The Form II type reduced coenzyme Q10 crystals obtained by the above method can be recovered, for example, by a solid-liquid separation and drying process using a currently known method as described in Patent Document 2 or 3. For example, pressure filtration or centrifugal filtration can be used in the solid-liquid separation process. In addition, the dried crystals or crystalline solids can be crushed, graded (sieved), and recovered as needed.

[0104] In this embodiment, as a more preferred method, the content of Form II type reduced coenzyme Q10 crystals can also be increased by drying the Form II type reduced coenzyme Q10 crystals after 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. As an upper limit, it is generally 52°C or lower, preferably 51°C or lower. At temperatures below 46°C, although drying is performed, the content of Form II type reduced coenzyme Q10 crystals hardly increases. Furthermore, at temperatures above 52°C, the reduced coenzyme Q10 crystals may sometimes melt during drying.

[0105] It should be noted that if the desired proportion of Form II type reduced coenzyme Q10 crystals has been achieved in the crystallization precipitation process, it is not limited to the above. For example, drying can be carried out at 25°C or higher, preferably 30°C or higher, and more preferably 35°C or higher.

[0106] Furthermore, there is no particular limitation on the heating time during drying, but it is preferably 4 hours or more, more preferably 10 hours or more, and more preferably 20 hours or more. As for the upper limit of the heating time, there is no particular limitation, but it is usually 72 hours or less, preferably 48 hours or less, and more preferably 36 hours or less.

[0107] It should be noted that the various steps in the method of this embodiment, specifically the step of collecting the mixture described above in the crystallization section, the seed crystal addition step, the crystallization precipitation step, the solid-liquid separation and drying recovery steps, and other subsequent processing steps, are preferably carried out under a deoxygenating atmosphere. The deoxygenating atmosphere can be achieved by replacing the atmosphere with a non-reactive gas, reducing pressure, boiling, or a combination thereof. Preferably, at least the atmosphere is replaced with a non-reactive gas, i.e., a non-reactive gas atmosphere is used. Examples of such non-reactive gases include nitrogen, helium, argon, hydrogen, and carbon dioxide, with nitrogen being the most preferred.

[0108] Whether the obtained reduced coenzyme Q10 crystals or its crystalline solids contain Form II reduced coenzyme Q10 crystals or the proportion thereof can be determined, for example, by using a differential scanning calorimeter (DSC).

[0109] As described above, Form II type reduced coenzyme Q10 crystals, when measured by DSC at a heating rate of 1°C / min, show an endothermic peak around 52±2°C, while Form I type reduced coenzyme Q10 crystals, under the same conditions, show an endothermic peak around 48±1°C. Even when Form II type reduced coenzyme Q10 crystals are mixed with existing Form I type reduced coenzyme Q10 crystals or their crystalline solids, the presence and proportion of Form II type reduced coenzyme Q10 crystals can be determined based on the presence or absence of the peak around 52±2°C, or the height of the endothermic peak, or the ratio of the endothermic heat. According to the present invention, high-purity Form II type reduced coenzyme Q10 crystals or their crystalline solids can be obtained efficiently. According to this embodiment, Form II type reduced coenzyme Q10 crystals can be obtained through a crystallization precipitation process, but crystalline solids are sometimes obtained through subsequent drying processes, such as partial crystal melting. Therefore, this embodiment includes cases where crystals are obtained and cases where crystalline solids are obtained.

[0110] <Form II type reduced coenzyme Q10 crystallization apparatus>

[0111] The Form II-type crystallization apparatus for reducing coenzyme Q10 crystallization according to this embodiment includes: a crystallization section capable of holding a mixture containing alcohol and reduced coenzyme Q10; a turbidity detection section capable of detecting the turbidity change rate of the mixture held in the crystallization section; a temperature regulation section capable of regulating the temperature in the crystallization section; and a control section capable of controlling the temperature regulation performed by the temperature regulation section based on the turbidity change rate of the mixture obtained by the turbidity detection section.

[0112] The crystallization apparatus of this embodiment is an apparatus capable of carrying out the above-described method for manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids thereof.

[0113] As a schematic diagram illustrating one embodiment of the crystallization apparatus of this embodiment, the above-described examples can be cited. Figure 1 The crystallization apparatus shown. A turbidity sensor 5a is installed in the crystallization section 1. More specifically, in… Figure 1 In this configuration, a turbidity sensor 5a is installed inside the crystallization section 1. Alternatively, 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 located outside the crystallization section. Figure 1 In this configuration, the temperature control unit, which serves as the constant temperature water bath 9 and the heat medium 11, is located outside the crystallization section 1. However, in other configurations, it may also be located inside the crystallization section 1. For example, the temperature control unit may be provided by installing a heater or similar device inside the crystallization section 1.

[0114] As the control performed by the control unit, it is preferable to control the temperature of the mixture and the cooling rate of the mixture by changing at least one of them based on a given range of turbidity change rate and a measured value of turbidity change rate. In the control unit, it is preferable, for example, to execute a program stored in the storage unit, compare the measured value of the turbidity change rate with a given range of turbidity change rate stored in the storage unit, thereby determining the necessity of changing at least one of the temperature of the mixture and the cooling rate of the mixture, and based on the result, to activate the temperature control unit via software to achieve temperature control. When the turbidity is formalin turbidity (FTU), the given range of turbidity change rate is a range determined based on the formalin turbidity (FTU) change rate. Setting this range within the range of 2 to 45 FTU / min is preferred when the FTU is between 1,000 and 10,000. More preferably, the given range is set within the range of 2 to 43 FTU / min when the FTU is between 1,000 and 10,000, and even more preferably, the given range is set within the range of 2 to 35 FTU / min.

[0115] Example

[0116] The following examples illustrate this implementation, but this disclosure is not limited to these examples.

[0117] <Ratio of Form II crystals in reduced coenzyme Q10 crystals>

[0118] Regarding the ratio of Form II crystals in the reduced coenzyme Q10 crystals obtained in the examples, the crystals were analyzed by DSC measurement based on the following conditions, and calculated based on the height (Y difference) of the endothermic peak of the Form I crystals (hereinafter referred to as the Y difference of Form I) and the height (Y difference) of the endothermic peak of the Form II crystals (hereinafter referred to as the Y difference of Form II), and based on the following formula.

[0119] Form II ratio (%) = (Form II Y-difference) / (Form I Y-difference + Form II Y-difference) × 100

[0120] (DSC measurement conditions)

[0121] Device: DSC6220 (made with SII nanotechnology)

[0122] Sample container: Aluminum pot & lid (SSC000C008)

[0123] Heating rate: 1℃ / min

[0124] Sample volume: 5±2mg

[0125] <Methods for Determining the Rate of Change of FTU>

[0126] Regarding the FTU change rate in the examples, the formalin turbidity (FTU) of the mixture of ethanol and reduced coenzyme Q10 was measured using a turbidimeter, and the FTU change rate at time point (T) was calculated using the following formula. Furthermore, for the turbidimeter used in this embodiment, the turbidity (FTU) when the reduced coenzyme Q10 crystals were present in the mixture at a concentration of 40,000 mg / L was set to 9,999 FTU for correction.

[0127] FTU rate of change T (FTU / min) = (Turbidity measurement value) T (FTU) - Turbidity Measurement Value T-X (FTU)) / X(min)

[0128] (In the above formula, the rate of change of FTU) T This refers to the rate of change of FTU at a time point (T), the turbidity measurement value. T (FTU) refers to the measured FTU value at time point (T), which is the turbidity measurement value. T-X (FTU) refers to the FTU measurement value X minutes before time point T.

[0129] Turbidimeter: Backscattered light turbidity sensor (InPro8200, METTLER TOLEDO Co., Ltd.)

[0130] Measurement range: 0–10,000 FTU

[0131] The FTU was measured from the moment the seed crystal was added until it reached the upper limit of 10,000, and the rate of change of FTU was calculated. The rate of change of FTU at a certain time point T was calculated as shown in the above formula: calculate the increase in FTU at time point T compared to the FTU at time point X minutes earlier (T-Xmin), and divide by X minutes. It should be noted that, in the embodiment, the rate of change of FTU was calculated based on the measured FTU, the previous measured FTU, and the measurement interval.

[0132] <Evaluation Method for Oxidative Stability (Relative QH Ratio)>

[0133] The oxidative stability of the reduced coenzyme Q10 crystals obtained in the examples was evaluated using the following methods.

[0134] The reduced coenzyme Q10 crystals obtained in the examples were stored in an open system for one month in constant temperature baths set at 40°C and 75% RH (relative humidity) and 25°C and 60% RH. Then, the content ratio of reduced coenzyme Q10 (QH) and oxidized coenzyme Q10 was calculated using high performance liquid chromatography.

[0135] The relative QH ratio is calculated as a relative value of the oxidative stability of reduced coenzyme Q10 crystals by setting the content ratio of reduced coenzyme Q10 in the initial reduced coenzyme Q10 crystals before storage in the constant temperature bath, i.e., the content ratio of reduced coenzyme Q10 when the crystals obtained by the example are measured immediately after crystallization, to 100.

[0136] Relative QH ratio (%) = Reduced CoQ10 ratio after storage / Initial reduced CoQ10 ratio × 100

[0137] The following describes the high-performance liquid chromatography (HPLC) conditions for determining the concentrations of reduced and oxidized coenzyme Q10.

[0138] (HPLC conditions)

[0139] Column: SYMMETRY C18 (Waters manufacture), 250mm (length), 4.6mm (inner diameter)

[0140] Mobile phase: C2H5OH:CH3OH = 4:3 (v:v)

[0141] Detection wavelength: 210nm

[0142] Flow rate: 1 ml / min

[0143] [Example 1]

[0144] After nitrogen replacement in a 3L separable flask, add 160g of reduced coenzyme Q10 and 1440g of ethanol with a purity of ≥99.5% by weight (reduced coenzyme Q10 concentration: 10wt%), while stirring with a stirring blade (stirring power required: 0.03kw / m). 3 While heating to 50℃, prepare a uniform reduced coenzyme Q10 solution (QH solution) (1600g, 2800ml).

[0145] While using stirring blades to stir (stirring requires 0.03kw / m), 3 The QH solution was cooled from 50°C to 36.0°C. 3.2 g (2.0 wt%) of Form II reduced coenzyme Q10 crystals were added as seed crystals to the QH solution (FTU18) cooled to 36.0°C to begin the precipitation of reduced coenzyme Q10 crystals (crystallization). Hereinafter, the QH solution with added seed crystals will be referred to as the "crystallization mixture".

[0146] After adding the seed crystals, the formalin turbidity (FTU) in the mixture was periodically measured until it reached 10,000. During the period from 1,000 to 10,000 FTU, the cooling rate and temperature were controlled at an FTU change rate of approximately 20.8 FTU / min. Once the formalin turbidity in the mixture reached 10,000 FTU, it was cooled to 25°C at a rate of 1°C / hr, and then cooled from 25°C to 1°C at a rate of 10°C / hr.

[0147] After cooling to 1°C, the slurry was separated into solid and liquid components by filtration. The resulting crystals were dried under reduced pressure at 40°C for 24 hours to obtain Form II type reduced coenzyme Q10 crystals.

[0148] The obtained reduced coenzyme Q10 crystals contained 100% Form II crystals and did not include any Form I reduced coenzyme Q10 crystals. Furthermore, the relative QH ratio of the obtained Form II reduced coenzyme Q10 crystals was 91.8% after one month at 25°C and 60% RH, and 88.1% after one month at 40°C and 75% RH.

[0149] Table 1 shows the elapsed time, turbidity, set temperature, and FTU change rate when the time point when the FTU of Example 1 is about 1,000 (942) is set to 0 min.

[0150] [Table 1]

[0151]

[0152] [Example 2]

[0153] After nitrogen replacement in a 500mL four-necked flask, add 32.8g of reduced coenzyme Q10 and 295.2g of ethanol with a purity of ≥99.5% by weight (reduced coenzyme Q10 concentration: 10wt%), while stirring with a stirring blade (stirring power required: 0.007kw / m). 3 While heating to 50℃, prepare a uniform reduced coenzyme Q10 solution (QH solution) of 328g (410mL).

[0154] While using stirring blades for mixing (the stirring power required is 0.007 kW / m²), the mixture is stirred. 3 The QH solution was cooled from 50°C to 34.0°C. 0.65 g (2.0 wt%) of Form II reduced coenzyme Q10 crystals were added as seed crystals to the QH solution cooled to 34.0°C to begin the precipitation of reduced coenzyme Q10 crystals (crystallization).

[0155] After adding seed crystals, the formalin turbidity (FTU) in the mixture was periodically measured until it reached 10,000. The cooling rate and temperature were controlled to maintain an FTU change rate of approximately 55.6 FTU / min as the FTU increased from 1,000 to 10,000. If the FTU change rate significantly deviated from 55.6 FTU / min, the crystallization rate (precipitation rate) was adjusted by heating the mixture and holding the temperature for a certain period. Once the formalin turbidity in the mixture reached 10,000 FTU, it was cooled to 25°C at a rate of 1°C / hr, and then cooled from 25°C to 1°C at a rate of 10°C / hr.

[0156] After cooling to 1°C, the slurry was separated into solid and liquid components by filtration. The resulting crystals were then dried under reduced pressure at 40°C for 24 hours to obtain Form II type reduced coenzyme Q10 crystals.

[0157] The relative QH ratio of the Form II type reduced coenzyme Q10 crystals obtained after one month at 25℃ and 60% RH was 85.1%, and the relative QH ratio after one month at 40℃ and 75% RH was 81.4%.

[0158] Table 2 shows the elapsed time, turbidity, set temperature, and FTU change rate when the time point when the FTU of Example 2 is about 1,000 (870) is set to 0 min.

[0159] [Table 2]

[0160]

[0161] [Example 3]

[0162] After nitrogen replacement in a 500mL separable flask, add 32.8g of reduced coenzyme Q10 and 295.2g of ethanol with a purity of ≥99.5% by weight (reduced coenzyme Q10 concentration: 10wt%), while stirring with a stirring blade (stirring power required: 0.007kw / m). 3 While heating to 50℃, prepare a uniform reduced coenzyme Q10 solution (QH solution) of 328g (410mL).

[0163] While using stirring blades for mixing (the stirring power required is 0.007 kW / m²), the mixture is stirred. 3 The QH solution was cooled from 50°C to 34.5°C. 0.65 g (2.0 wt%) of Form II reduced coenzyme Q10 crystals were added as seed crystals to the QH solution cooled to 34.5°C to begin the precipitation of reduced coenzyme Q10 crystals (crystallization).

[0164] After adding seed crystals, the formalin turbidity (FTU) in the mixture was periodically measured until it reached 10,000. During the period from 1,000 to 10,000 FTU, the cooling rate or temperature was controlled at an FTU change rate of approximately 33.3 FTU / min. If the FTU change rate significantly deviated from 33.3 FTU / min, the crystallization rate (precipitation rate) was adjusted by heating the mixture and holding the temperature for a certain period. Once the formalin turbidity in the mixture reached 10,000 FTU, it was cooled to 25°C at 1°C / hr and then cooled from 25°C to 1°C at 10°C / hr.

[0165] After cooling to 1°C, the slurry was separated into solid and liquid components by filtration. The resulting crystals were then dried under reduced pressure at 40°C for 24 hours to obtain Form II type reduced coenzyme Q10 crystals.

[0166] The relative QH ratio of the Form II type reduced coenzyme Q10 crystals obtained after one month at 25℃ and 60% RH was 89.4%, and the relative QH ratio after one month at 40℃ and 75% RH was 87.3%.

[0167] Table 3 shows the elapsed time, turbidity, set temperature, and FTU change rate when the time point when the FTU of Example 3 is about 1,000 (877) is set to 0 min.

[0168] [Table 3]

[0169]

[0170] [Example 4]

[0171] After nitrogen replacement in a 500mL separable flask, add 27.8g of reduced coenzyme Q10 and 250.2g of ethanol with a purity of ≥99.5% by weight (reduced coenzyme Q10 concentration: 10wt%), while stirring with a stirring blade (stirring power required: 0.007kw / m). 3 While heating to 50℃, prepare a homogeneous reduced coenzyme Q10 solution (QH solution) of 278g (347mL).

[0172] While stirring the QH solution at 50℃ using stirring blades (stirring power required: 0.007kw / m),... 3 While cooling to 36.8°C, 0.56 g (2.0 wt%) of Form II type reduced coenzyme Q10 crystals were added as seed crystals to the QH solution (FTU683) cooled to 36.8°C to begin the precipitation of reduced coenzyme Q10 crystals (crystallization).

[0173] After adding seed crystals, the formalin turbidity (FTU) in the mixture was periodically measured while it remained at 10,000. The cooling rate or temperature was controlled to maintain an FTU change rate of approximately 6.9 FTU / min between 1,000 and 10,000. If the FTU change rate significantly deviated from 6.9 FTU / min, the crystallization rate (precipitation rate) was adjusted by heating the mixture and holding the temperature for a certain period. Once the formalin turbidity in the mixture reached 10,000 FTU, it was cooled to 25°C at a rate of 1°C / hr, and then cooled from 25°C to 1°C at a rate of 10°C / hr.

[0174] After cooling to 1°C, the slurry was separated into solid and liquid components by filtration. The resulting crystals were then dried under reduced pressure at 40°C for 24 hours to obtain Form II type reduced coenzyme Q10 crystals.

[0175] The obtained reduced coenzyme Q10 crystals had a Form II crystal ratio of 100%. Furthermore, the relative QH ratio of the obtained Form II reduced coenzyme Q10 crystals was 92.2% after one month at 25°C and 60% RH, and 90.1% after one month at 40°C and 75% RH.

[0176] Tables 4 and 5 show the elapsed time, turbidity, set temperature, and FTU change rate when the time point when the FTU of Example 4 is about 1,000 (933) is set to 0 min.

[0177] [Table 4]

[0178]

[0179] [Table 5]

[0180]

[0181] Table 6 shows the proportion of Form II crystals (Form II ratio) and the relative QH ratio of the reduced coenzyme Q10 crystals obtained in the examples.

[0182] [Table 6]

[0183]

[0184] It is evident that the Form II type reduced coenzyme Q10 crystals obtained in the examples exhibit excellent oxidative stability. According to the manufacturing method of Form II type reduced coenzyme Q10 crystals or its crystalline solids in this embodiment, Form II type reduced coenzyme Q10 crystals or its crystalline solids can be manufactured stably.

[0185] All publications, patents and patent applications referenced in this specification are incorporated herein by direct reference.

[0186] The upper and / or lower limits of the numerical ranges described in this specification can be arbitrarily combined to define the preferred range. For example, the upper and lower limits of the numerical ranges can be arbitrarily combined to define the preferred range, the upper limits of the numerical ranges can be arbitrarily combined with each other to define the preferred range, and the lower limits of the numerical ranges can be arbitrarily combined with each other to define the preferred range.

[0187] It should be understood that, throughout the entirety of this specification, unless otherwise specified, the singular form also includes the concept of its plural form. Therefore, it should be understood that, unless otherwise specified, articles in the singular form (e.g., "a," "an," "the," etc. in the English context) also include the concept of their plural forms.

[0188] The above describes this embodiment in detail, but the specific structure is not limited to this embodiment. Even if there are design changes that do not depart from the spirit of this disclosure, these are also included in this disclosure.

Claims

1. A method for manufacturing Form II type reduced coenzyme Q10 crystals or crystalline solids thereof, the method using a crystallization apparatus comprising a crystallization section, a turbidity detection section capable of detecting turbidity within the crystallization section, and a temperature control section capable of adjusting the temperature within the crystallization section. Furthermore, the method includes: The mixture containing alcohol and reduced coenzyme Q10 is collected in the crystallization section; Form II type reduced coenzyme Q10 crystals were added as seed crystals to the mixture; Form II type reduced coenzyme Q10 crystals are precipitated in the mixture after the seed crystals are added. The precipitation process includes controlling the temperature via the temperature regulating unit based on the turbidity change rate obtained from the turbidity detection unit. The control is based on a given range of turbidity change rate and a measured value of the turbidity change rate, controlling at least one of the temperature and cooling rate of the mixture. If the measured turbidity change rate is greater than the given range, it is determined that the crystallization rate is fast, and the temperature of the mixture can be lowered. The rise may reduce the cooling rate. The given range is determined based on the rate of change of formalin turbidity (FTU). The given range is set within the range of 2 to 45 FTU / min during the period when FTU is 1,000 to 10,000.

2. The manufacturing method according to claim 1, wherein, The alcohol is a monohydric alcohol with 1 to 5 carbon atoms.

3. The manufacturing method according to claim 2, wherein, The monohydric alcohol with 1 to 5 carbon atoms is ethanol.

4. The manufacturing method according to claim 1, wherein, The alcohol is an alcohol that accounts for more than 95% by weight of the total amount of water and alcohol.

5. A Form II type crystallization apparatus for reducing coenzyme Q10 crystallization, comprising: The crystallization section is capable of holding a mixture containing alcohol and reduced coenzyme Q10; A turbidity detection unit detects the rate of change in turbidity of the mixture contained in the crystallization unit; A temperature regulating unit is configured to regulate the temperature within the crystallization section; and The control unit controls the temperature adjustment performed by the temperature control unit based on the turbidity change rate of the mixture obtained by the turbidity detection unit. The control unit, based on a given range of turbidity change rate and a measured value of the turbidity change rate, changes at least one of the temperature and cooling rate of the mixture. If the measured turbidity change rate is greater than the given range, it determines that the crystallization rate is fast, and can either increase the temperature of the mixture or decrease the cooling rate. The given range is determined based on the rate of change of formalin turbidity (FTU). The given range is set within the range of 2 to 45 FTU / min during the period when FTU is 1,000 to 10,000.

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