Process for producing Form II reduced coenzyme Q10 crystals or crystalline solids thereof

Abstract

The purpose of the present disclosure is to provide a production method that is for reduced coenzyme Q10 Form-II type crystals or a crystalline solid thereof and that enables excellent filtering ability of a slurry containing reduced coenzyme Q10 Form-II type crystals.　One embodiment of the present invention is a production method that is for reduced coenzyme Q10 Form-II type crystals or a crystalline solid thereof, and that comprises: adding reduced coenzyme Q10 Form-II type crystals as seed crystals to a mixture liquid containing reduced coenzyme Q10 and an alcohol; and precipitating reduced coenzyme Q10 Form-II type crystals in the mixture liquid after the seed crystals have been added. During the precipitation, within at least 80% or more of time of a period in which the formazin turbidity unit (FTU) changes from 1,000 to 10,000, the FTU change rate is maintained at at least 15 FTU / min.

Description

Technical Field

[0001] The present disclosure relates to a method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof.

Background Art

[0002] Coenzyme Q is an essential component widely distributed in living organisms from bacteria to mammals and is known as a component of the mitochondrial electron transport system in cells in vivo. Coenzyme Q functions as a transfer component in the electron transport system by repeating oxidation and reduction in mitochondria. In addition, reduced coenzyme Q is known to have an antioxidant effect. In humans, coenzyme Q10, which has a repeating structure of 10 side chains of coenzyme Q, is the main component. In vivo, usually about 40 to 90% exists in the reduced form. Physiological actions of coenzyme Q include activation of energy production by mitochondrial activation, activation of cardiac function, stabilization effect on cell membranes, and protective effect on cells by antioxidant action.

[0003] Most of the coenzyme Q10 currently manufactured and sold is oxidized coenzyme Q10. However, in recent years, reduced coenzyme Q10, which exhibits higher oral absorbability than oxidized coenzyme Q10, has also appeared on the market and has come to be used.

[0004] General methods for obtaining reduced coenzyme Q10 have already been disclosed (Patent Document 1). Furthermore, several methods for obtaining reduced coenzyme Q10 as crystals are also known. For example, a method of crystallizing reduced coenzyme Q10 in an alcohol solution and / or a ketone solution to produce crystals (Patent Document 2), a method of performing crystallization by adding a high-concentration liquid phase of reduced coenzyme Q10 to a poor solvent (Patent Document 3), etc. have been reported.

[0005] On the one hand, Patent Document 4 describes that coenzyme Q10 in the reduced form exhibits crystal polymorphism, and the newly emerged crystal form (hereinafter referred to as the reduced coenzyme Q10 crystal of Form II, or Form II crystal) is reported to be much more stable than the conventional reduced coenzyme Q10 (hereinafter referred to as the reduced coenzyme Q10 crystal of Form I, or Form I crystal) and also superior in other physical properties. Further, Patent Document 5 describes a method for producing the reduced coenzyme Q10 crystal of Form II. In Patent Document 5, in claim 1, a solution having a temperature of 32 to 43 °C, containing at least one organic solvent selected from the group consisting of alcohol, hydrocarbon, fatty acid ester, and nitrogen compound and reduced coenzyme Q10, is prepared by adding the reduced coenzyme Q10 crystal of Form II as a seed crystal, and a method for producing the reduced coenzyme Q10 crystal of Form II is disclosed, which includes precipitating the reduced coenzyme Q10 crystal of Form II in the said mixture.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0007] Patent Document 4 describes a method of crystallization under specific conditions as a method for obtaining Form II reduced coenzyme Q10 crystals. However, this method requires a long time and may have a low recovery rate, and is not necessarily an optimal method industrially. The method disclosed in Patent Document 5 aims to provide an efficient manufacturing method suitable for industrial-scale production for obtaining Form II reduced coenzyme Q10 crystals, and mainly discloses a method focusing on temperature.

[0008] Conventionally, after obtaining a slurry containing Form II reduced coenzyme Q10 crystals of the Form II type, solid-liquid separation is performed by means such as filtration, and the crystals are obtained through appropriate steps such as drying. The inventors considered that when filtering a slurry containing Form II reduced coenzyme Q10 crystals, if the filterability of the slurry is poor, frequent cleaning or replacement of the filtration device is required.

[0009] In the course of studying a method for producing Form II reduced coenzyme Q10 crystals by focusing on factors other than temperature, the inventors found that a slurry containing Form II reduced coenzyme Q10 crystals obtained by a specific production method has excellent filterability. Therefore, the present disclosure aims to provide a method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof, which has excellent filterability of a slurry containing Form II reduced coenzyme Q10 crystals.

Means for Solving the Problems

[0010] When precipitating Form II reduced coenzyme Q10 crystals in a mixed solution containing alcohol and reduced coenzyme Q10, as the precipitation progresses, the turbidity increases because the amount of Form II reduced coenzyme Q10 crystals in the mixed solution increases. The inventors found that by controlling the rate of change of this turbidity, a slurry containing Form II reduced coenzyme Q10 crystals has excellent filterability.

[0011] Examples of the embodiments of the present invention are described as follows. (1) Adding Form II reduced coenzyme Q10 crystals as seed crystals to a mixed solution containing alcohol and reduced coenzyme Q10, and precipitating Form II reduced coenzyme Q10 crystals in the mixed solution after the addition of the seed crystals, wherein in the precipitation, the FTU change rate is maintained at 15 FTU / min or more for 80% or more of the time during the period until the formazin turbidity (FTU) reaches 1,000 to 10,000. A method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof. (2) The production method according to (1), wherein the median diameter (D50) of the produced Form II reduced coenzyme Q10 crystals is 80 μm or more. (3) The production method according to (1) or (2), wherein in the precipitation, the FTU change rate is maintained at 110 FTU / min or less for 80% or more of the time during the period until the formazin turbidity (FTU) reaches 1,000 to 10,000. (4) The production method according to any one of (1) to (3), wherein the median diameter (D50) of the produced Form II reduced coenzyme Q10 crystals is 130 μm or less. (5) The production method according to any one of (1) to (4), wherein the alcohol is a monohydric alcohol having 1 to 5 carbon atoms. (6) The production method according to (5), wherein the monohydric alcohol having 1 to 5 carbon atoms is ethanol. (7) The production method according to any one of (1) to (6), wherein the alcohol is 95% by weight or more of alcohol based on the total amount of water and alcohol. This specification incorporates the disclosure of Japanese Patent Application No. 2021-052652, which is the basis of the priority of this application.

Effects of the Invention

[0012] The method of the present disclosure is excellent in the filterability of the slurry containing Form II reduced coenzyme Q10 crystals.

Modes for Carrying Out the Invention

[0013] Hereinafter, the present invention will be described in detail.

[0014] <Reduced Coenzyme Q10> As used herein, the "reduced coenzyme Q10" may contain oxidized coenzyme Q10 in part as long as the reduced coenzyme Q10 is the main component. Here, the main component means, for example, contained at 50% by weight or more, usually 60% by weight or more, preferably 70% by weight or more, more preferably 80% by weight or more, still more preferably 90% by weight or more, particularly preferably 95% by weight or more, and most preferably 98% by weight or more. Here, the above ratio is the ratio of the reduced coenzyme Q10 to the total amount of coenzyme Q10.

[0015] As described above, there are two types of crystal polymorphs of reduced coenzyme Q10, the conventionally known Form I type and the newly discovered Form II type. Specifically, the crystal form of reduced coenzyme Q10 with a melting point of around 48 °C and showing 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 is Form I type, and the crystal form of reduced coenzyme Q10 with a melting point of around 52 °C and showing 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 is Form II type. In this specification, by differential scanning calorimetry (DSC), when the temperature is raised at a rate of 5 °C / min, whether it has an endothermic peak at 54 ± 2 °C, or when the measurement is similarly performed at a heating rate of 1 °C / min, whether it has an endothermic peak at 52 ± 2 °C, or in powder X-ray (Cu-Kα) diffraction, whether it shows characteristic peaks at diffraction angles (2θ ± 0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3°, or a crystal of reduced coenzyme Q10 that satisfies even one of them is referred to as a "crystal of Form II type reduced coenzyme Q10". Of course, it may satisfy all the conditions.

[0016] In addition, the "crystalline solid" in this specification means a solid that contains an amorphous component without a crystal structure together with a part having a crystal structure. That is, the "crystalline solid thereof" in the "Form II reduced coenzyme Q10 crystal or its crystalline solid" means a solid that "contains an amorphous component without a crystal structure therein together with a part having the crystal structure of the Form II reduced coenzyme Q10 crystal".

[0017] <alcohol> The inventors have found that in alcohol, since the saturation concentration of Form II crystals is smaller than the saturation concentration 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.

[0018] 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. Ethanol, in which the saturation concentration of Form II crystals is sufficiently smaller than the saturation concentration of Form I crystals and which is easy to handle, is particularly preferred as the alcohol. Note that the above-exemplified alcohols may be used alone or in combination of two or more.

[0019] The alcohol in this specification may be a solvent mainly composed of alcohol, and may be a hydrous alcohol containing water. The lower the water content of the alcohol, the easier the selective precipitation of Form II crystals. For this reason, for the alcohol, the alcohol 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, based on the total amount of water and alcohol. Note that an alcohol having an alcohol concentration of 99.5% by weight or more means anhydrous alcohol. Also, the upper limit of the alcohol concentration is 100% by weight or less.

[0020] As the alcohol, hydrous ethanol or anhydrous ethanol is particularly preferred. As for 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, and particularly preferably 99.5% by weight or more. Also, the upper limit of the ethanol concentration is 100% by weight or less.

[0021] <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 this embodiment includes adding a Form II reduced coenzyme Q10 crystal as a seed crystal to a mixed solution containing an alcohol and reduced coenzyme Q10, and precipitating a Form II reduced coenzyme Q10 crystal in the mixed solution after the addition of the seed crystal. In the precipitation, the production method of the Form II reduced coenzyme Q10 crystal or the crystalline solid thereof is such that the FTU change rate is maintained at 15 FTU / min or more for 80% or more of the period until the formazin turbidity (FTU) reaches 1,000 to 10,000.

[0022] 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".

[0023] The mixed solution containing an alcohol and reduced coenzyme Q10 is not particularly limited as long as it contains an alcohol and reduced coenzyme Q10. It may be a homogeneous solution in which reduced coenzyme Q10 is dissolved in the alcohol, or it may be a slurry in which a part of reduced coenzyme Q10 is dissolved in the alcohol but a part is not dissolved and is suspended. Preferably, it is a homogeneous solution in which reduced coenzyme Q10 is dissolved in the alcohol.

[0024] As the reduced coenzyme Q10 used in the mixture containing alcohol and reduced coenzyme Q10, it may be in the form of crystals or amorphous state, and its crystal polymorphs are also not limited. Therefore, the conventionally known Form I type of reduced coenzyme Q10 can also be used. In addition, since it is possible to increase its purity during crystal precipitation, it may be an impure one or an unpurified or roughly purified reduced coenzyme Q10. Furthermore, the extract of reduced coenzyme Q10 obtained by a conventionally known method or the reaction solution containing reduced coenzyme Q10 obtained from oxidized coenzyme Q10 by a known reduction method can be used as it is, or can be used as the above-mentioned mixture after being purified and / or solvent-substituted as necessary.

[0025] The mixture containing alcohol and reduced coenzyme Q10 may further contain other organic solvents other than alcohol (including hydrous alcohol), but the alcohol content (purity of alcohol) per total amount of the solvent components is preferably 95% by weight or more, 97% by weight or more, 99% by weight or more, and the upper limit is preferably 100% by weight or less. The purity of alcohol 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.

[0026] The dissolved 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, still 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, still more preferably 20% by weight or less, and particularly preferably 15% by weight or less.

[0027] A mixture 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 the reduced coenzyme Q10. The temperature is preferably 70°C or lower, more preferably 55°C or lower. After dissolving the reduced coenzyme Q10 and before adding the seed crystal, it is preferable to cool the mixture containing alcohol and reduced coenzyme Q10 to the temperature at which the seed crystal is to be added as described below.

[0028] The addition amount of the Form II type reduced coenzyme Q10 crystal serving as the seed crystal (seed crystal addition amount) is not particularly limited, but is preferably 0.1% by weight or more, more preferably 0.5% by weight or more, still more preferably 0.8% by weight or more, and particularly preferably 1% by weight or more with respect to the amount (100% by weight) of reduced coenzyme Q10 in the mixture before the addition of the seed crystal. The upper limit is not particularly limited, but is preferably 20% by weight or less, more preferably 4% by weight or less, and still more preferably 2.2% by weight or less with respect to the amount (100% by weight) of reduced coenzyme Q10 in the mixture before the addition of the seed crystal. The reduced coenzyme Q10 crystal used as the seed crystal may contain Form I type reduced coenzyme Q10 crystal or amorphous as long as it contains Form II type reduced coenzyme Q10 crystal, but it is preferable that the purity of the Form II type reduced coenzyme Q10 crystal is higher. As the seed crystal, a Form II type reduced coenzyme Q10 crystal having, for example, 50% by weight or more, preferably 75% by weight or more, more preferably 80% by weight or more, and still more preferably 90% by weight or more is preferably used.

[0029] The temperature of the mixture at the time of adding the seed crystal is preferably 30 to 43°C. The temperature of the mixture at the time of adding the seed crystal 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 the Form II type reduced coenzyme Q10 crystal is easy.

[0030] The crystal precipitation step includes maintaining the FTU change rate at 15 FTU / min or more for 80% or more of the period until the formazin turbidity (FTU) reaches from 1,000 to 10,000. The FTU change rate is preferably 16 FTU / min or more, more preferably 18 FTU / min or more, and still more preferably 20 FTU / min or more. As the precipitation of crystals progresses, the FTU increases. However, by maintaining the FTU change rate within the above range for 80% or more of the period until the FTU reaches from 1,000 to 10,000, the filterability of the slurry containing Form II reduced coenzyme Q10 crystals is excellent. The inventors of the present invention speculate that the increase in FTU means that the precipitation of crystals is progressing, and by setting the FTU change rate within a specific range, it is possible to suppress the formation of crystals with a small median diameter due to slow precipitation. Further, even when the FTU change rate deviates from the above specific range in a part of the period until the FTU reaches from 1,000 to 10,000, as long as the FTU change rate is within the above specific range for 80% or more of the period until the FTU reaches from 1,000 to 10,000, it has been found that Form II reduced coenzyme Q10 crystals with excellent filterability can be stably produced. The time of 80% or more of the period until the FTU reaches from 1,000 to 10,000 means, for example, 240 minutes or more when it takes 300 minutes until the FTU reaches from 1,000 to 10,000, and 720 minutes or more when it takes 900 minutes.

[0031] Preferably, at the time of adding the seed crystal, the mixed solution is a homogeneous solution in which reduced coenzyme Q10 is dissolved in alcohol. The FTU of the mixed solution at the time of adding the seed crystal is usually 0 to 250, preferably 0 to 230, and more preferably 0 to 200. This range is preferable because Form II reduced coenzyme Q10 crystals preferentially precipitate.

[0032] The FTU change rate at a certain time point (T) can be calculated by the following formula. FTU change rate T (FTU / min) = (turbidity measurement value T(FTU) - Turbidity measurement value T-20 (FTU)) / 20 (min) (In the above formula, the FTU change rate T means the FTU change rate at time point (T), and the turbidity measurement value T (FTU) means the measured value of FTU at time point (T), and the turbidity measurement value T-20 (FTU) means the measured value of FTU 20 minutes before time point T.)

[0033] That is, in this embodiment, the FTU change rate can be calculated by measuring FTU every 20 minutes and dividing the increase in FTU during that period by 20. That is, if in a certain aspect, even if the FTU change rate is outside the range of this embodiment for a very short period (for example, 1 minute), when FTU is measured every 20 minutes and the FTU change rate is within the range of this embodiment, then that aspect is considered to satisfy the requirements of the FTU change rate in this embodiment.

[0034] It is preferable to maintain the FTU change rate at 110 FTU / min or less for 80% or more of the time during the period when the formazin turbidity (FTU) increases from 1,000 to 10,000, more preferably 90 FTU / min or less, and even more preferably 60 FTU / min or less.

[0035] In this embodiment, maintaining the FTU change rate within the above - mentioned specific range, for example, the FTU change rate is 15 FTU / min or more, preferably 20 FTU / min or more, for the entire period (100% of the time) during the period when FTU increases from 1,000 to 10,000 is one of the preferred aspects. Also, maintaining the FTU change rate within 110 FTU / min or less, preferably 85 FTU / min or less, more preferably 60 FTU / min or less, for the entire period (100% of the time) during the period when FTU increases from 1,000 to 10,000 is also one of the preferred aspects.

[0036] The temperature of the mixed solution during the period when the formazine turbidity (FTU) ranges 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 preferable because it is easy to maintain the FTU change rate within the above range.

[0037] When the FTU is 10,000, the temperature of the mixed solution 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.

[0038] In the crystal precipitation step, the temperature of the mixed solution can be appropriately adjusted according to the formazine turbidity and the FTU change rate at that time. The temperature of the mixed solution may be constant, or may be decreased stepwise or continuously. Also, the temperature of the mixed solution may be maintained at a constant temperature for a certain period and then decreased stepwise or continuously. In a preferred embodiment, the temperature of the mixed solution at the time of adding the seed crystal is 34°C or higher and 38°C or lower, the temperature of the mixed solution when the FTU is 10,000 is 30°C or higher and 37°C or lower, and it is preferable that the temperature when the FTU is 10,000 is 0.4°C or higher and 8°C or lower lower than the temperature at the time of adding the seed crystal. Note that maintaining at a constant temperature preferably means maintaining at a predetermined temperature (set temperature) ±3°C, and more preferably means maintaining at a predetermined temperature (set temperature) ±1°C.

[0039] As the cooling rate when decreasing the temperature of the mixed solution, 0.05°C / hr or higher and 20°C / hr or lower is preferable, and 0.1°C / hr or higher and 15°C / hr or lower is more preferable. It is also a preferred embodiment to change the cooling rate over time. For example, after adding the seed crystal, the temperature is maintained for a certain time, for example, 0.5 to 8 hours, and then the cooling rate is 0.05°C / hr or higher and less than 0.5°C / hr for 3 to 20 hours, and then the cooling rate is 0.5°C / hr or higher and 15°C / hr or lower. Another example is that after adding the seed crystal, the cooling rate is 0.05°C / hr or higher and less than 0.5°C / hr for 3 to 20 hours, and then the cooling rate is 0.5°C / hr or higher and 15°C / hr or lower.

[0040] In the crystal precipitation step, it is preferable to lower the temperature of the mixed solution even after the formazine turbidity reaches 10,000 to precipitate crystals. The cooling rate at that time can be set based on the aforementioned range, for example. Also, when the temperature of the mixed solution reaches 23 - 34°C, most of the reduced coenzyme Q10 contained in the mixed solution has already precipitated. Therefore, after the temperature reaches 23 - 34°C, for example, the cooling rate can be increased to 1°C / hr or more and 20°C / hr or less.

[0041] The temperature at the end of the crystal precipitation step, that is, 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 system of the mixed solution, but is preferably 0°C or higher.

[0042] The precipitation of crystals is preferably carried out while forcibly flowing the mixed solution. From the viewpoint of suppressing the formation of supersaturation and smoothly performing nucleation and crystal growth, or from the viewpoint of improving quality, the stirring power required per unit volume is usually 0.003 kW / m 3 or more, preferably 0.004 kW / m 3 or more, more preferably 0.005 kW / m 3 or more, still more preferably 0.006 kW / m 3 or more of the flow is preferably applied to the mixed solution. Also, as the stirring power required, usually 0.1 kW / m 3 or less, preferably 0.03 kW / m 3 or less of the flow is preferably applied to the mixed solution. The above-mentioned forced flow is usually applied by the rotation of the stirring blade, but it is not necessarily required to use a stirring blade as long as the above flow can be obtained. For example, a method such as circulation of the mixed solution can be used.

[0043] In the above crystallization step, a mixed solution (slurry) in which Form II reduced coenzyme Q10 crystals are precipitated is obtained. Since the method according to the present embodiment has excellent filterability of the slurry, Form II reduced coenzyme Q10 crystals can be easily recovered from the slurry by filtration.

[0044] The Form II reduced coenzyme Q10 crystals obtained by the above method are recovered from the slurry through the steps of solid-liquid separation and drying by a conventionally known method as described in Patent Documents 2 and 3, for example. For solid-liquid separation, pressure filtration, centrifugal filtration, etc. can be used. Further, the dried crystals or crystalline solids can be pulverized and classified (screened) as needed and then recovered.

[0045] The median diameter (D50) of the Form II reduced coenzyme Q10 crystals obtained by the above method is preferably 80 μm or more, more preferably 83 μm or more, and particularly preferably 85 μm or more. Also, the median diameter (D50) of the Form II reduced coenzyme Q10 crystals is preferably 130 μm or less, more preferably 125 μm or less, and particularly preferably 120 μm or less. When the median diameter (D50) is within the above range, it is preferable because the filterability of the slurry containing the Form II reduced coenzyme Q10 crystals is excellent.

[0046] In the present embodiment, as one of more preferable embodiments, the drying of the Form II reduced coenzyme Q10 crystals after the above solid-liquid separation can be carried out under heating to improve the content ratio of the Form II reduced coenzyme Q10 crystals. 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. When it is less than 46°C, drying proceeds, but the content ratio of the Form II reduced coenzyme Q10 crystals hardly improves. Also, when it exceeds 52°C, the reduced coenzyme Q10 crystals may melt during drying.

[0047] However, if the content ratio of the target Form II reduced coenzyme Q10 crystals has already been achieved in the crystal precipitation step, it is not limited as described above. For example, drying may be carried out at 25°C or higher, preferably 30°C or higher, more preferably 35°C or higher.

[0048] Also, the heating time when drying is performed is not particularly limited, but 4 hours or more is preferred, 10 hours or more is preferred, and 20 hours or more is more preferred. There is no particular limitation on the upper limit of the heating time, but it is usually 72 hours or less, preferably 48 hours or less, more preferably 36 hours or less.

[0049] In addition, each step in the method of this embodiment, specifically, the seed crystal addition step, the crystal precipitation step, and the recovery steps such as solid-liquid separation and drying, as well as other subsequent treatment steps, etc., are preferably carried out under a deoxygenated atmosphere. The deoxygenated atmosphere can be achieved by replacing the atmosphere with an inert gas, reducing the pressure, boiling, or combining these. At least, replacement of the atmosphere with an inert gas, that is, using an inert gas atmosphere is preferred. Examples of the above-mentioned inert gas include nitrogen gas, helium gas, argon gas, hydrogen gas, carbon dioxide gas, etc., and nitrogen gas is preferably used.

[0050] Whether the obtained crystals of reduced coenzyme Q10 or its crystalline solid contains Form II reduced coenzyme Q10 crystals and the content ratio thereof can be determined, for example, by measuring with a differential scanning calorimeter (DSC).

[0051] As described above, when the reduced coenzyme Q10 crystal of Form II is measured by DSC at a heating rate of 1 °C / min, it shows an endothermic peak around 52 ± 2 °C, and the reduced coenzyme Q10 crystal of Form I shows an endothermic peak around 48 ± 1 °C under the same conditions. Even when the reduced coenzyme Q10 crystal of Form II is mixed with the conventional reduced coenzyme Q10 crystal of Form I or its crystalline solid, the presence or absence of the reduced coenzyme Q10 crystal of Form II and its content ratio 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, the slurry containing the reduced coenzyme Q10 crystal of Form II has excellent filterability. Therefore, the method for producing the reduced coenzyme Q10 crystal of Form II or its crystalline solid of the present invention can reduce the frequency of cleaning and replacing the filtration device, and is excellent in productivity. In addition, according to the present embodiment, the reduced coenzyme Q10 crystal of Form II can be obtained by the crystal precipitation step, but a crystalline solid may be obtained by melting some crystals or the like in the subsequent drying step or the like. Therefore, this embodiment includes the case where crystals are obtained and the case where crystalline solids are obtained.

Example

[0052] Hereinafter, the present embodiment will be described with reference to examples, but the present disclosure is not limited to these examples.

[0053] <Method for evaluating filterability> The slurries obtained in the examples and comparative examples were subjected to constant pressure filtration with a filtrate volume of 200 ml and a filtration pressure of 0.1 hPa, the filtration rate was measured, and the average filtration specific resistance (α av ) was calculated and used for the evaluation of filterability.

[0054] <Apparatus for measuring median diameter> The median diameters of the reduced coenzyme Q10 crystals obtained in the examples and comparative examples were measured using the following apparatus. Particle size distribution measuring device: Partica LA-960

[0055] <Ratio 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 and comparative examples was calculated based on the following formula from the height of the endothermic peak (Y difference) of Form I crystals (hereinafter, Y difference of Form I) and the height of the endothermic peak (Y difference) of Form II crystals (hereinafter, Y difference of Form II) obtained by analyzing the crystals by DSC measurement under the following conditions. Form II Ratio (%) = Y difference of Form II / (Y difference of Form I + Y difference of Form II) × 100

[0056] (DSC Measurement Conditions) Apparatus: DSC6220 (manufactured by SII Nanotechnology) Sample Container: Aluminum Pan & Cover (SSC000C008) Heating Rate: 1 °C / min Sample Amount: 5 ± 2 mg

[0057] <Measurement Method of FTU Change Rate> The FTU change rate in the examples and comparative examples was calculated by measuring the formazin turbidity (FTU) of the mixed solution of ethanol and reduced coenzyme Q10 with a turbidimeter, and 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 the turbidity (FTU) of 9,999 FTU when the 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-20 (FTU)) / 20 (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-20 (FTU) means the measured value of FTU 20 minutes before time point T.) Turbidimeter: Backscattered Light Type Turbidity Sensor (InPro8200, METTLER TOLEDO Co., Ltd.) Measurement Range: 0 ~ 10,000 FTU

[0058] The measurement of FTU was carried out from immediately after the addition of the seed crystal until FTU reached the measurement upper limit of 10,000. The FTU change rate was calculated during the period when FTU was 1,000 to 10,000. 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 the time point 20 minutes before (T - 20 min) and dividing it by 20 minutes, as shown by the above formula.

[0059] [Example 1] After replacing the nitrogen in a separable flask with a volume of 3 L, 144 g of reduced coenzyme Q10 and 1296 g of ethanol with a purity of 99.5 wt% or more were added (concentration of reduced coenzyme Q10: 10 wt%), and the mixture was stirred with a stirring blade (required stirring power 0.03 kw / m 3 ) while heating to 50 °C to obtain a uniform reduced coenzyme Q10 solution (QH solution) (1440 g, 1800 ml).

[0060] The QH solution at 50 °C was cooled to 35.0 °C with stirring by a stirring blade (required stirring power 0.03 kw / m 3 ). To the QH solution (FTU 199) cooled to 35.0 °C, 2.9 g (2.0 wt%) of Form II type reduced coenzyme Q10 crystals were added as seed crystals to initiate the precipitation (crystallization) of reduced coenzyme Q10 crystals. Hereinafter, the QH solution to which the seed crystals were added is referred to as the "crystallization mixture".

[0061] After holding at 35.0 °C for 1 hour after the addition of the seed crystals, it was cooled from 35.0 °C to 32.0 °C at 0.2 °C / hr (primary cooling). Then, it was cooled to 25 °C at 1 °C / hr, and from 25 °C to 1 °C at 10 °C / hr.

[0062] During crystallization, the formazin turbidity (FTU) of the crystallization mixture was measured with a turbidimeter, and it was confirmed that the maximum of the FTU change rate was 32.5 FTU / min during the entire period until the formazin turbidity (FTU) reached 1,000 to 10,000, and the FTU change rate was maintained at 15.3 to 32.5 FTU / min for 80% or more of the time during the period until the FTU reached 1,000 to 10,000.

[0063] After cooling to 1 °C, a part of the obtained slurry was separated, and the filterability was evaluated (calculation of the average filtration specific resistance (α av )) was performed. Solid-liquid separation by filtration was performed on the remaining slurry, and the obtained crystals were dried under reduced pressure at 40 °C for 24 hours to obtain Form II reduced coenzyme Q10 crystals.

[0064] The Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%, and Form I reduced coenzyme Q10 crystals were not contained. Also, the median diameter of the reduced coenzyme Q10 crystals was 115.3 μm, and α av was 0.47×10 10 m / kg.

[0065] [Example 2] After replacing the atmosphere in a 500 mL four-necked flask with nitrogen, 33 g of reduced coenzyme Q10 and 295 g of ethanol with 99.5 wt% or more were added (reduced coenzyme Q10 concentration: 10 wt%), and the mixture was heated to 50 °C with stirring by a stirring blade (stirring power required: 0.007 kw / m 3 ) to obtain a uniform QH solution (328 g, 410 ml).

[0066] The QH solution at 50 °C was cooled to 36.8 °C with stirring by a stirring blade (stirring power required: 0.007 kw / m 3 ). To the QH solution cooled to 36.8 °C, 0.66 g (2.0 wt%) of Form II reduced coenzyme Q10 crystals was added as seed crystals, and precipitation (crystallization) of reduced coenzyme Q10 crystals was started.

[0067] The temperature was controlled with the goal of maintaining the FTU change rate in the period until the formazin turbidity (FTU) of the crystallization mixture after the addition of the seed crystal reached from 1,000 to 10,000 near 55.6 FTU / min. After the formazin turbidity 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. It was confirmed that the maximum of the FTU change rate was 105.2 FTU / min and the minimum was 30.6 FTU / min throughout the period until the formazin turbidity (FTU) reached from 1,000 to 10,000, and that the FTU change rate was maintained at 81.0 FTU / min or less for 80% or more of the time in the period until the formazin turbidity (FTU) reached from 1,000 to 10,000.

[0068] After cooling to 1°C, a part of the obtained slurry was taken, and the filterability was evaluated (calculation of the average filtration specific resistance (α av ). Solid-liquid separation by filtration was performed on the remaining slurry, and the obtained crystals were dried under reduced pressure at 40°C for 24 hours to obtain Form II type reduced coenzyme Q10 crystals.

[0069] The ratio of Form II type crystals in the obtained reduced coenzyme Q10 crystals was 100%, and no Form I type reduced coenzyme Q10 crystals were contained. Also, the median diameter of the reduced coenzyme Q10 crystals was 87.6 μm, and α av was 0.98×10 10 m / kg.

[0070] [Example 3] After purging a 500 mL four-necked flask with nitrogen, 33 g of reduced coenzyme Q10 and 295 g of ethanol with 99.5 wt% or more were added (reduced coenzyme Q10 concentration: 10 wt%), and it was heated to 50°C with stirring by a stirring blade (stirring required power 0.007 kw / m 3 ) to obtain a uniform QH solution (328 g, 410 ml).

[0071] The 50°C QH solution was stirred with a stirring blade (stirring required power 0.007 kw / m 3) While cooling to 34.5°C. To the QH solution cooled to 34.5°C, 0.66 g (2.0 wt%) of Form II reduced coenzyme Q10 crystals was added as seed crystals, and the precipitation (crystallization) of reduced coenzyme Q10 crystals was initiated.

[0072] The target was to maintain the change rate of FTU in the period until the formazin turbidity (FTU) of the crystallization mixture after seed crystal addition reached from 1,000 to 10,000 at around 33.3 FTU / min, and the set temperature was controlled. After the formazin turbidity 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. It was confirmed that the maximum of the FTU change rate was 41.7 FTU / min and the minimum was 14.4 FTU / min during the entire period until the formazin turbidity (FTU) reached from 1,000 to 10,000, and the FTU change rate was maintained at 22.5 - 41.7 FTU / min for 80% or more of the time during the period until the FTU reached from 1,000 to 10,000.

[0073] After cooling to 1°C, a part of the obtained slurry was separated, and the filterability was evaluated (calculation of the average filtration specific resistance (α av ). The remaining 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.

[0074] The Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%. Also, the median diameter of the reduced coenzyme Q10 crystals was 107.3 μm, and α av was 0.48×10 10 m / kg.

[0075] [Comparative Example 1] After replacing the atmosphere in a 500 mL four-necked flask with nitrogen, 28 g of reduced coenzyme Q10 and 250 g of ethanol with a purity of 99.5 wt% or more were added (reduced coenzyme Q10 concentration: 10 wt%), and it was heated to 50°C with stirring by a stirring blade (stirring required power 0.007 kw / m 3 ) to obtain a uniform QH solution (278 g, 347 ml).

[0076] The QH solution at 50 °C was cooled to 36.8 °C while being stirred by a stirring blade (stirring power required: 0.007 kw / m 3 ). To the QH solution cooled to 36.8 °C, 0.6 g (2.0 wt%) of Form II reduced coenzyme Q10 crystals was added as seed crystals, and precipitation (crystallization) of the reduced coenzyme Q10 crystals was initiated.

[0077] The set temperature was controlled with the aim of maintaining the change rate of the formazin turbidity (FTU) of the crystallization mixture after the addition of the seed crystals at around 6.9 FTU / min until the formazin turbidity of the crystallization mixture reached from 1,000 to 10,000. After the formazin turbidity 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. It was confirmed that the change rate of FTU was maintained at less than 15 FTU / min for 95% or more of the time during the period until the formazin turbidity (FTU) reached from 1,000 to 10,000.

[0078] After cooling to 1 °C, a part of the obtained slurry was separated, and the filterability was evaluated (calculation of the average filtration specific resistance (α av ). Solid-liquid separation by filtration was performed on the remaining slurry, 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 ratio of Form II crystals in the obtained reduced coenzyme Q10 crystals was 100%, and no Form I reduced coenzyme Q10 crystals were contained. Also, the median diameter of the reduced coenzyme Q10 crystals was 68.2 μm, and α av was 3.4×10 10 m / kg.

[0080] The results of the examples and comparative examples are shown in Table 1.

[0081]

Table 1

[0082] The slurry obtained in the example (the slurry cooled to 1°C) had a significantly lower average filtration specific resistance (α av ) than the slurry obtained in the comparative example and was excellent in filterability. From this, when precipitating Form II reduced coenzyme Q10 crystals in the crystallization mixture after adding seed crystals, it can be seen that the slurry containing Form II reduced coenzyme Q10 crystals has excellent filterability when the FTU change rate is maintained within a specific range for 80% or more of the period until the formazin turbidity (FTU) reaches 1,000 to 10,000. That is, by maintaining the FTU change rate within a specific range, it becomes possible to efficiently recover Form II reduced coenzyme Q10 crystals by simple filtration, so it can be seen that the productivity of Form II reduced coenzyme Q10 crystals or their crystalline solids is excellent.

[0083] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0084] The upper and / or lower limit values of the numerical ranges described in this specification can define preferred ranges by arbitrarily combining them. For example, the upper and lower limit values of the numerical range can be arbitrarily combined to define a preferred range, the upper limit values of the numerical range can be arbitrarily combined to define a preferred range, and the lower limit values of the numerical range can be arbitrarily combined to define a preferred range.

[0085] Throughout this specification, it should be understood that singular expressions include the concepts of their plurals unless otherwise specified. Therefore, singular articles (e.g., "a", "an", "the", etc. in English) should be understood to include the concepts of their plurals unless otherwise specified.

[0086] Although the above embodiment has been described in detail, the specific configuration is not limited to this embodiment, and even if there are design changes within the scope not departing from the gist of the present disclosure, they are included in the present disclosure.

Claims

1. adding Form II reduced coenzyme Q10 crystals as seed crystals to a mixed solution containing alcohol and reduced coenzyme Q10, and precipitating Form II reduced coenzyme Q10 crystals in the mixed solution after the addition of the seed crystals, A method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof, wherein in the precipitation, the FTU change rate is maintained at 15 FTU / min or more for 80% or more of the time during the period until the formazin turbidity (FTU) reaches 1,000 to 10,000.

2. The production method according to claim 1, wherein the median diameter (D50) of the produced Form II reduced coenzyme Q10 crystals is 80 μm or more.

3. The production method according to claim 1 or 2, wherein in the precipitation, the FTU change rate is maintained at 110 FTU / min or less for 80% or more of the time during the period until the formazin turbidity (FTU) reaches 1,000 to 10,000.

4. The production method according to any one of claims 1 to 3, wherein the median diameter (D50) of the produced Form II reduced coenzyme Q10 crystals is 130 μm or less.

5. The production method according to any one of claims 1 to 4, wherein the alcohol is a monohydric alcohol having 1 to 5 carbon atoms.

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

7. The production method according to any one of claims 1 to 6, wherein the alcohol is 95% by weight or more of alcohol based on the total amount of water and alcohol.

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