Method for producing reduced coenzyme q10 form ii crystals

Abstract

To provide an efficient production method for obtaining a reduced coenzyme Q10 Form II-type crystal having a stable crystal form.SOLUTION: The production method of the present invention comprises a step of adding a seed crystal of a Form II-type crystal to a mixed solution containing ethanol and reduced coenzyme Q10, and a step of precipitating the Form II-type crystal, wherein a dissolved concentration Ci of reduced coenzyme Q10 before adding the seed crystal is equal to or greater than the saturated concentration of the Form II-type crystal and less than the saturated concentration of the Form I-type crystal at a temperature Ti when adding the seed crystal, and wherein the crystal precipitation step comprises adjusting a temperature Tp of the mixed solution so that a dissolved concentration Cp of reduced coenzyme Q10 is equal to or greater than the saturated concentration of the Form II-type crystal and less than the saturated concentration of the Form I-type crystal.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a method for producing Form II reduced coenzyme Q10 crystals with excellent stability.

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 within the living body. Coenzyme Q functions as a transfer component in the electron transport system by repeating oxidation and reduction within 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, and in the living body, usually about 40 to 90% exists in the reduced form. Physiological effects of coenzyme Q include activation of energy production by mitochondrial activation, activation of cardiac function, stabilization effect on cell membranes, and cell protection effect by antioxidant action, etc.

[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 compared to oxidized coenzyme Q10, has also entered the market and is being used.

[0004] General methods for obtaining reduced coenzyme Q10 have already been disclosed (Patent Document 1). Furthermore, several methods are known for obtaining reduced coenzyme Q10 as crystals. 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. The newly emerged crystal form (hereinafter referred to as Form II reduced coenzyme Q10 crystal or Form II crystal) is reported to be much more stable than the conventional reduced coenzyme Q10 (hereinafter referred to as Form I reduced coenzyme Q10 crystal or Form I crystal) and also superior in other physical properties.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0007] Patent Document 4 describes a method for obtaining Form II reduced coenzyme Q10 crystals by performing crystallization under specific conditions. However, this method requires a long time and the recovery amount may be small, and it is not necessarily an optimal method industrially. Also, as a result of preliminary studies, it was found that once Form I crystals precipitate during crystallization, thereafter, Form I crystals preferentially precipitate over Form II crystals, resulting in a low recovery rate of Form II crystals. Therefore, in order to efficiently obtain Form II reduced coenzyme Q10 crystals with a high recovery rate, it is necessary to selectively precipitate only Form II crystals. Therefore, an object of the present invention is to provide an efficient production method for obtaining Form II reduced coenzyme Q10 crystals, which are a stable crystal form.

Means for Solving the Problems

[0008] The inventors have found that in ethanol, the saturation concentration of Form II reduced coenzyme Q10 crystals is lower than that of Form I reduced coenzyme Q10 crystals. Based on this finding, they have found that Form II reduced coenzyme Q10 crystals can be efficiently obtained by the following method. (1) Adding Form II reduced coenzyme Q10 crystals as seed crystals to a mixed solution containing ethanol and reduced coenzyme Q10, and precipitating Form II reduced coenzyme Q10 crystals in the mixed solution after the addition of the seed crystals, wherein the dissolved concentration C of reduced coenzyme Q10 in the mixed solution before the addition of the seed crystals i is not less than the saturation concentration of Form II crystals and less than the saturation concentration of Form I crystals at the temperature T i of the mixed solution at the time of adding the seed crystals, and in the step of precipitating the crystals, adjusting the temperature T p of the mixed solution so that the dissolved concentration C p of reduced coenzyme Q10 in the mixed solution is not less than the saturation concentration of Form II crystals and less than the saturation concentration of Form I crystals, A method for producing Form II reduced coenzyme Q10 crystals, characterized by the above. (2) Ethanol may contain water, and the ethanol concentration is Z (v / v)% based on the total amount of water and ethanol, where Z is 90 to 100, wherein when the units of the C i and the C p are % by weight, and the units of the T i and the T p are K, when the C i and the C p are 1.5% by weight or more, the following conditions (Equation 1) A II ·T i +B II ≦logC i <A I ·Ti +B I (Formula 2) A II ·T p +B II ≤ logC p <A I ·T p +B I (Formula 3) A I = 0.0089·Z - 0.6754 (Formula 4) B I = -2.3607·Z + 172.70 (Formula 5) A II = 0.0086·Z - 0.6844 (Formula 6) B II = -2.3178·Z + 178.26 The production method according to (1), which satisfies all of them. (3) The T i is 20°C or higher and 43°C or lower, and the production method according to (1) or (2). (4) The T i is 20°C or higher and less than 32°C, and the production method according to (1) or (2). (5) The T p is 5°C or higher and 43°C or lower, and the production method according to any one of (1) to (4). (6) The precipitation of the crystal includes p maintaining the T at a constant temperature, and the production method according to any one of (1) to (5). (7) The precipitation of the crystal includes p decreasing the T over time, and the production method according to any one of (1) to (6). (8) The precipitation of the crystal includes maintaining the T at a constant temperature in the range of 20°C or higher and 43°C or lower, and p subsequently, decreasing the temperature of the mixed solution to a temperature of 25°C or lower and lower than the constant temperature at a rate of -15°C / hour or lower and the production method according to any one of (1) to (7). This specification includes the disclosure content of Japanese Patent Application No. 2020 - 021358, which is the basis of the priority of this application. This specification includes the disclosure content of Japanese Patent Application No. 2020 - 021358, which is the basis of the priority of this application.

Advantages of the Invention

[0009] According to the method of the present invention, Form II reduced coenzyme Q10 crystals can be efficiently produced.

Brief Description of the Drawings

[0010]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

MODE FOR CARRYING OUT THE INVENTION

[0011] Hereinafter, the present invention will be described in detail.

[0012] <Reduced coenzyme Q10> In the present specification, "reduced coenzyme Q10" may contain a part of oxidized coenzyme Q10 as long as reduced coenzyme Q10 is the main component. Here, the main component means, for example, contained in an amount of 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, especially 98% by weight or more. Here, the above ratio is the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10.

[0013] As described above, there are two types of crystal polymorphs of reduced coenzyme Q10, namely the conventionally known Form I and the newly discovered Form II. 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, 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. 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 satisfies even one of them, the crystal of reduced coenzyme Q10 is referred to as "the crystal of Form II reduced coenzyme Q10". Of course, it may satisfy all the conditions.

[0014] In addition, the "crystalline solid" in this specification means a solid containing a part having a crystal structure and an amorphous component having no crystal structure therein.

[0015] <ethanol> The inventors of the present invention have found that in ethanol, the saturation concentration of Form II crystals is smaller than that of Form I crystals. Furthermore, by adjusting the temperature of the mixture of ethanol and reduced coenzyme Q10 so that the dissolved concentration of reduced coenzyme Q10 in ethanol is equal to or higher than the saturation concentration of Form II crystals and lower than the saturation concentration of Form I crystals, it is possible to efficiently precipitate Form II crystals.

[0016] In the present invention, the ethanol may be a solvent mainly composed of ethanol, and may be hydrous ethanol containing water. Surprisingly, under the same temperature conditions, the difference between the saturation concentration of Form II crystals and the saturation concentration of Form I crystals in ethanol is greater as the water content in ethanol is lower, and the selective precipitation of Form II crystals is easier. For this reason, with respect to the total amount of water and ethanol, the ethanol concentration is preferably, for example, 80 (v / v)% or more, 90 (v / v)% or more, 95 (v / v)% or more, and is also preferably 100 (v / v)% or less, 99.8 (v / v)% or less, 99.5 (v / v)% or less.

[0017] <Method for Producing Reduced Coenzyme Q10 Crystals of Form II> The method for producing reduced coenzyme Q10 crystals of Form II according to one or more embodiments of the present invention is adding reduced coenzyme Q10 crystals of Form II as seed crystals to a mixed solution containing ethanol and reduced coenzyme Q10, and precipitating reduced coenzyme Q10 crystals of Form II in the mixed solution after the addition of the seed crystals, wherein the dissolved concentration C of reduced coenzyme Q10 in the mixed solution before the addition of the seed crystals i is, at the temperature T of the mixed solution at the time of adding the seed crystals i above the saturation concentration of Form II crystals and below the saturation concentration of Form I crystals, and in the step of precipitating the crystals, the temperature T of the mixed solution p is adjusted so that the dissolved concentration C of reduced coenzyme Q10 in the mixed solution p is above the saturation concentration of Form II crystals and below the saturation concentration of Form I crystals, characterized by this.

[0018] In the following description, the step of adding as seed crystals may be referred to as the "seed crystal addition step", and the step of precipitating reduced coenzyme Q10 crystals of Form II may be referred to as the "crystal precipitation step".

[0019] The mixed solution containing ethanol and reduced coenzyme Q10 is not particularly limited as long as it contains ethanol and reduced coenzyme Q10. It may be a uniform solution in which reduced coenzyme Q10 is dissolved in ethanol, or it may be a slurry in which a part of reduced coenzyme Q10 is dissolved in ethanol but a part is not dissolved and is suspended. Preferably, it is a uniform solution in which reduced coenzyme Q10 is dissolved in ethanol.

[0020] The reduced coenzyme Q10 used in the mixed solution containing ethanol and reduced coenzyme Q10 is not limited regardless of whether it is in a crystalline or amorphous state, nor is its crystal polymorphism limited. Therefore, conventionally known Form I type reduced coenzyme Q10 can also be used. In addition, since its purity can be increased in crystal precipitation, it may be one having impurities or an unpurified or roughly purified reduced coenzyme Q10. Furthermore, an extract of reduced coenzyme Q10 obtained by a conventionally known method or a reaction solution containing reduced coenzyme Q10 obtained from oxidized coenzyme Q10 by a known reduction method can be used as it is or, if necessary, after being purified and / or solvent-substituted as the above-mentioned mixed solution.

[0021] The mixed solution containing ethanol and reduced coenzyme Q10 may further contain other organic solvents other than ethanol (including hydrous ethanol), but the ethanol content per total amount of the solvent components is preferably 95 (v / v)% or more, 97 (v / v)% or more, 99 (v / v)% or more, and the upper limit is preferably 100 (v / v)% or less. Most preferably, it is 100 (v / v)%. Examples of other organic solvents include at least one selected from the group consisting of alcohols other than ethanol, hydrocarbons, fatty acid esters, and nitrogen compounds.

[0022] The dissolved concentration C of reduced coenzyme Q10 in the mixed solution containing ethanol and reduced coenzyme Q10 before the addition of seed crystals i is a concentration that is equal to or higher than the saturation concentration of Form II type crystals and lower than the saturation concentration of Form I type crystals at the temperature T i That's all. The dissolved concentration C of reduced coenzyme Q10 before the addition of seed crystals iis, 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, even more preferably 9% by weight or more, and even more preferably 10% by weight or more, and can be, for example, 50% by weight or less, preferably 45% by weight or less, more preferably 30% by weight or less.

[0023] In a mixed solution containing ethanol and reduced coenzyme Q10, the dissolved concentration C of reduced coenzyme Q10 i is the temperature T of the above mixed solution at the time of adding the seed crystal i In this case, since it is equal to or higher than the saturation concentration of Form II crystals and lower than the saturation concentration of Form I crystals, it is a saturated or supersaturated solution of Form II crystals and an unsaturated solution of Form I crystals. Such a solution is obtained by heating a raw material mixture containing ethanol and reduced coenzyme Q10 to a temperature of 42°C or higher, more preferably 70°C or lower, particularly preferably 55°C or lower, to dissolve reduced coenzyme Q10, and cooling the heated solution to the temperature T i to prepare a saturated or supersaturated solution of Form II crystals.

[0024] The addition amount (seed crystal addition amount) of Form II reduced coenzyme Q10 crystals serving as seed crystals 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, based on the amount of reduced coenzyme Q10 in the above mixed solution before adding the seed crystals. The upper limit is not particularly limited, but is preferably 20% by weight or less, more preferably 4% by weight or less, and particularly preferably 2% by weight or less, based on the amount of reduced coenzyme Q10 in the above mixed solution before adding the seed crystals. The reduced coenzyme Q10 crystals used as seed crystals may contain Form I reduced coenzyme Q10 crystals or amorphous substances as long as they contain Form II reduced coenzyme Q10 crystals, but it is preferable that the purity of the Form II reduced coenzyme Q10 crystals is higher. As the seed crystals, Form II reduced coenzyme Q10 crystals are preferably used, for example, those having a content of 50% by weight or more, preferably 75% by weight or more, more preferably 80% by weight or more, and even more preferably 90% by weight or more.

[0025] The temperature T of the mixed solution at the time of adding the seed crystal i is preferably in the range of 20°C or higher and 43°C or lower. Temperature T i When it is 20°C or higher, the difference between the saturation concentration of Form II crystals and the saturation concentration of Form I crystals is large, and the saturation concentration of Form I crystals is high, so it is suitable for the selective precipitation of Form II crystals. Temperature T i When it is 43°C or lower, the crystal formation rate is high. Temperature T i When it is more preferably 25°C or higher, more preferably 30°C or higher, more preferably 32°C or higher, and more preferably 35°C or higher, the difference between the saturation concentration of Form II crystals and the saturation concentration of Form I crystals is even larger, and the saturation concentration of Form I crystals is high, so the selective precipitation of Form II crystals is even easier. Temperature T i The upper limit is more preferably 40°C or lower. Also, T i When it is 20°C or higher and less than 32°C, it is also one of the preferred embodiments.

[0026] The crystal precipitation step is to adjust the temperature T of the mixed solution after adding the seed crystal p so that the dissolved concentration C of reduced coenzyme Q10 in the mixed solution p is equal to or higher than the saturation concentration of Form II crystals and less than the saturation concentration of Form I crystals.

[0027] Temperature T p can be appropriately adjusted according to the dissolved concentration C of reduced coenzyme Q10 at that time. For example, temperature T p can be 5°C or higher and 43°C or lower. In the crystal precipitation step, temperature T p may be a constant temperature, but since the dissolved concentration C of reduced coenzyme Q10 decreases as the crystal precipitates, it is preferable to perform cooling crystallization in which the temperature T p of the mixed solution is decreased over time to promote crystallization. "Decreasing the temperature T p over time" means that the temperature T p is decreased over time. p Decreasing over time" means that the temperature T pincluding decreasing stepwise or continuously over time.

[0028] In the crystal precipitation step, it is preferable to control the amount of crystal precipitation per unit time to control the formation of supersaturation. The preferable amount of precipitation per unit time is, for example, a rate equal to or lower than the rate at which about 50% of the total precipitation amount per unit time precipitates (i.e., a maximum of 50% amount / hour), and preferably, a rate equal to or lower than the rate at which 25% of the total precipitation amount per unit time precipitates (i.e., a maximum of 25% amount / hour).

[0029] In a preferable example of the crystal precipitation step, temperature T p is maintained at a constant temperature, for example, the temperature range cited as the preferable range of temperature T i at the time of seed crystal addition, for example, a constant temperature in the range of 20°C or higher and 43°C or lower. In particular, temperature T p is maintained at a constant temperature in the temperature range cited as the preferable range of temperature T i at the time of seed crystal addition for 1 hour or more after adding the seed crystal, for example, a constant temperature in the range of 20°C or higher and 43°C or lower. Although the time for maintaining the mixed solution within the temperature range is not particularly limited, it is preferably 1 hour or more, more preferably 2 hours or more, still more preferably 4 hours or more, and particularly preferably 10 hours or more. The upper limit of the time for maintaining the mixed solution within the temperature range is not particularly limited, but an effect sufficient can be obtained in about 24 hours. Note that maintaining at a constant temperature preferably means maintaining at a predetermined temperature (set temperature) ±3°C, more preferably means maintaining at a predetermined temperature (set temperature) ±1°C, and still more preferably means maintaining at a predetermined temperature (set temperature) ±0.5°C.

[0030] When performing cooling crystallization, after maintaining the temperature T p of the mixed solution within the above temperature range after adding the seed crystal, it is preferable to decrease it stepwise or continuously. The rate of decrease (cooling rate) of temperature T p may be constant or may be changed.

[0031] When performing cooling crystallization, the cooling rate is not particularly limited. For example, the temperature drop per hour is more preferably 15 °C or less (= -15 °C / hour or less as the temperature change rate), more preferably 10 °C or less, more preferably 5 °C or less, more preferably 1 °C or more, and more preferably 2 °C or more. As an example of performing cooling crystallization, after adding seed crystals, the temperature T of the mixed solution p is maintained within the above temperature range, and then the temperature of the mixed solution is lowered at a rate of -15 °C / hour or less to a temperature that is 25 °C or lower and lower than the constant temperature. The cooling rate when the temperature of the mixed solution is lowered over time may be constant or may change. In particular, in an embodiment where the cooling rate continuously or stepwise increases as the temperature of the mixed solution decreases, that is, the temperature drop per hour increases, the reduced coenzyme Q10 in which the remaining amount in the liquid phase decreases as the temperature of the mixed solution decreases can be efficiently crystallized. For example, until the temperature of the mixed solution reaches 25 °C, the mixed solution is preferably cooled at a rate of a temperature drop of 5 °C or less per hour, more preferably 3 °C or less per hour. In the stage of further cooling the mixed solution to a temperature lower than 25 °C, the mixed solution can be cooled at a rate of a temperature drop of preferably 6 °C or more, more preferably 8 °C or more per hour. The end-point temperature when performing cooling crystallization 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 more, and more preferably 3 °C or more.

[0032] The precipitation of crystals is preferably carried out while forcibly flowing the mixed solution after adding seed crystals. In order to suppress the formation of supersaturation and perform nucleation and crystal growth smoothly, or from the viewpoint of improving quality, the stirring power required per unit volume is usually about 0.01 kW / m 3 or more, preferably 0.03 kW / m 3 or more, more preferably 0.1 kW / m 3 or more, and even more preferably 0.3 kW / m 3It is preferable to impart the above flow to the mixed solution. The above forced flow is usually imparted by the rotation of a stirring blade, but it is not necessarily required to use a stirring blade as long as the above flow is obtained, and for example, a method such as circulation of the mixed solution may be utilized.

[0033] The crystallization step is to adjust the temperature T of the mixed solution p such that the dissolved concentration C of reduced coenzyme Q10 p is equal to or higher than the saturation concentration of Form II crystals and lower than the saturation concentration of Form I crystals. For example, from the addition of seed crystals until preferably 70% by weight or more, more preferably 80% by weight or more, more preferably 85% by weight or more, more preferably 90% by weight or more of the total amount of reduced coenzyme Q10 contained in the mixed solution precipitates as crystals, or from the addition of seed crystals until the dissolved concentration C of reduced coenzyme Q10 p reaches 1.5% by weight or less, when the temperature T of the mixed solution p is adjusted so as to satisfy the above conditions, since most of the reduced coenzyme Q10 precipitates as Form II crystals, the temperature conditions may deviate from the above conditions thereafter.

[0034] The present inventors surprisingly found that when the ethanol concentration is Z (v / v)% with respect to the total amount of water and ethanol in the mixed solution, Z is 90 to 100, the unit of the dissolved concentration C of reduced coenzyme Q10 in the mixed solution is % by weight, and the unit of the temperature T of the mixed solution is K, the solubility (saturation concentration) C of Form I crystals at the temperature T (K) I (% by weight), and the solubility (saturation concentration) C of Form II crystals at the temperature T (K) II (% by weight) can be represented by Formula 7 and Formula 8, respectively, with A I , B I , A II , B II being constants. (Formula 7) log C I = A I ·T + B I (Formula 8) log C II = A II·T + B II

[0035] And each constant A I , B I , A II , B II It has been found that they can be expressed by the following formulas 3, 4, 5, and 6 respectively, taking the ethanol concentration Z as a variable. (Formula 3) A I = 0.0089·Z - 0.6754 (Formula 4) B I = -2.3607·Z + 172.70 (Formula 5) A II = 0.0086·Z - 0.6844 (Formula 6) B II = -2.3178·Z + 178.26

[0036] Therefore, in the seed crystal addition step, when the dissolved concentration C i of reduced coenzyme Q10 and the temperature T i of the mixed solution satisfy the following formula 1, the dissolved concentration C i of reduced coenzyme Q10 is equal to or higher than the saturation concentration of Form II crystals and lower than the saturation concentration of Form I crystals. Here, the unit of C i is wt%, and the unit of T i is K. It has been found that formula 1 holds when C i is 1.5 wt% or higher. (Formula 1) A II ·T i + B II ≦ log C i < A I ·T i + B I

[0037] Similarly, in the crystal precipitation step, when the dissolved concentration C p of reduced coenzyme Q10 and the temperature T p of the mixed solution satisfy the following formula 2, the dissolved concentration C p of reduced coenzyme Q10 is equal to or higher than the saturation concentration of Form II crystals and lower than the saturation concentration of Form I crystals. Here, the unit of C p is wt%, and the unit of Tp Let the unit of p be K. It has been found that Equation 2 holds when C (Equation 2) A II ·T p +B II ≦logC p <A I ·T p +B I

[0038] The Form II reduced coenzyme Q10 crystal or crystalline solid obtained by the above method is recovered through solid-liquid separation and drying steps 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. Also, the dried crystals or crystalline solids can be pulverized and classified (screened) as needed for recovery.

[0039] In the present invention, as one of the more preferred embodiments, drying of the Form II reduced coenzyme Q10 crystal or crystalline solid after the above solid-liquid separation can be carried out under heating to improve the content ratio of the Form II reduced coenzyme Q10 crystal. 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 crystal hardly improves. Also, when it exceeds 52°C, the reduced coenzyme Q10 crystal may melt during drying. Also, the heating time when drying is carried out under the above temperature conditions is not particularly limited, but preferably 4 hours or more, preferably 10 hours or more, and more preferably 20 hours or more.

[0040] In addition, if the content ratio of the target Form II reduced coenzyme Q10 crystal has already been achieved in the crystal precipitation step, it is not subject to the above limitations. For example, drying can be carried out at 25°C or higher, preferably 30°C or higher, and more preferably 35°C or higher.

[0041] In addition, each step in the method of the present invention, specifically, the seed crystal addition step, crystal precipitation step, recovery steps such as solid-liquid separation and drying described above, and other subsequent treatment steps 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 methods. At least, it is preferable to use replacement with an inert gas in the atmosphere, that is, to use an inert gas atmosphere. Examples of the inert gas include nitrogen gas, helium gas, argon gas, hydrogen gas, carbon dioxide gas, etc., and nitrogen gas is preferably used.

[0042] Whether the obtained reduced coenzyme Q10 crystal or crystalline solid contains Form II type reduced coenzyme Q10 crystal and its content ratio can be determined, for example, by measuring with a differential scanning calorimeter (DSC).

[0043] As described above, when the Form II type reduced coenzyme Q10 crystal is measured by DSC at a heating rate of 1 °C / min, it shows an endothermic peak around 52 ± 2 °C, and the Form I type reduced coenzyme Q10 crystal shows an endothermic peak around 48 ± 1 °C under the same conditions. Even when the Form II type reduced coenzyme Q10 crystal is mixed with the conventional Form I type reduced coenzyme Q10 crystal or its crystalline solid, the presence and content ratio of the Form II type reduced coenzyme Q10 crystal 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 method of the present invention, high-purity Form II type reduced coenzyme Q10 crystal or crystalline solid can be efficiently obtained.

Examples

[0044] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples only.

[0045] <Ratio of Form II type reduced coenzyme Q10 crystal> The ratio of Form II crystals in the recovered reduced coenzyme Q10 crystals was analyzed by DSC measurement under the following conditions, and the ratio of Form II reduced coenzyme Q10 crystals (Form II ratio) was calculated based on the following formula from the height of the endothermic peak (Y difference) of the Form I reduced coenzyme Q10 crystals obtained (hereinafter, I - Y difference) and the height of the endothermic peak (Y difference) of the Form II reduced coenzyme Q10 crystals (hereinafter, II - Y difference). (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

[0046]

Equation

[0047] <Measurement of the dissolved concentration of reduced coenzyme Q10 in the liquid phase> The dissolved concentration of reduced coenzyme Q10 in the liquid phase was measured by analyzing the liquid phase sample by high performance liquid chromatography under the following conditions. (HPLC conditions) Column: SYMMETRY C18 (manufactured by Waters) 250 mm (length) 4.6 mm (inner diameter) Mobile phase: C2H5OH:CH3OH = 4:3 (v:v) Detection wavelength: 210 nm Flow rate: 1 ml / min Retention time of reduced coenzyme Q10: 9.1 min.

[0048] <Experiment 1> The solubility (saturation concentration) (wt%) of Form I reduced coenzyme Q10 crystals (Form I crystals) and Form II reduced coenzyme Q10 crystals (Form II crystals) was determined at each temperature of 298.15 K (25 °C), 303.15 K (30 °C), 308.15 K (35 °C), and 313.15 K (40 °C) in hydrous ethanol with ethanol concentrations of 99.5 (v / v)%, 95 (v / v)%, and 90 (v / v)%.

[0049] The solubility was measured according to the following procedure. Approximately 10 g of Form I crystals or Form II crystals was added to approximately 30 g of each hydrous ethanol, stirred under a nitrogen atmosphere, and held at each temperature of 25 °C, 30 °C, 35 °C, and 40 °C for about 1 hour. Sampling was performed at each temperature, and the liquid phase sample was obtained by rapid filtration. This sample was analyzed under the above HPLC conditions to calculate the solubility.

[0050] The measurement results are shown in Tables 1 to 3. Also, Figure 1 shows a graph in which the results shown in Tables 1 to 3 are plotted with the temperature (K) on the x-axis and the solubility (wt%) of the reduced coenzyme Q10 crystals on the y-axis.

[0051] [Table 1]

[0052] [Table 2]

[0053] [Table 3]

[0054] As shown in Tables 1 to 3 and Figure 1, it was confirmed that in hydrous ethanol of any concentration, the solubility of Form I crystals was higher than that of Form II crystals, and that the higher the ethanol concentration, the higher the solubility of the crystals of each form.

[0055] Therefore, graphs plotting the solubility of Form I crystals and Form II crystals in aqueous ethanol of each concentration shown in Table 1, Table 2, and Table 3, with the temperature (K) on the x-axis and the natural logarithm of the solubility (wt%) of coenzyme Q10 crystals on the y-axis, are shown in Figure 2, Figure 3, and Figure 4, respectively. The equation of the regression line and the correlation coefficient are shown in each graph. Since the correlation coefficient is sufficiently large, the validity of linear regression on the semi-logarithmic graph was confirmed. The solubility (saturation concentration) C I (wt%) of Form I crystals and the solubility (saturation concentration) C II (wt%) of Form II crystals at temperature T (K) in aqueous ethanol of each concentration can be expressed by Formula 7 and Formula 8, respectively, with A I , B I , A II , B II as constants respectively. (Formula 7) logC I = A I ·T + B I (Formula 8) logC II = A II ·T + B II

[0056] The values of A I , B I , A II , B II at each ethanol concentration are as follows.

[0057]

Table 4

[0058] A I , B I , A II , B II To confirm the correlation between the ethanol concentration and A

[0059] A I and A IIis directly proportional to the change in the concentration of aqueous ethanol, and B I and B II were confirmed to be inversely proportional to the change in the concentration of aqueous ethanol. From these results, it was confirmed that the constants A I , B I , A II , B II have the relationships expressed by Formula 3, Formula 4, Formula 5, and Formula 6 with the ethanol concentration Z ((v / v) %), respectively.

[0060] <Experiment 2> After purging the inside of a 500 mL separable flask (made of borosilicate glass) with nitrogen, 40.0 g of reduced coenzyme Q10 and 360 g of 99.5% ethanol were added (reduced coenzyme Q10 concentration: 10 wt%), and the mixture was heated to 42 °C with stirring by a stirring blade (required stirring power 0.1 kw / m 3 ) to obtain a uniform solution. After cooling this solution to 35 °C, 0.4 g (1 wt%) of reduced coenzyme Q10 crystals containing Form II type reduced coenzyme Q10 crystals was added as seed crystals.

[0061] The mixture after seed crystal addition was held at 35 °C for 15 hours to precipitate crystals. Then, the mixture was cooled to 25 °C over 5 hours at a constant cooling rate of -2 °C / hour, and subsequently cooled to 10 °C over 1.5 hours at a constant cooling rate of -10 °C / hour to further precipitate crystals. After reaching 10 °C, the mixture was filtered for solid-liquid separation, and the obtained crystals were dried under reduced pressure at 35 °C for 10 hours to obtain Form II type reduced coenzyme Q10 crystals (Form II ratio: 100%, recovery rate 97%).

[0062] In this experiment, the liquid phase of the mixture was sampled immediately before seed crystal addition (0 hours later), 3 hours later, 6 hours later, 9 hours later, 12 hours later, 15 hours later (up to this point at 35 °C), 17.5 hours later (30 °C), 20 hours later (25 °C), 20.5 hours later (20 °C), 21.5 hours later (10 °C), and the dissolved concentration C (wt%) of reduced coenzyme Q10 dissolved in the liquid phase sample was measured by high performance liquid chromatography. The measurement results are shown in Table 5. Also, the natural logarithm LogC of the measured dissolved concentration C is shown in Table 5.

[0063] Furthermore, ethanol concentration 99.5 (v / v)% was substituted into Z in Formula 3, Formula 4, Formula 5, and Formula 6 to determine constant A I , B I , A II , B II The values were obtained. Using these constants, according to the above Formula 7 and Formula 8, the saturation concentration C I (wt%) of Form I crystals at each temperature (unit converted to Kelvin) shown in Table 5, LogC I , and the saturation concentration C II (wt%) of Form II crystals, LogC II were obtained.

[0064]

Table 5

[0065] At the time of adding seed crystals at 35°C and up to the crystallization time of 20 hours when the temperature was maintained at 35°C and then cooled to 25°C, the dissolved concentration C of reduced coenzyme Q10 in the liquid phase was higher than the saturation concentration C II of Form II crystals and less than the saturation concentration C I of Form I crystals. At crystallization times of 20.5 hours (20°C) and 21.5 hours (10°C), the dissolved concentration C exceeded the saturation concentration C I of Form I crystals, but at the crystallization time of 20 hours, the dissolved concentration C of reduced coenzyme Q10 in the liquid phase was reduced to 1.5 wt%. Crystallization precipitation of most of the reduced coenzyme Q10 dissolved at the time of adding seed crystals occurred under the condition that the dissolved concentration C in the liquid phase was higher than the saturation concentration C II of Form II crystals and less than the saturation concentration C I of Form I crystals, so crystals with a Form II ratio of 100% could be obtained.

[0066] All publications, patents, and patent applications cited in this specification are hereby incorporated by reference in their entirety.

Claims

1. adding Form II reduced coenzyme Q10 crystals as seed crystals to a mixed solution containing ethanol and reduced coenzyme Q10, and precipitating Form II reduced coenzyme Q10 crystals in the mixed solution after the addition of the seed crystals, The dissolved concentration C of reduced coenzyme Q10 in the mixed solution before the addition of the seed crystal ｉ is such that at the temperature T of the mixed solution at the time of adding the seed crystal ｉ it is not less than the saturation concentration of Form II crystals and less than the saturation concentration of Form I crystals, In the step of precipitating the crystals, the temperature T of the mixed solution ｐ is adjusted such that the dissolved concentration C of reduced coenzyme Q10 in the mixed solution ｐ is not less than the saturation concentration of Form II crystals and less than the saturation concentration of Form I crystals. A method for producing Form II reduced coenzyme Q10 crystals, characterized by comprising the above.

2. The ethanol may contain water, and the ethanol concentration is Z (v / v)% with respect to the total amount of water and ethanol, and Z is 90 to 100, said C ｉ and said C ｐ are in units of wt%, and when the units of said T ｉ and said T ｐ are in units of K Said C ｉ and said C ｐ when it is 1.5% by weight or more The following conditions (Formula 1) A ＩＩ · T ｉ + B ＩＩ ≤ log C ｉ < A Ｉ · T ｉ + B Ｉ (Formula 2) A ＩＩ · T ｐ + B ＩＩ ≤ log C ｐ < A Ｉ · T ｐ + B Ｉ (Formula 3) A Ｉ = 0.0089 · Z - 0.6754 (Formula 4) B Ｉ = -2.3607 · Z + 172.70 (Formula 5) A ＩＩ = 0.0086 · Z - 0.6844 (Formula 6) B ＩＩ = -2.3178 · Z + 178.26 All of which are satisfied, the production method according to claim 1.

3. The above-mentioned T ｉ The production method according to claim 1 or 2, wherein the temperature is 20°C or higher and 43°C or lower.

4. The above-mentioned T ｉ The manufacturing method according to claim 1 or 2, wherein the temperature is 20°C or higher and lower than 32°C.

5. The aforementioned T ｐ is 5°C or higher and 43°C or lower. The manufacturing method according to any one of claims 1 to 4.

6. Precipitating the crystals includes maintaining the T ｐ at a constant temperature, and the production method according to any one of claims 1 to 5.

7. Precipitating the crystal includes decreasing the T ｐ with time, and the production method according to any one of claims 1 to 6.

8. The precipitation of the crystals is said T ｐ is maintained at a constant temperature in the range of 20°C or higher and 43°C or lower, and subsequently reducing the temperature of the mixed solution to a temperature of 25°C or lower and lower than the certain temperature at a rate of -15°C / hour or less The production method according to any one of claims 1 to 7, comprising the above.

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