Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
  • C07C41/01—Preparation of ethers
  • C07C41/34—Separation; Purification; Stabilisation; Use of additives
  • C07C41/40—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
  • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C50/00—Quinones
  • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
  • C07C50/28—Quinones containing groups having oxygen atoms singly bound to carbon atoms with monocyclic quinoid structure

Definitions

• the present disclosure relates to a method for producing Form II reduced coenzyme Q10 crystals with excellent stability or a crystalline solid thereof.
• Coenzyme Q is an essential component that is widely distributed in living organisms, from bacteria to mammals, and is known as a component of the mitochondrial electron transport system in cells in living organisms. Coenzyme Q repeats oxidation and reduction in mitochondria, thereby serving as a transfer component in the electron transport system, and reduced coenzyme Q is known to have an antioxidant effect.
• coenzyme Q10 which has 10 repeating structures in the side chain of coenzyme Q, is the main component, and about 40 to 90% of the coenzyme exists in vivo as a reduced form.
• Physiological actions of coenzyme Q include activation of energy production by mitochondrial activation, activation of cardiac function, stabilization of cell membranes, and protection of cells by antioxidant action.
• Patent Document 1 A general method for obtaining reduced coenzyme Q10 has 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), or adding a high-concentration liquid phase of reduced coenzyme Q10 to a poor solvent. A method (Patent Document 3) for crystallization by crystallization has been reported.
• Patent Document 4 describes that crystal polymorphism is observed in reduced coenzyme Q10. Or called Form II type crystal) is much more stable than conventional reduced coenzyme Q10 (hereinafter, this crystal is called Form I type reduced coenzyme Q10 crystal, or Form I type crystal), and other It is also reported to have excellent physical properties.
• Patent Document 5 describes a method for producing Form II-type reduced coenzyme Q10 crystals.
• at least one organic solvent selected from the group consisting of alcohols, hydrocarbons, fatty acid esters and nitrogen compounds, and reduced coenzyme Q10 are contained, and the temperature is 32 to 43 C.
• a method for producing Form II reduced coenzyme Q10 crystals comprising:
• Patent Document 4 describes a method of crystallization under specific conditions as a method for obtaining Form II reduced coenzyme Q10 crystals. This method is not necessarily industrially optimal.
• the method disclosed in Patent Document 5 aims to provide an efficient production method suitable for industrial-scale production for obtaining Form II reduced coenzyme Q10 crystals. A method focused primarily on temperature is disclosed. The inventors thought that a more efficient manufacturing method could be provided by paying attention to factors other than temperature.
• an object of the present disclosure is to provide an efficient production method for obtaining Form II type reduced coenzyme Q10 crystals, which is a stable crystal form, or a crystalline solid thereof.
• an object of the present disclosure is to provide a production method for obtaining FormII-type reduced coenzyme Q10 crystals or a crystalline solid thereof having excellent oxidation stability.
• Form II reduced coenzyme Q10 crystals When forming Form II reduced coenzyme Q10 crystals in a mixed solution containing alcohol and reduced coenzyme Q10, as the precipitation progresses, Form II reduced coenzyme Q10 crystals in the mixed solution increase. Turbidity increases due to increase.
• the present inventors have found that Form II reduced coenzyme Q10 crystals can be efficiently produced by controlling the rate of change in turbidity, and the resulting Form II reduced coenzyme Q10 crystals or a crystalline solid thereof was found to be excellent in oxidation stability.
• Example aspects of this embodiment 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; Precipitating Form II reduced coenzyme Q10 crystals in the mixed solution after adding the seed crystals; In the precipitation, the formazin turbidity (FTU) is maintained at 45 FTU/min or less for 70% or more of the period from 1,000 to 10,000, Form II reduced coenzyme Q10 A method for producing crystals or crystalline solids thereof. (2) The production method according to (1), wherein the temperature of the mixture during the period is 30 to 43°C.
• the FTU change rate is maintained above 0 FTU/min for 70% or more of the period from 1,000 to 10,000 in formazin turbidity (FTU), (1) or ( 2) The manufacturing method as described in.
• the production method according to (4), wherein the monohydric alcohol having 1 to 5 carbon atoms is ethanol.
• This specification includes the disclosure content of Japanese Patent Application No. 2021-052888, which is the basis of priority of this application.
• Form II reduced coenzyme Q10 crystals or crystalline solids thereof can be efficiently produced.
• the Form II reduced coenzyme Q10 crystals or the crystalline solid thereof obtained by the method of the present disclosure are excellent in oxidation stability.
• reduced coenzyme Q10 may partially contain oxidized coenzyme Q10 as long as it contains reduced coenzyme Q10 as a main component.
• the main component is, for example, 50% by weight or more, usually 60% by weight or more, preferably 70% by weight or more, more preferably 80% by weight or more, still more preferably 90% by weight or more, particularly preferably 95% by weight. More preferably, it means that the content is 98% by weight or more.
• the ratio is the ratio of reduced coenzyme Q10 to the total amount of coenzyme Q10.
• reduced coenzyme Q10 has two types of crystal polymorphs: the conventionally known Form I type and the recently discovered Form II type. Specifically, the melting point is around 48° C., and the diffraction angles (2 ⁇ 0.2°) are 3.1°, 18.7°, 19.0°, and 20° in powder X-ray (Cu—K ⁇ ) diffraction.
• the crystal form of reduced coenzyme Q10 showing characteristic peaks at 2° and 23.0° is Form I type, and has a melting point of around 52°C. ⁇ 0.2°) Crystal form of reduced coenzyme Q10 showing characteristic peaks at 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3° is Form II type.
• DSC differential scanning calorimetry
• Crystal solid as used herein means a solid containing therein a portion having a crystalline structure and an amorphous component having no crystalline structure. That is, the "crystalline solid thereof” in "Form II reduced coenzyme Q10 crystal or crystalline solid thereof” means “a portion having a crystal structure of a Form II reduced coenzyme Q10 crystal and having a crystal structure. means "a solid that contains no amorphous component therein”.
• the alcohol is preferably a monohydric alcohol having 1 to 5 carbon atoms.
• monohydric alcohols having 1 to 5 carbon atoms include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and n-pentanol.
• ethanol is particularly preferred because the saturation concentration of Form II crystals is sufficiently lower than the saturation concentration of Form I crystals and is easy to handle.
• alcohol what was illustrated above may be used individually, and 2 or more types may be mixed and used.
• the alcohol in the present specification may be a solvent containing alcohol as a main component, and may be a hydrous alcohol containing water.
• alcohol has an alcohol concentration of, 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, and still more preferably 99% by weight, based on the total amount of water and alcohol. It is at least 99.5% by weight, particularly preferably at least 99.5% by weight.
• Alcohol having an alcohol concentration of 99.5% by weight or more means anhydrous alcohol.
• the upper limit of the alcohol concentration is 100% by weight or less.
• Ethanol has an ethanol concentration of, 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, and still more preferably 99% by weight, based on the total amount of water and ethanol. It is at least 99.5% by weight, particularly preferably at least 99.5% by weight. Moreover, the upper limit of the ethanol concentration is 100% by weight or less.
• Form II reduced coenzyme Q10 crystals or crystalline solids thereof are added to a mixed solution containing alcohol and reduced coenzyme Q10. adding as seed crystals, and precipitating FormII-type reduced coenzyme Q10 crystals in the mixed solution after adding the seed crystals, wherein the precipitation has a formazin turbidity (FTU) of 1,
• FTU formazin turbidity
• the step of adding Form II reduced coenzyme Q10 crystals as seed crystals is referred to as the "seeding step”
• the step of precipitating Form II reduced coenzyme Q10 crystals is referred to as the “crystal precipitation step”.
• the mixed solution containing alcohol and reduced coenzyme Q10 is not particularly limited as long as it contains alcohol and reduced coenzyme Q10.
• it may be a slurry in which reduced coenzyme Q10 is partly dissolved in alcohol but partly not dissolved but suspended in alcohol.
• reduced coenzyme Q10 is dissolved in alcohol. Homogeneous solution.
• the reduced coenzyme Q10 used in the mixture containing alcohol and reduced coenzyme Q10 may be in a crystalline or amorphous state, and its crystal polymorphism may be used. Therefore, conventionally known Form I reduced coenzyme Q10 can also be used. In addition, since it is possible to increase the purity by crystal precipitation, it may be an unpurified or partially purified reduced coenzyme Q10 containing impurities. 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 may be used as it is or as necessary. Purified and/or solvent-substituted one can also be used as the mixed solution.
• the mixed solution containing alcohol and reduced coenzyme Q10 may further contain organic solvents other than alcohol (including hydrous alcohol), but the alcohol content (alcohol purity ) is preferably 95% by weight or more, 97% by weight or more, or 99% by weight or more, and the upper limit is preferably 100% by weight or less.
• the purity of the alcohol is most preferably 99.5 wt% or higher.
• Other organic solvents include at least one selected from the group consisting of hydrocarbons, fatty acid esters and nitrogen compounds.
• the dissolved concentration of reduced coenzyme Q10 before addition of seed crystals in the mixed solution containing alcohol and reduced coenzyme Q10 is, for example, 2% by weight or more, preferably 3% by weight or more, and more preferably 5% by weight. Above, more preferably 7% by weight or more, particularly preferably 9% by weight or more.
• the dissolved concentration of reduced coenzyme Q10 before addition of seed crystals is, for example, 50% by weight or less, preferably 45% by weight or less, more preferably 30% by weight or less, even more preferably 20% by weight or less, and particularly preferably 15% by weight. It is below.
• a mixed solution containing alcohol and reduced coenzyme Q10 is prepared by heating a raw material mixture containing alcohol and reduced coenzyme Q10 to a temperature of, for example, 42° C. or higher to dissolve reduced coenzyme Q10. can get.
• the temperature is preferably 70° C. or lower, more preferably 55° C. or lower.
• the mixture containing the alcohol and the reduced coenzyme Q10 is preferably cooled to the temperature at which the seed crystals are added, which will be described later. .
• the amount of Form II-type reduced coenzyme Q10 crystals to be added (the amount of seed crystals to be added) is not particularly limited, but the amount of reduced coenzyme Q10 (100 % by weight), preferably 0.1% by weight or more, more preferably 0.5% by weight or more, even more preferably 0.8% by weight or more, and particularly preferably 1% by weight or more.
• the upper limit is not particularly limited, it is preferably 20% by weight or less, more preferably 4% by weight or less, relative to the amount (100% by weight) of reduced coenzyme Q10 in the mixed solution before adding seed crystals. 2% by weight or less is more preferable.
• the reduced coenzyme Q10 crystals used as seed crystals may contain Form I reduced coenzyme Q10 crystals or amorphous forms, as long as they contain Form II reduced coenzyme Q10 crystals. However, it is preferable that the purity of Form II reduced coenzyme Q10 crystals is high.
• Form II reduced coenzyme Q10 crystals for example, 50% by weight or more, preferably 75% by weight or more, more preferably 80% by weight or more, more preferably 90% by weight or more, are used as seed crystals. good.
• the temperature of the mixed liquid at the time of adding the seed crystals is preferably 30 to 43°C.
• the temperature of the mixed solution at the time of adding the seed crystals is more preferably 32° C. or higher, particularly preferably 34° C. or higher, and more preferably 40° C. or lower. Within this range, selective precipitation of Form II reduced coenzyme Q10 crystals is easy.
• the crystal precipitation step includes maintaining the FTU change rate at 45 FTU/min or less for 70% or more of the period from 1,000 to 10,000 in formazin turbidity (FTU).
• the FTU change rate is preferably 43 FTU/min or less, more preferably 40 FTU/min or less.
• the reduced coenzyme Q10 is uniformly dissolved in alcohol in the mixed solution at the time of adding the seed crystals.
• the FTU of the mixed liquid at the time of seed crystal addition is usually 0-250, preferably 0-230, more preferably 0-200. This range is preferable because Form II reduced coenzyme Q10 crystals preferentially precipitate.
• the FTU change rate at a certain time (T) can be calculated by the following formula.
• FTU change rate T (FTU/min) (measured turbidity value T (FTU) - measured turbidity value T-20 (FTU))/20 (min)
• the FTU change rate T means the FTU change rate at time (T)
• the turbidity measurement value T (FTU) means the FTU measurement value at time (T)
• the turbidity measurement value T- 20 (FTU) means the FTU measurement 20 minutes before time T.
• the FTU change rate can be calculated by measuring the FTU every 20 minutes and dividing the increase in FTU during that period by 20 minutes. That is, in a certain aspect, even if the FTU change rate is outside the range of this embodiment for a very short time (for example, 1 minute), when the FTU is measured every 20 minutes, the FTU change rate is When within the scope of the embodiment, the aspect assumes that the FTU rate of change satisfies the requirements of the embodiment.
• the FTU change rate it is preferable to maintain the FTU change rate above 0 FTU/min for 70% or more of the period from 1,000 to 10,000 in formazin turbidity (FTU). More preferably, the FTU change rate is, for example, 5 FTU/min or more.
• the FTU change rate is in the above-mentioned specific range for 70% or more of the period until the formazin turbidity (FTU) becomes 1,000 to 10,000, so that the oxidation stability is excellent. Form II reduced coenzyme Q10 crystals can be produced efficiently.
• the FTU change rate it is preferable to maintain the FTU change rate at 5 FTU / min or more and 45 FTU / min or less for 70% or more of the period until the formazin turbidity (FTU) becomes 1,000 to 10,000. It is one of the aspects.
• the FTU change rate is 80% or more of the period until the FTU becomes 1,000 to 10,000, and the FTU change rate is in the specific range described later. from the viewpoint of stably producing reduced coenzyme Q10 crystals.
• the FTU change rate is maintained at more than 0 FTU / min and 45 FTU / min or less for 80% or more of the time from 1,000 to 10,000 formazin turbidity (FTU). More preferably, the FTU change rate is maintained at more than 0 FTU/min and no more than 30 FTU/min.
• the FTU change rate is set to the entire period from 1,000 to 10,000 (100% of the time), the above-mentioned specific range, for example, the FTU change rate is 45 FTU / min or less, preferably Maintaining at more than 0 FTU/min and 45 FTU/min or less, more preferably 5 FTU/min or more and 45 FTU/min or less is a preferred embodiment from the viewpoint of stably producing Form II-type reduced coenzyme Q10 crystals with excellent oxidation stability. one of.
• the temperature of the mixed solution is preferably 30° C. or higher and 43° C. or lower, and preferably 30.5° C. or higher and 42° C. or lower during the period until the formazin turbidity (FTU) becomes 1,000 to 10,000. It is more preferably 31° C. or higher and 41° C. or lower, particularly preferably. Within the above range, it is easy to maintain the FTU change rate within the above range, which is preferable.
• the temperature of the mixture is preferably 29° C. or higher and 38° C. or lower, more preferably 30° C. or higher and 37° C. or lower, and 31° C. or higher and 36° C. or lower. Especially preferred.
• the temperature of the mixed solution can be adjusted as appropriate according to the formazin turbidity and FTU change rate at that time.
• the temperature of the mixed liquid may be constant, but may be lowered stepwise or continuously.
• the temperature of the mixture may be maintained at a constant temperature for a certain period of time and then lowered stepwise or continuously.
• the temperature of the mixture at the time of adding the seed crystals is 34° C. or more and 38° C. or less
• the temperature of the mixture at the time when the FTU is 10,000 is 30° C. or more and 37° C. or less.
• the temperature at which the FTU is 10,000 is preferably 0.4° C. or more and 8° C.
• the term "maintained at a constant temperature” means preferably to maintain a predetermined temperature (set temperature) ⁇ 3°C, more preferably to maintain a predetermined temperature (set temperature) ⁇ 1°C.
• the cooling rate when lowering the temperature of the mixture is preferably 0.05°C/hr or more and 20°C/hr or less, more preferably 0.1°C/hr or more and 15°C/hr or less. It is also a preferred embodiment to change the cooling rate over time.
• the temperature is maintained for a certain period of time, for example, 0.5 to 8 hours, and the cooling rate is set to 0.05° C./hr or more and less than 0.5° C./hr for 3 to 20 hours thereafter, After that, the cooling rate is set to 0.5° C./hr or more and 15° C./hr or less, and after adding the seed crystal, the cooling rate is set to 0.05° C./hr or more and less than 0.5° C./hr for 3 to 20 hours. After that, the cooling rate is set to 0.5° C./hr or more and 15° C./hr or less.
• the temperature of the mixed solution it is preferable to lower the temperature of the mixed solution and precipitate crystals even after the formazin turbidity reaches 10,000.
• the cooling rate at that time can be set, for example, based on the range described above.
• the temperature of the mixed solution reaches 23 to 34°C, most of the reduced coenzyme Q10 contained in the mixed solution has already precipitated, so after the temperature reaches 23 to 34°C, For example, it is possible to increase the cooling rate from 1° C./hr to 20° C./hr.
• the temperature at the time of finishing the crystal precipitation step is preferably 25°C or less, more preferably 20°C or less, more preferably 10°C or less, more preferably 7°C or less, more preferably 5°C or less. is.
• the lower limit of the end point temperature is the solidification temperature of the mixed liquid system, and is preferably 0° C. or higher.
• Precipitation of crystals is preferably carried out while forcibly flowing the liquid mixture.
• the power required for stirring 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, more preferably 0.006 kW/m 3 or more, to the mixture.
• the above-mentioned forced flow is usually provided by rotating a stirring blade, but if the above-mentioned flow is obtained, it is not always necessary to use a stirring blade, and for example, a method of circulating the mixed liquid may be used.
• the Form II-type reduced coenzyme Q10 crystals obtained by the above method are recovered through a solid-liquid separation and drying process by conventionally known methods such as those described in Patent Documents 2 and 3, for example.
• pressure filtration, centrifugal filtration, or the like can be used for solid-liquid separation.
• the dried crystals and crystalline solids can be recovered by pulverizing and classifying (sieving) as necessary.
• the Form II reduced coenzyme Q10 crystals after the solid-liquid separation are dried under heating to obtain Form II reduced coenzyme Q10 crystals. It is also possible to improve the content ratio.
• the drying temperature is preferably 46° C. or higher, more preferably 47° C. or higher, and even more preferably 49° C. or higher.
• the upper limit is usually 52°C or lower, preferably 51°C or lower. If the temperature is less than 46° C., drying progresses, but the content of Form II-type reduced coenzyme Q10 crystals hardly increases. If the temperature exceeds 52°C, the reduced coenzyme Q10 crystals may melt during drying.
• the above conditions are not limited.
• the drying may be carried out at °C or higher.
• the heating time for drying is also not particularly limited, but is preferably 4 hours or longer, preferably 10 hours or longer, and more preferably 20 hours or longer.
• the upper limit of the heating time is not particularly limited, but is usually 72 hours or less, preferably 48 hours or less, more preferably 36 hours or less.
• each step in the method of the present embodiment specifically, the seed crystal addition step and the crystal precipitation step described above, the recovery step such as solid-liquid separation and drying, and other subsequent treatment steps, etc.
• a deoxygenated atmosphere can be achieved by replacing the atmosphere with an inert gas, reducing pressure, boiling, or a combination thereof. It is preferable to at least replace the atmosphere with an inert gas, ie use an inert gas atmosphere.
• the inert gas include nitrogen gas, helium gas, argon gas, hydrogen gas, carbon dioxide gas, etc. Nitrogen gas is preferred.
• Form II reduced coenzyme Q10 crystals are contained in the obtained reduced coenzyme Q10 crystals or crystalline solid thereof and the content ratio thereof are measured by, for example, a differential scanning calorimeter (DSC). It is possible to discriminate by DSC.
• Form II reduced coenzyme Q10 crystals show an endothermic peak at around 52 ⁇ 2° C. when measured by DSC at a heating rate of 1° C./min, indicating that Form I reduced coenzyme Q10 The crystal shows an endothermic peak around 48 ⁇ 1° C. under the same conditions.
• Form II reduced coenzyme Q10 crystals are mixed with conventional Form I reduced coenzyme Q10 crystals or a crystalline solid thereof, the presence or absence of the peak near 52 ⁇ 2 ° C. and the endotherm thereof.
• the presence or absence of Form II reduced coenzyme Q10 crystals and their content can be determined from the height of the peak and the ratio of the endothermic amounts.
• Form II reduced coenzyme Q10 crystals or a crystalline solid thereof can be efficiently obtained.
• FormII-type reduced coenzyme Q10 crystals can be obtained through the crystal precipitation step. can be obtained. Therefore, this embodiment encompasses cases where crystals are obtained and where crystalline solids are obtained.
• the obtained Form II reduced coenzyme Q10 crystals or the crystalline solid thereof are excellent in oxidation stability.
• Form II crystals in reduced coenzyme Q10 crystals The ratio of Form II crystals in the reduced coenzyme Q10 crystals obtained in Examples and Comparative Examples was determined by analyzing the crystals by DSC measurement under the following conditions, and measuring the endothermic peak height (Y difference ) (hereinafter referred to as Form I Y difference) and the height of the endothermic peak (Y difference) of Form II type crystal (hereinafter referred to as Form II Y difference).
• Form II ratio (%) Y difference of Form II / (Y difference of Form I + Y difference of Form II) x 100
• DSC measurement conditions Apparatus: DSC6220 (manufactured by SII Nano Technology)
• Sample container Aluminum pan & cover (SSC000C008) Heating rate: 1°C/min Sample amount: 5 ⁇ 2 mg
• the reduced coenzyme Q10 crystals obtained in Examples and Comparative Examples were stored in an open system in a constant temperature bath set at 40°C RH (relative humidity) 75% and 25°C RH 60% for 1 or 2 months, and then subjected to high-speed storage.
• the content ratio of reduced coenzyme Q10 (QH) and oxidized coenzyme Q10 is calculated using liquid chromatography.
• the content ratio of reduced coenzyme Q10 in the initial reduced coenzyme Q10 crystals before storage in a constant temperature bath that is, using the crystals obtained in Examples and Comparative Examples, measured immediately after obtaining the crystals.
• the oxidation stability of the reduced coenzyme Q10 crystal was calculated as a relative QH ratio by the following formula.
• Relative QH ratio (%) reduced coenzyme Q10 ratio after storage/initial reduced coenzyme Q10 ratio ⁇ 100
• FTU change rate in Examples and Comparative Examples was obtained by measuring the formazin turbidity (FTU) of a mixture of ethanol and reduced coenzyme Q10 with a turbidimeter, and the FTU change rate at time (T) was calculated using the following formula: Calculated by Further, the turbidity meter used in this embodiment was calibrated with a turbidity (FTU) of 9,999 FTU when crystals of reduced coenzyme Q10 were present in the mixed solution at a concentration of 40000 mg/L.
• FTU formazin turbidity
• FTU change rate T (FTU/min) (measured turbidity value T (FTU) - measured turbidity value T-20 (FTU))/20 (min)
• the FTU change rate T means the FTU change rate at time (T)
• the turbidity measurement value T (FTU) means the FTU measurement value at time (T)
• the turbidity measurement value T- 20 (FTU) means the FTU measurement 20 minutes before time T.
• Turbidity meter Backscattered light turbidity sensor (InPro8200, Mettler Toledo Corporation) Measurement range: 0 to 10,000 FTU
• the FTU measurement was performed immediately after the addition of the seed crystal until the FTU reached the upper measurement limit of 10,000, and the FTU change rate was calculated during the period when the FTU was between 1,000 and 10,000.
• the FTU change rate at a certain point T is obtained by calculating the amount of increase in the FTU at the point T from the FTU at the point 20 minutes before (T-20min) and dividing it by 20 minutes. rice field.
• Example 1 After replacing a separable flask with a volume of 3 L with nitrogen, add 144 g of reduced coenzyme Q10 and 1296 g of ethanol with a purity of 99.5% by weight or more (reduced coenzyme Q10 concentration: 10% by weight), and stir with a stirring blade (stirring required The mixture was heated to 50° C. with a power of 0.03 kw/m 3 ) to obtain a uniform reduced coenzyme Q10 solution (QH solution) (1440 g, 1800 ml).
• QH solution uniform reduced coenzyme Q10 solution
• the QH solution at 50°C was cooled to 35.5°C while stirring with a stirring blade (required power for stirring: 0.03 kw/m 3 ).
• To the QH solution (FTU124) cooled to 35.5° C. 2.9 g (2.0 wt %) of Form II reduced coenzyme Q10 crystals were added as seed crystals, and precipitation of reduced coenzyme Q10 crystals (crystallization ) was started.
• the QH solution to which the seed crystals are added is hereinafter referred to as "crystallization mixture”.
• the temperature was maintained at 35.5°C for 1 hour, and then cooled from 35.5°C to 33.5°C at 0.15°C/hr (primary cooling). Thereafter, cooling was performed at 1°C/hr to 25°C, and cooling was performed at 10°C/hr from 25°C to 1°C.
• the formazin turbidity (FTU) of the crystallization mixture was measured with a turbidimeter, and during the entire period from 1,000 to 10,000, The maximum FTU change rate is 22.2 FTU/min, the minimum is 3.1 FTU/min, and the FTU change rate is 5 for 70% or more of the time from 1,000 to 10,000. It was confirmed that it was maintained at ⁇ 22.2 FTU/min.
• the Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%, and Form I reduced coenzyme Q10 crystals were not included.
• the relative QH ratio of the obtained Form II reduced coenzyme Q10 crystal at 25°C RH60% for 1 month was 94.5%, and the relative QH ratio at 25°C RH60% for 2 months was 91.5%.
• 40° C. RH 75% for 1 month the relative QH ratio was 88.0%.
• Example 2 A QH solution was prepared in the same manner as in Example 1, and a QH solution cooled to 35.5°C was obtained. The same method as in Example 1 except that the holding time of the crystallization mixed solution after addition of seed crystals at 35.5°C was changed to 5 hours, and primary cooling was performed to 32.5°C at 0.3°C/hr. to obtain FormII type reduced coenzyme Q10 crystals.
• the formazin turbidity (FTU) of the crystallization mixture was measured with a turbidimeter, and during the entire period from 1,000 to 10,000, The maximum FTU change rate is 19.3 FTU/min, the minimum is 2.8 FTU/min, and the FTU change rate is 5 for 70% or more of the time from 1,000 to 10,000. It was confirmed that it was maintained at ⁇ 19.3 FTU/min.
• the Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%, and Form I reduced coenzyme Q10 crystals were not included.
• the relative QH ratio of the obtained FormII type reduced coenzyme Q10 crystal at 25°C RH60% for 1 month was 95.4%, and the relative QH ratio at 25°C RH60% for 2 months was 92.3%.
• 40° C. RH 75% for 1 month the relative QH ratio was 90.4%.
• Example 3 A QH solution was prepared in the same manner as in Example 1 to obtain a QH solution (FTU68) cooled to 36.0°C.
• Form II type was formed in the same manner as in Example 1 except that the seed crystal addition temperature was changed to 36.0 ° C., the temperature was not maintained after addition, and the primary cooling was performed at 0.15 ° C./hr to 33.5 ° C. Crystals of reduced coenzyme Q10 were obtained.
• the formazin turbidity (FTU) of the crystallization mixture was measured with a turbidimeter, and during the entire period from 1,000 to 10,000, It was confirmed that the maximum FTU change rate was 21.2 FTU/min and the minimum was 5.3 FTU/min.
• the Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%, and Form I reduced coenzyme Q10 crystals were not included.
• the relative QH ratio of the obtained FormII type reduced coenzyme Q10 crystal at 25°C RH60% for 1 month was 95.0%, and the relative QH ratio at 25°C RH60% for 2 months was 92.1%. , 40° C. RH 75% for 1 month, the relative QH ratio was 91.0%.
• Example 4 A QH solution was prepared in the same manner as in Example 1 to obtain a QH solution (FTU118) cooled to 36.0°C.
• Form II reduced coenzyme Q10 crystals were obtained in the same manner as in Example 1, except that the seed crystal addition temperature was changed to 36.0°C and the primary cooling was performed at 0.3°C/hr to 32.0°C. rice field.
• the formazin turbidity (FTU) of the crystallization mixture was measured with a turbidimeter, and during the entire period from 1,000 to 10,000, The maximum FTU change rate is 20.3 FTU/min, the minimum is 0.6 FTU/min, and the FTU change rate is 5 for 70% or more of the period from 1,000 to 10,000. .3 to 20.3 FTU/min was maintained.
• the Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%, and Form I reduced coenzyme Q10 crystals were not included.
• the relative QH ratio of the obtained Form II reduced coenzyme Q10 crystal at 25°C RH60% for 1 month was 93.6%, and the relative QH ratio at 25°C RH60% for 2 months was 90.9%.
• 40° C. RH 75% for 1 month the relative QH ratio was 90.6%.
• Example 5 A QH solution was prepared in the same manner as in Example 1 to obtain a QH solution (FTU74) cooled to 35.0°C.
• Form II type was formed in the same manner as in Example 1 except that the seed crystal addition temperature was changed to 35.0 ° C., the temperature was not maintained after addition, and the primary cooling was performed at 0.3 ° C./hr to 30.5 ° C. Crystals of reduced coenzyme Q10 were obtained.
• the formazin turbidity (FTU) of the crystallization mixture was measured with a turbidimeter, and during the entire period from 1,000 to 10,000, The maximum FTU change rate is 31.5 FTU/min, the minimum is 2.2 FTU/min, and the FTU change rate is 5 for 70% or more of the time from 1,000 to 10,000. .3 to 31.5 FTU/min, FTU change rate of 2.2 to 28.7 FTU/min for more than 80% of the time from 1,000 to 10,000 FTU was confirmed to be maintained.
• the Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%, and Form I reduced coenzyme Q10 crystals were not included.
• the relative QH ratio of the obtained Form II reduced coenzyme Q10 crystal at 25°C RH60% for 1 month was 93.4%, and the relative QH ratio at 25°C RH60% for 2 months was 90.2%.
• 40° C. RH 75% for 1 month the relative QH ratio was 86.2%.
• Example 6 A QH solution was prepared in the same manner as in Example 1 and cooled to 36.0°C. Form II reduced coenzyme Q10 crystals were added as seed crystals to the QH solution (FTU187) cooled to 36.0°C (2.0 wt% when the reduced coenzyme Q10 in the QH solution was 100 wt%). Then, precipitation (crystallization) of reduced coenzyme Q10 crystals was started.
• the target is to maintain the FTU change rate at 20.8 FTU / min during the period from 1,000 to 10,000 in the formazin turbidity (FTU) of the crystallization mixed solution after the addition of seed crystals. controlled. After the formazin turbidity of the crystallization 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.
• FTU formazin turbidity
• the maximum FTU change rate is 41.2 FTU / min and the minimum is 0.7 FTU / min in the entire period from the formazin turbidity (FTU) to 1,000 to 10,000, FTU is The FTU change rate is maintained at 7.2 to 33.4 FTU/min for 70% or more of the period from 1,000 to 10,000, FTU from 1,000 to 10,000 It was confirmed that the FTU change rate was maintained at 0.7 to 30 FTU/min for 80% or more of the period until the
• the Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%, and Form I reduced coenzyme Q10 crystals were not included.
• the relative QH ratio of the obtained Form II type reduced coenzyme Q10 crystal at 25°C RH60% for 1 month was 89.6%, and the relative QH ratio at 40°C RH75% for 1 month was 86.5%. rice field.
• Example 7 After purging a four-necked flask with a volume of 500 mL with nitrogen, add 28 g of reduced coenzyme Q10 and 250 g of ethanol with a purity of 99.5% by weight or more (reduced coenzyme Q10 concentration: 10 wt %), and stir with a stirring blade (stir A homogeneous QH solution (278 g, 347 ml) was obtained by heating to 50° C. with a power requirement of 0.007 kw/m 3 ).
• the QH solution at 50°C was cooled to 36.8°C while stirring with a stirring blade (required power for stirring: 0.007 kw/m 3 ).
• 0.6 g (2.0 wt%) of Form II reduced coenzyme Q10 crystals were added as seed crystals to initiate precipitation (crystallization) of reduced coenzyme Q10 crystals. did.
• the set temperature was set with the goal of maintaining the FTU change rate at around 6.9 FTU/min during the period from 1,000 to 10,000 in the formazin turbidity (FTU) of the crystallization mixed solution after seed crystal addition. controlled. After the formazin turbidity reached 10,000 FTU, it was cooled to 25°C at 1°C/hr and from 25°C to 1°C at 10°C/hr. The FTU change rate is maintained at 5 to 21 FTU / min in 70% or more of the period until the formazin turbidity (FTU) is 1,000 to 10,000, FTU is from 1,000 It was confirmed that the FTU change rate was maintained between 0.6 and 21 FTU/min for 80% or more of the time until reaching 10,000.
• the Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%, and Form I reduced coenzyme Q10 crystals were not included.
• the relative QH ratio of the obtained Form II reduced coenzyme Q10 crystal at 25°C RH60% for one month was 92.2%, and the relative QH ratio at 40°C RH75% for one month was 90.1%. rice field.
• Example 8 After purging a four-neck flask with a volume of 500 mL with nitrogen, add 33 g of reduced coenzyme Q10 and 295 g of ethanol of 99.5 wt% or more (reduced coenzyme Q10 concentration: 10 wt%), and stir with a stirring blade (stirring required It was heated to 50° C. with a power of 0.007 kw/m 3 ) to obtain a homogeneous QH solution (328 g, 410 ml).
• the QH solution at 50°C was cooled to 34.5°C while stirring with a stirring blade (required power for stirring: 0.007 kw/m 3 ).
• 0.66 g (2.0 wt%) of Form II reduced coenzyme Q10 crystals were added as seed crystals to initiate precipitation (crystallization) of reduced coenzyme Q10 crystals. did.
• the target is to maintain the FTU change rate at around 33.3 FTU/min during the period from 1,000 to 10,000 in the formazin turbidity (FTU) of the crystallization mixed solution after seed crystal addition. controlled. After the formazin turbidity reached 10,000 FTU, it was cooled to 25°C at 1°C/hr and from 25°C to 1°C at 10°C/hr.
• the maximum FTU change rate is 43.3 FTU / min and the minimum is 15.0 FTU / min in the entire period from the formazin turbidity (FTU) to 1,000 to 10,000, FTU is It was confirmed that the FTU change rate was maintained between 15.0 and 39.9 FTU/min for 70% or more of the period from 1,000 to 10,000.
• the Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was 100%, and Form I reduced coenzyme Q10 crystals were not included.
• the relative QH ratio of the obtained Form II reduced coenzyme Q10 crystal at 25°C RH 60% for 1 month was 89.4%, and the relative QH ratio at 40°C RH 75% for 1 month was 87.3%. rice field.
• the QH solution at 50°C was cooled to 36.8°C while stirring with a stirring blade (required power for stirring: 0.007 kw/m 3 ).
• 0.66 g (2.0 wt%) of Form II reduced coenzyme Q10 crystals were added as seed crystals to initiate precipitation (crystallization) of reduced coenzyme Q10 crystals. did.
• the target is to maintain the FTU change rate at around 55.6 FTU/min during the period from 1,000 to 10,000 in the formazin turbidity (FTU) of the crystallization mixture after adding the seed crystals. controlled. After the formazin turbidity reached 10,000 FTU, it was cooled to 25°C at 1°C/hr and from 25°C to 1°C at 10°C/hr.
• FTU formazin turbidity
• the maximum FTU change rate is 108.7 FTU / min and the minimum is 30.6 FTU / min in the entire period from the formazin turbidity (FTU) to 1,000 to 10,000, the formazin It was confirmed that the FTU change rate could not be maintained at 45 FTU/min or less for 70% or more of the time during which the turbidity (FTU) increased from 1,000 to 10,000.
• the Form II crystal ratio in the obtained reduced coenzyme Q10 crystals was less than 100%.
• the relative QH ratio of the obtained Form II reduced coenzyme Q10 crystal at 25°C RH60% for 1 month was 85.1%, and the relative QH ratio at 40°C RH75% for 1 month was 81.4%. rice field.
• Table 1 shows the results of Examples and Comparative Examples.
• the oxidation stability of the Form II reduced coenzyme Q10 crystals obtained in Examples was found to be extremely high compared to the results of Comparative Examples. From this fact, the period until the formazin turbidity (FTU) becomes 1,000 to 10,000 is It can be seen that Form II reduced coenzyme Q10 crystals with excellent oxidation stability can be obtained by maintaining the FTU change rate within a specific range for 70% or more of the time.
• the method of the example is a method for obtaining Form II reduced coenzyme Q10 crystals, which is a stable crystal form, or a crystalline solid thereof. It can be said that it is an efficient manufacturing method.
• a preferred range can be defined by arbitrarily combining the upper and lower limits of the numerical range
• a preferred range can be defined by arbitrarily combining the upper limits of the numerical range
• the lower limit of the numerical range Any combination of values can be used to define a preferred range.

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