WO2022202215A1 - ＦｏｒｍＩＩ型の還元型補酵素Ｑ１０結晶又はその結晶性固体の製造方法及び晶析装置 - Google Patents

ＦｏｒｍＩＩ型の還元型補酵素Ｑ１０結晶又はその結晶性固体の製造方法及び晶析装置 Download PDF

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WO2022202215A1
WO2022202215A1 PCT/JP2022/009362 JP2022009362W WO2022202215A1 WO 2022202215 A1 WO2022202215 A1 WO 2022202215A1 JP 2022009362 W JP2022009362 W JP 2022009362W WO 2022202215 A1 WO2022202215 A1 WO 2022202215A1
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Prior art keywords
turbidity
reduced coenzyme
crystals
ftu
temperature
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PCT/JP2022/009362
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English (en)
French (fr)
Japanese (ja)
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昴 谷崎
直生 大野
貴識 橋本
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Kaneka Corp
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Kaneka Corp
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Priority to US18/283,863 priority Critical patent/US20240166589A1/en
Priority to EP22775011.4A priority patent/EP4317125B1/en
Priority to JP2023508903A priority patent/JP7739411B2/ja
Priority to CN202280022270.5A priority patent/CN117062795A/zh
Publication of WO2022202215A1 publication Critical patent/WO2022202215A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0004—Crystallisation cooling by heat exchange
    • B01D9/0013—Crystallisation cooling by heat exchange by indirect heat exchange
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0036—Crystallisation on to a bed of product crystals; Seeding
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0063—Control or regulation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/02—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains containing only carbon and hydrogen atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D2009/0086—Processes or apparatus therefor
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present disclosure relates to a method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof and a crystallizer.
  • 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 present inventors have extensively studied a method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof, and controlled the precipitation of Form II reduced coenzyme Q10 crystals based only on temperature. In some cases, even when Form II reduced coenzyme Q10 crystals are repeatedly produced under the same temperature conditions, there is a lot difference in the oxidation stability of the resulting Form II reduced coenzyme Q10 crystals or the crystalline solid thereof. found to be large.
  • the present inventors investigated a method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof, and found that temperature was controlled based on the rate of change in turbidity. It was found that Form II reduced coenzyme Q10 crystals or crystalline solids thereof can be stably produced. Therefore, the present disclosure provides a method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof, which enables stable production of Form II reduced coenzyme Q10 crystals or a crystalline solid thereof. for the purpose. It is another object of the present invention to provide a crystallizer that can be used in carrying out a method for producing Form II type reduced coenzyme Q10 crystals or a crystalline solid thereof.
  • Form II reduced coenzyme Q10 crystals in a mixed solution containing alcohol and reduced coenzyme Q10 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-type reduced coenzyme Q10 crystals with high oxidation stability or crystalline solids thereof can be stably produced by controlling the temperature based on the rate of change in turbidity. Found it.
  • Example aspects of this embodiment are described as follows. (1) Using a crystallizer provided with a crystallization unit, a turbidity detection unit capable of detecting turbidity in the crystallization unit, and a temperature control unit capable of adjusting the temperature in the crystallization unit, housing a liquid mixture containing alcohol and reduced coenzyme Q10 in a crystallization unit; adding Form II reduced coenzyme Q10 crystals as seed crystals to the mixed solution; Precipitating Form II reduced coenzyme Q10 crystals in the mixed solution after adding the seed crystals; The precipitation includes controlling the temperature by the temperature control unit based on the turbidity change rate obtained from the turbidity detection unit, A method for producing Form II type reduced coenzyme Q10 crystals or a crystalline solid thereof.
  • the control is a control that changes at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid based on the predetermined range of the turbidity change rate and the measured value of the turbidity change rate.
  • the predetermined range is a range determined based on the formazin turbidity (FTU) rate of change
  • the production method according to (4), wherein the monohydric alcohol having 1 to 5 carbon atoms is ethanol.
  • a crystallization unit capable of accommodating a mixed solution containing alcohol and reduced coenzyme Q10; a turbidity detection unit that detects a turbidity change rate of the mixed liquid contained in the crystallization unit; a temperature control unit capable of controlling the temperature in the crystallization unit; and a control unit controlling the adjustment of the temperature by the temperature control unit based on the turbidity change rate of the mixed liquid obtained from the turbidity detection unit.
  • a crystallizer for Form II reduced coenzyme Q10 crystals capable of accommodating a mixed solution containing alcohol and reduced coenzyme Q10; a turbidity detection unit that detects a turbidity change rate of the mixed liquid contained in the crystallization unit; a temperature control unit capable of controlling the temperature in the crystallization unit; and a control unit controlling the adjustment of the temperature by the temperature control unit based on the turbidity change rate of the mixed liquid obtained from the turbidity detection unit.
  • the control is a control that changes at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid based on the predetermined range of the turbidity change rate and the measured value of the turbidity change rate.
  • Crystallizer as described. the predetermined range is a range determined based on the formazin turbidity (FTU) rate of change,
  • FTU formazin turbidity
  • the crystallizer according to (8), wherein the predetermined range is set within a range of 2 to 45 FTU/min for a period from 1,000 to 10,000 FTU.
  • Form II reduced coenzyme Q10 crystals or a crystalline solid thereof of the present disclosure Form II reduced coenzyme Q10 crystals or a crystalline solid thereof can be produced stably.
  • the crystallizer of the present disclosure can be used when carrying out the production method.
  • FIG. 1 is a schematic diagram of one aspect of the crystallizer of the present embodiment.
  • 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.
  • the method for producing a Form II reduced coenzyme Q10 crystal or a crystalline solid thereof includes a crystallization unit, a turbidity detection unit capable of detecting turbidity in the crystallization unit, and a temperature in the crystallization unit.
  • a mixture containing alcohol and reduced coenzyme Q10 is placed in the crystallization unit using a crystallizer equipped with a temperature control unit capable of adjusting the adding coenzyme Q10 crystals as seed crystals, and precipitating Form II-type reduced coenzyme Q10 crystals in the mixed solution after adding the seed crystals, wherein the precipitation is detected by the turbidity detection unit.
  • a method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof comprising controlling the temperature with a temperature controller based on the obtained turbidity change rate.
  • 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”.
  • a crystallization unit In the method for producing Form II reduced coenzyme Q10 crystals according to the present embodiment, a crystallization unit, a turbidity detection unit capable of detecting turbidity in the crystallization unit, and a temperature capable of adjusting the temperature in the crystallization unit A crystallizer equipped with a control section is used.
  • a schematic diagram of one embodiment of a crystallizer is shown in FIG. In the crystallizer shown in FIG. 1, a state in which a liquid mixture 3 containing alcohol and reduced coenzyme Q10 is accommodated inside a crystallization unit 1 is illustrated.
  • the crystallization unit 1 is provided with a turbidity detection unit 5 (for example, a turbidity meter) and preferably with a temperature detection unit 7 (for example, a thermometer).
  • a temperature detection unit 7 for example, a thermometer
  • the temperature of the crystallization unit 1 can be adjusted by a temperature control unit composed of a constant temperature water bath 9 and a heat medium 11 (for example, water).
  • the turbidity detector 5 has a turbidity sensor 5a and a converter 5b that converts the signal detected by the turbidity sensor 5a into turbidity such as an FTU value.
  • the crystallizer shown in FIG. 1 preferably has stirring blades 15 for stirring the inside of the crystallization unit 1 .
  • the crystallizer shown in FIG. 1 is one aspect of the crystallizer for Form II reduced coenzyme Q10 crystals according to the present embodiment, which will be described later.
  • the control unit 13 is a control mechanism that controls temperature adjustment by the temperature control unit, and may be a central control mechanism that controls other conditions (for example, stirring conditions).
  • the control unit 13 can be configured by, for example, a software program for realizing various processes, a CPU that executes the software program, various hardware controlled by the CPU, and the like.
  • the control unit 13 is a computer including a CPU, an input/output circuit, and the like.
  • Programs, data, and control parameters required for the operation of the control unit 13 can be stored in a storage unit (not shown) in this embodiment.
  • the storage destinations of these programs and data are not particularly limited. These programs, data, and the like may be stored in a separately provided storage device such as a disk or flash memory. Alternatively, the information may be stored in an external server, storage unit, or the like that is communicatively connected.
  • the mixed liquid containing alcohol and reduced coenzyme Q10 accommodated in the crystallization unit is not particularly limited as long as it contains alcohol and reduced coenzyme Q10, and reduced coenzyme Q10 is dissolved in alcohol. It may be a homogeneous solution, or it may be a slurry in which reduced coenzyme Q10 is partly dissolved in alcohol but partly not dissolved but suspended. Enzyme Q10 is a homogeneous solution dissolved in alcohol.
  • 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 alcohol purity is most preferably 99.5% by weight or higher.
  • 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 controlling the temperature with the temperature control unit based on the turbidity change rate obtained from the turbidity detection unit.
  • an increase in turbidity means precipitation of crystals
  • the turbidity change rate (the amount of change in turbidity per unit time) is an index of the crystal precipitation rate.
  • Examples of the control include control to change at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid based on the predetermined range of the turbidity change rate and the measured value of the turbidity change rate.
  • the measured turbidity change rate when the measured turbidity change rate is greater than a predetermined range, it can be determined that the crystal precipitation rate is high, and the temperature of the liquid mixture can be increased or the cooling rate can be decreased. As another example, when the measured turbidity change rate is smaller than a predetermined range, it is determined that the crystal precipitation rate is slow, and the temperature of the mixed liquid is lowered or the cooling rate is increased. can be done.
  • the control is preferably performed based on the predetermined range of the turbidity change rate and the measured value of the turbidity change rate, but when the measured value deviates from the predetermined range, the temperature of the mixed liquid and the It is not necessary to perform control to change at least one of the cooling rates, and if it is expected that the measured value of the turbidity change rate will quickly return to within a predetermined range, the temperature of the mixed liquid and the cooling of the mixed liquid You don't have to change the speed. For example, when the temperature of the mixed liquid is maintained constant, as the crystal precipitation progresses, the crystal precipitation rate slows down and the turbidity change rate decreases.
  • control may be performed by changing at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid each time based on the turbidity change rate, and after setting the temperature program in advance, the turbidity change rate may be performed by changing at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid when an abnormality occurs.
  • the turbidity may be turbidity based on any index, such as kaolin turbidity and formazin turbidity (FTU), and from the viewpoint of versatility, formazin turbidity is preferred.
  • FTU formazin turbidity
  • the turbidity change rate can be calculated, for example, by dividing the difference between the turbidity at a certain point in time and the turbidity measured before that by the measurement interval.
  • the turbidity change rate at a certain time (T) can be calculated by the following formula.
  • Turbidity change rate T (turbidity / min) (measured turbidity value T - measured turbidity value TX) / X (min)
  • the turbidity change rate T means the turbidity change rate at the time (T)
  • the turbidity measurement value T means the turbidity measurement value at the time (T)
  • the turbidity measurement value T- X means the turbidity measurement X minutes before time T.
  • the FTU change rate at a certain time can be calculated by the following formula.
  • FTU change rate T (FTU/min) (measured turbidity value T (FTU) - measured turbidity value TX (FTU))/ X (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- X (FTU) means the measured value of FTU X minutes before time T.
  • the frequency of obtaining the turbidity change rate there is no particular limit to the frequency of obtaining the turbidity change rate, but if the turbidity change rate is measured too frequently, it may be affected by measurement errors and concentration differences in the mixed liquid, and the turbidity change rate may not be stable. If the turbidity change rate is obtained too infrequently, the crystal precipitation rate may not be sufficiently controlled. From this point of view, the turbidity change rate is preferably determined, for example, every 3 to 180 minutes, more preferably every 5 to 30 minutes, and even more preferably every 10 to 30 minutes. Note that the measurement interval may or may not be constant, and is not particularly limited.
  • the predetermined range is FTU from 1,000 to 10 ,000, it is one of the preferable modes to be set within the range of 2 to 45 FTU/min.
  • the predetermined range is more preferably set within the range of 2 to 43 FTU/min for the period from FTU to 1,000 to 10,000, more preferably set within the range of 2 to 35 FTU/min. More preferred.
  • Turbidity, such as FTU increases as crystal precipitation progresses. Especially immediately after adding seed crystals, FTU tends to increase rapidly and measurement errors tend to increase. Maintaining the rate of change is not always practical.
  • the predetermined range is set in the period from 1,000 to 10,000 FTU. By setting such a predetermined range, it is possible to carry out the method for producing Form II reduced coenzyme Q10 crystals or a crystalline solid thereof with good reproducibility.
  • the mixed solution at the time of adding the seed crystals is preferably a uniform solution in which reduced coenzyme Q10 is dissolved in alcohol.
  • the FTU of the mixture at the time of seed crystal addition is usually 0 to 250, preferably 0 to 230, more preferably 0 to 200. is. This range is preferable because Form II reduced coenzyme Q10 crystals preferentially precipitate.
  • the temperature of the mixed liquid is preferably 30 ° C. or higher and 43 ° C. or lower during the period from 1,000 to 10,000 FTU, and 30.5 ° C. It is more preferably 42° C. or higher, and particularly preferably 31° C. or higher and 41° C. or lower. Within the above range, it is easy to maintain the FTU change rate within the above range, which is preferable.
  • the temperature of the mixed liquid is preferably 29° C. or higher and 38° C. or lower, and preferably 30° C. or higher and 37° C. or lower at the time when the FTU is 10,000. It is more preferably 31° C. or higher and 36° C. or lower, particularly preferably.
  • the temperature of the mixture may be constant in the crystal precipitation process, but may be lowered stepwise or continuously. Also, 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, and 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. or less lower than the temperature at the time of adding the seed crystal.
  • 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 turbidity to be measured is FTU
  • 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 step of accommodating the mixed liquid described above in the crystallization unit, the seed crystal addition step, the crystal precipitation step, and recovery such as solid-liquid separation and drying
  • 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 crystallizer for Form II reduced coenzyme Q10 crystals includes a crystallization unit capable of accommodating a mixture containing alcohol and reduced coenzyme Q10, and the crystallization unit accommodated in the crystallization unit. Based on the turbidity change rate of the mixture obtained from the turbidity detection unit that detects the turbidity change rate of the mixture, the temperature control unit that can adjust the temperature in the crystallization unit, and the turbidity detection unit, A crystallizer for Form II reduced coenzyme Q10 crystals, comprising a controller for controlling temperature adjustment by the temperature controller.
  • the crystallization apparatus is an apparatus capable of carrying out the method for producing Form II type reduced coenzyme Q10 crystals or a crystalline solid thereof described above.
  • the crystallizer shown in FIG. 1 can be mentioned.
  • a turbidity sensor 5a is installed in the crystallization unit 1, and more specifically, the turbidity sensor 5a is installed inside the crystallization unit 1 in FIG.
  • a light-transmitting material such as glass may be used for all or part of the crystallization section, and the turbidity sensor 5a may be installed outside the crystallization section.
  • the temperature control section is arranged outside the crystallization section 1 as the constant temperature water bath 9 and the heat medium 11, but in another embodiment, it may be arranged inside the crystallization section 1. .
  • the temperature control section may be provided by installing a heater or the like inside the crystallization section 1 .
  • the control performed by the control unit is preferably a control that changes at least one of the temperature of the mixed liquid and the cooling rate of the mixed liquid based on the predetermined range of the turbidity change rate and the measured value of the turbidity change rate. .
  • the control unit for example, by executing a program stored in the storage unit, by comparing the measured value of the turbidity change rate and the predetermined range of the turbidity change rate stored in the storage unit, the mixed liquid It is preferable to use software to determine whether it is necessary to change at least one of the temperature and the cooling rate of the liquid mixture, and to control the temperature by acting on the temperature control unit according to the determination result.
  • the predetermined range of the turbidity change rate is a range determined based on the formazin turbidity (FTU) change rate, and the range is from 1,000 FTU
  • One of the preferred modes is to set the FTU/min within the range of 2 to 45 FTU/min until reaching 10,000.
  • the predetermined range is more preferably set within the range of 2 to 43 FTU/min for the period from FTU to 1,000 to 10,000, more preferably set within the range of 2 to 35 FTU/min. , more preferred.
  • 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 FTU change rate in the examples was obtained by measuring the formazin turbidity (FTU) of a mixed solution of ethanol and reduced coenzyme Q10 with a turbidimeter, and the FTU change rate at time (T) was calculated by the following formula. . 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 TX (FTU))/ X (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- X (FTU) means the measured value of FTU X 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.
  • the FTU change rate at a certain point T is obtained by calculating the increase in the FTU at the point T from the FTU at the point X minutes before (T-Xmin) and dividing it by X minutes. rice field.
  • the FTU rate of change was calculated from the measured FTU, the previously measured FTU, and the measurement interval.
  • the reduced coenzyme Q10 crystals obtained in Examples were stored in an open system for one month in a constant temperature bath set at 40°C RH (relative humidity) 75% and 25°C RH 60%, and then subjected to high performance liquid chromatography. The content ratio of reduced coenzyme Q10 (QH) and oxidized coenzyme Q10 is calculated.
  • the content ratio of reduced coenzyme Q10 in the initial reduced coenzyme Q10 crystals before storage in a constant temperature bath that is, the reduced coenzyme Q10 measured immediately after obtaining the crystals using the crystals obtained in the example.
  • 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
  • Example 1 After replacing a separable flask with a volume of 3 L with nitrogen, add 160 g of reduced coenzyme Q10 and 1440 g of ethanol with a purity of 99.5 wt% or more (reduced coenzyme Q10 concentration: 10 wt%), 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) (1600 g, 2800 ml).
  • QH solution uniform reduced coenzyme Q10 solution
  • the QH solution at 50°C was cooled to 36.0°C while being stirred with a stirring blade (power required for stirring: 0.03 kw/m 3 ).
  • a stirring blade power required for stirring: 0.03 kw/m 3 .
  • To the QH solution (FTU18) cooled to 36.0 ° C. 3.2 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 formazin turbidity (FTU) in the mixture was periodically measured until the formazin turbidity (FTU) in the mixture reached 10,000, and the FTU was between 1,000 and 10,000.
  • the cooling rate and cooling temperature were controlled so that the FTU change rate was around 20.8 FTU/min until the temperature reached 20.8 FTU/min.
  • the formazin turbidity in the mixture reached 10,000 FTU, it was cooled to 25°C at 1°C/hr, and then cooled from 25°C to 1°C at 10°C/hr.
  • 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 crystals at 25°C RH 60% for 1 month was 91.8%, and the relative QH ratio at 40°C RH 75% for 1 month was 88.1%. rice field.
  • Table 1 shows the elapsed time, turbidity, set temperature, and FTU change rate when the FTU in Example 1 reached around 1,000 (942) as 0 min.
  • Example 2 After purging a four-necked flask with a volume of 500 mL with nitrogen, 32.8 g of reduced coenzyme Q10 and 295.2 g of ethanol with a purity of 99.5% by weight or more are added (reduced coenzyme Q10 concentration: 10% by weight) and stirred. The mixture was heated to 50° C. while stirring with a blade (required stirring power: 0.007 kw/m 3 ) to obtain 328 g (410 mL) of a uniform reduced coenzyme Q10 solution (QH solution).
  • QH solution uniform reduced coenzyme Q10 solution
  • the QH solution at 50°C was cooled to 34.0°C while stirring with a stirring blade (required power for stirring: 0.007 kw/m 3 ).
  • 0.65 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 formazin turbidity (FTU) in the mixture was periodically measured until the formazin turbidity (FTU) in the mixture reached 10,000, and the FTU was between 1,000 and 10,000.
  • the cooling rate and cooling temperature were controlled so that the FTU rate of change was around 55.6 FTU/min until the temperature reached 55.6 FTU/min.
  • the mixed solution is heated and the temperature is maintained for a certain period of time to increase the crystallization speed (crystal precipitation speed). It was adjusted.
  • the formazin turbidity in the mixture reached 10,000 FTU, it was cooled to 25°C at 1°C/hr, and then cooled from 25°C to 1°C at 10°C/hr.
  • the obtained Form II reduced coenzyme Q10 crystals had a relative QH ratio of 85.1% at 25°C RH 60% for 1 month, and a relative QH ratio of 81.4% at 40°C RH 75% for 1 month.
  • Table 2 shows the elapsed time, turbidity, set temperature, and FTU rate of change when the FTU in Example 2 reached around 1,000 (870) as 0 min.
  • Example 3 After replacing a separable flask with a volume of 500 mL with nitrogen, 32.8 g of reduced coenzyme Q10 and 295.2 g of ethanol with a purity of 99.5% by weight or more were added (reduced coenzyme Q10 concentration: 10 wt%), and a stirring blade was added. The mixture was heated to 50° C. with stirring (required power for stirring: 0.007 kw/m 3 ) to obtain 328 g (410 mL) of a uniform reduced coenzyme Q10 solution (QH solution).
  • 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 ).
  • 0.65 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 formazin turbidity (FTU) in the mixture was periodically measured until the formazin turbidity (FTU) in the mixture reached 10,000, and the FTU was between 1,000 and 10,000.
  • the cooling rate and cooling temperature were controlled so that the FTU change rate was around 33.3 FTU/min until the temperature reached 33.3 FTU/min.
  • the mixed solution is heated and the temperature is maintained for a certain period of time to increase the crystallization speed (crystal precipitation speed). It was adjusted.
  • the formazin turbidity in the mixture reached 10,000 FTU, it was cooled to 25°C at 1°C/hr, and then cooled from 25°C to 1°C at 10°C/hr.
  • the obtained Form II reduced coenzyme Q10 crystals had a relative QH ratio of 89.4% at 25°C RH 60% for 1 month, and a relative QH ratio of 87.3% at 40°C RH 75% for 1 month.
  • Table 3 shows the elapsed time, turbidity, set temperature, and FTU rate of change when the FTU in Example 3 reached around 1,000 (877) as 0 min.
  • Example 4 After replacing a separable flask with a volume of 500 mL with nitrogen, 27.8 g of reduced coenzyme Q10 and 250.2 g of ethanol with a purity of 99.5% by weight or more were added (reduced coenzyme Q10 concentration: 10% by weight), and a stirring blade was added. The mixture was heated to 50° C. with stirring (required power for stirring: 0.007 kw/m 3 ) to give 278 g (347 mL) of a uniform reduced coenzyme Q10 solution (QH solution).
  • 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 ).
  • the formazin turbidity (FTU) in the mixture was periodically measured until the formazin turbidity (FTU) in the mixture reached 10,000, and the FTU was between 1,000 and 10,000.
  • the cooling rate and cooling temperature were controlled so that the FTU rate of change was around 6.9 FTU/min until the temperature reached 6.9 FTU/min.
  • the mixed solution is heated and the temperature is maintained for a certain period of time to increase the crystallization speed (crystal precipitation speed). It was adjusted.
  • the formazin turbidity in the mixture reached 10,000 FTU, it was cooled to 25°C at 1°C/hr, and then cooled from 25°C to 1°C at 10°C/hr.
  • the Form II crystal ratio in the obtained reduced coenzyme Q10 crystal was 100%.
  • 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.
  • Tables 4 and 5 show the elapsed time, turbidity, set temperature, and FTU change rate when the FTU in Example 4 reached around 1,000 (933) as 0 min.
  • Table 6 shows the ratio of Form II type crystals (Form II ratio) and the relative QH ratio of the reduced coenzyme Q10 crystals obtained in Examples.
  • Form II reduced coenzyme Q10 crystals obtained in Examples are excellent in oxidation stability. It can be seen that Form II reduced coenzyme Q10 crystals or crystalline solids thereof can be stably produced.
  • 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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CN202280022270.5A CN117062795A (zh) 2021-03-26 2022-03-04 FormII型的还原型辅酶Q10结晶或其结晶性固体的制造方法及晶析装置

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WO2021161807A1 (ja) * 2020-02-12 2021-08-19 株式会社カネカ ＦｏｒｍＩＩ型の還元型補酵素Ｑ１０結晶の製造方法

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EP4692037A1 (en) 2023-03-30 2026-02-11 Kaneka Corporation Crystal and preparation of reduced coenzyme q10

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