Search

US-12617744-B2 - Production method for reduced coenzyme Q10 form-II type crystal or crystalline solid thereof

US12617744B2US 12617744 B2US12617744 B2US 12617744B2US-12617744-B2

Abstract

It is an object of the present disclosure to provide a method for producing a reduced coenzyme Q10 Form II crystal or a crystalline solid thereof, which is excellent in the filterability of a slurry containing a reduced coenzyme Q10 Form II crystal. The present embodiment is a method for producing a reduced coenzyme Q10 Form II crystal or a crystalline solid thereof, including: adding a reduced coenzyme Q10 Form II crystal as a seed crystal to a mixed solution containing an alcohol and a reduced coenzyme Q10; and precipitating a reduced coenzyme Q10 Form II crystal in the mixed solution after adding the seed crystal, wherein a change rate of formazin turbidity (FTU) is maintained at 15 FTU/min or more for 80% or more of a period during which the formazin turbidity (FTU) shifts from 1,000 to 10,000 in the precipitation.

Inventors

  • Subaru TANIZAKI
  • Tadao Ono
  • Takanori Hashimoto

Assignees

  • KANEKA CORPORATION

Dates

Publication Date
20260505
Application Date
20220304
Priority Date
20210326

Claims (8)

  1. 1 . A method for producing a reduced coenzyme Q10 Form II crystal or a crystalline solid thereof, comprising: adding a reduced coenzyme Q10 Form II crystal as a seed crystal to a mixed solution containing an alcohol and a reduced coenzyme Q10; and precipitating a reduced coenzyme Q10 Form II crystal in the mixed solution after adding the seed crystal, wherein a change rate of formazin turbidity (FTU) is maintained at 15 FTU/min or more for 80% or more of a period during which the formazin turbidity (FTU) shifts from 1,000 to 10,000 in the precipitation.
  2. 2 . The method according to claim 1 , wherein the reduced coenzyme Q10 Form II crystal produced has a median diameter (D50) of 80 μm or more.
  3. 3 . The method according to claim 1 , wherein the change rate of formazin turbidity (FTU) is maintained at 110 FTU/min or less for 80% or more of a period during which the formazin turbidity (FTU) shifts from 1,000 to 10,000 in the precipitation.
  4. 4 . The method according to claim 1 , wherein the reduced coenzyme Q10 Form II crystal produced has a median diameter (D50) of 130 μm or less.
  5. 5 . The method according to claim 1 , wherein the alcohol is a monohydric alcohol having 1 to 5 carbon atoms.
  6. 6 . The method according to claim 5 , wherein the monohydric alcohol having 1 to 5 carbon atoms is ethanol.
  7. 7 . The method according to claim 1 , wherein the alcohol is an alcohol of 95% or more by weight based on a total amount of water and alcohol.
  8. 8 . The method according to claim 2 , wherein the reduced coenzyme Q10 Form II crystal produced has a median diameter (D50) of 130 μm or less.

Description

TECHNICAL FIELD The present disclosure relates to a method for producing a reduced coenzyme Q10 Form II crystal or a crystalline solid thereof. BACKGROUND ART Coenzyme Q is an essential component widely distributed in living organisms from bacteria to mammals, and is known as a member of mitochondrial electron transfer system in cells in the living organisms. Coenzyme Q engages in electron transfer in the electron transfer system by the repetition of oxidation and reduction in mitochondria. Further, reduced coenzyme Q is known to have antioxidant activity. The major component in humans is coenzyme Q10 which is one having 10 repeating structures in the side chain of coenzyme Q, and usually, about 40% to 90% thereof is present in the living body as the reduced form. The physiological activity of coenzyme Q includes activation of energy production by mitochondrial activation, activation of cardiac function, an effect of stabilizing cell membranes, and an effect of protecting cells by antioxidant activity. While coenzyme Q10 currently produced and sold is, in large part, oxidized coenzyme Q10, reduced coenzyme Q10 which exhibits higher oral absorbability than that of oxidized coenzyme Q10 has also been commercially available and has come to be used in recent years. A common method for obtaining reduced coenzyme Q10 has already been disclosed (Patent Literature 1). Furthermore, several methods for obtaining reduced coenzyme Q10 as a crystal have also been known. For example, a method of crystallizing reduced coenzyme Q10 in an alcohol solution and/or a ketone solution to produce a crystal (Patent Literature 2), a method of adding a high concentration liquid phase of reduced coenzyme Q10 into a poor solvent for crystallization (Patent Literature 3), and the like have been reported. On the other hand, Patent Literature 4 reports that crystal polymorphism is found in reduced coenzyme Q10. It has been reported that a newly appearing crystal form (wherein this crystal is hereinafter referred to as a “reduced coenzyme Q10 Form II crystal or Form II crystal”) is much more stable than the conventional reduced coenzyme Q10 (wherein this crystal is hereinafter referred to as a “reduced coenzyme Q10 Form I crystal or Form I crystal”) and also, is excellent in other physical properties. In addition, Patent Literature 5 reports a method for producing a reduced coenzyme Q10 Form II crystal. Patent Literature 5 discloses a method for producing a reduced coenzyme Q10 Form II crystal, which comprises: adding a reduced coenzyme Q10 Form II crystal as a seed crystal to a solution with a temperature of 32° C. to 43° C., containing at least one organic solvent selected from the group consisting of an alcohol, a hydrocarbon, an aliphatic acid ester and a nitrogen compound, and reduced coenzyme Q10, to prepare a mixed solution; and precipitating a reduced coenzyme Q10 Form II crystal in the mixed solution, in claim 1. CITATION LIST Patent Literature Patent Literature 1: JP Patent Publication No. H10-109933 APatent Literature 2: WO2003/006409Patent Literature 3: JP Patent Publication No. 2003-089669 APatent Literature 4: WO2012/176842Patent Literature 5: WO2020/045571 SUMMARY OF INVENTION Technical Problem Patent Literature 4 discloses a method for obtaining a reduced coenzyme Q10 Form II crystal, in which crystallization is carried out under specific conditions. However, there is a case where it takes a long period of time and the recovered amount is small. Thus, it cannot be necessarily said that this method is industrially optimal. The method disclosed in Patent Literature 5 is intended to provide an efficient production method for obtaining a reduced coenzyme Q10 Form II crystal, wherein the production method is also suitable for production in an industrial scale, which focuses mainly on temperatures. A reduced coenzyme Q10 Form II crystal is conventionally obtained by solid-liquid separation by means of filtration or the like after obtaining a slurry containing the reduced coenzyme Q10 Form II crystal, followed by appropriate drying or other steps. The present inventors thought that when filtering a slurry containing a reduced coenzyme Q10 Form II crystal, filter cleaning and filter replacement will be necessary with high frequency in the case of poor filterability of the slurry. The present inventors made studies on a method for producing a reduced coenzyme Q10 Form II crystal with a focus on factors other than temperatures and accordingly found that a slurry containing a reduced coenzyme Q10 Form II crystal obtained by a specific production method is excellent in filterability. Accordingly, it is an object of the present disclosure to provide a method for producing a reduced coenzyme Q10 Form II crystal or a crystalline solid thereof, which is excellent in the filterability of a slurry containing a reduced coenzyme Q10 Form II crystal. Solution to Problem When precipitating a reduced coenzyme Q10 Form II crystal in a mixed solut