WO2022018161A1 - FORMES CRISTALLINES DE β-CRYPTOXANTHINE, FORMULATIONS LIQUIDES DE CELLES-CI ET PROCÉDÉS POUR LEUR FABRICATION - Google Patents

FORMES CRISTALLINES DE β-CRYPTOXANTHINE, FORMULATIONS LIQUIDES DE CELLES-CI ET PROCÉDÉS POUR LEUR FABRICATION Download PDF

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WO2022018161A1
WO2022018161A1 PCT/EP2021/070438 EP2021070438W WO2022018161A1 WO 2022018161 A1 WO2022018161 A1 WO 2022018161A1 EP 2021070438 W EP2021070438 W EP 2021070438W WO 2022018161 A1 WO2022018161 A1 WO 2022018161A1
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Prior art keywords
cryptoxanthin
crystal form
weight
range
temperature
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PCT/EP2021/070438
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English (en)
Inventor
Francesco ALOISE
Grace BAAKLINI
Fabiano Roberto PICCIOLO
Carlo Ronco
Christian Schaefer
Bernd Schlegel
Elodie VERDURAND
Christa Luise VOECKLER
Bettina Wuestenberg
Céline Sophie Charlotte FANTOU
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Dsm Ip Assets B.V.
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Publication of WO2022018161A1 publication Critical patent/WO2022018161A1/fr

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    • 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
    • C07C403/24—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 substituted by six-membered non-aromatic rings, e.g. beta-carotene
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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 invention relates to a new crystal form of b-cryptoxanthin, processes for its manufacture, liquid formulations comprising such crystal form and products thereof as well as processes for their manufacture.
  • b-Cryptoxanthin ⁇ -carotene-3-ol is a natural carotenoid pigment. It can be isolated from a variety of sources including the petals and flowers of plants in the genus Physalis (see WO 2014/115037, WO 2016/174600, and Xin Wen et al. , Journal of Agricultural and Food Chemistry 2017, 65, 6140-6151 ), be obtained by fermentation (see e.g. US 2009/0093015, WO 2008/045405), as well as be synthesized chemically (see e.g. D. E. Loeber et al., J. Chem. Soc. C 1971 , 404; F. Khachik et al., Synthesis 2011 , 3, 509-516).
  • b-cryptoxanthin In the human body, b-cryptoxanthin is converted to vitamin A (retinol) and is, therefore, considered a provitamin A. According to WO 2005/110122 it can be used to increase the protein formation in a human or an animal. Further health benefits of b-cryptoxanthin are e.g. disclosed in WO 2008/079287, WO 2004/037236, WO 2016/157157 and WO 2015/089385. b-Cryptoxanthin can be administered to humans or animals in the form of soft capsules.
  • soft capsules encompasses “soft-gel capsules”, as well as non-gelatine soft capsules and further soft capsules based on other materials of non-animal origin such as e.g. starch. They may be manufactured according to processes known to the person skilled in the art.
  • b-cryptoxanthin In order to produce soft capsules b-cryptoxanthin has to be provided in a semi-solid form, in a liquid form or in a suspension, whereby the suspension can be oily. b-Cryptoxanthin, however, is sparingly soluble in water and only partially soluble in many common edible oils. Thus, b-cryptoxanthin is advantageously dispersed in oil in order to be processable into soft capsules. The dispersion in oil has the further advantage that higher concentrations of b-cryptoxanthin - compared to dispersions in water - may be reached.
  • liquid formulations are manufactured without the use of an organic solvent, especially without the use of a halogenated hydrocarbon such as dichloromethane or chloroform.
  • a halogenated hydrocarbon such as dichloromethane or chloroform.
  • Crystal form IV of b-cryptoxanthin (“platelets”) is already known from the prior art.
  • Crystal form II of b-cryptoxanthin (“platelets”; see Figure 6) is also a new crystal form of b-cryptoxanthin.
  • crystal form I is easy to mill in oil, whereby a certain amount of another crystal form such as e.g. crystal form II and/or crystal form IV may be tolerated. This is surprising since the inventors expected crystal form II and crystal form IV to be milled more easily than crystal form I due to the higher surface of crystal form II and crystal form IV compared to crystal form I, whereas the opposite is the case.
  • the invention also relates to methods for preparing crystal form I. Interestingly, it was further found that the crystal form I can be prepared from crystal form II.
  • the invention is directed to liquid formulations, preferably to oily suspensions, comprising crystal form I of b-cryptoxanthin (“needles”), whereby a certain amount of another crystal form of b-cryptoxanthin such as e.g. crystal form II of b-cryptoxanthin (“platelets”) and/or crystal form IV of b-cryptoxanthin (“platelets”) may be tolerated.
  • seedles crystal form I of b-cryptoxanthin
  • another crystal form of b-cryptoxanthin such as e.g. crystal form II of b-cryptoxanthin (“platelets”) and/or crystal form IV of b-cryptoxanthin (“platelets”).
  • the invention is related to the use of such liquid formulations according to the invention in dietary supplements such as soft capsules.
  • the present invention relates to the new crystalline form I of b- cryptoxanthin, and any of its mixtures with crystal form II and crystal form IV.
  • Crystal form I of b-cryptoxanthin is anhydrous and ansolvated with needle-shaped crystals.
  • Crystal form II is an ethanol solvate (ethanolate) which means that the ethanol is incorporated in the crystal lattice with the b-cryptoxanthin resulting in platelets crystals.
  • Crystal form IV of b-cryptoxanthin is obtained amongst others by drying crystal form II of b-cryptoxanthin by higher temperatures and are also platelets.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • X-ray diffractometry is capable to reflect the differences in crystal structure.
  • X-ray diffraction on a single crystal yields a three-dimensional diffraction pattern of, normally, well-resolved peaks, which after phasing can be back-transformed into electron density.
  • powder diffraction experiment the sample consists of a huge number of crystallites with typical dimensions of 5x5x5 pm3. The powder is normally obtained by grinding or milling.
  • X-Ray Powder Diffraction (XRPD) patterns are obtained by collecting intensity data measured by a Rigaku Mim ' Flex 600 diffractometer.
  • the X-Ray analysis was performed with a step width 0.02 degree.
  • Thermal analysis methods are defined as those techniques in which a property of the analyte is determined as a function of an externally applied temperature.
  • DSC is an easy method to use routinely on a quantitative basis, and for this reason it has become a widely accepted method for identification and characterization.
  • a DSC1 from Mettler Toledo equipped with a sensor type FRS 5+ is used to investigate the thermodynamic relationship between different polymorphs.
  • b-Crypto- xanthin (normally 3 - 6 mg) was heated up at 10 K/min rate, from 25 °C to 220 °C in Al-pans while being purged with nitrogen.
  • Crystal form I of b-cryptoxanthin is characterized by the following parameters: l-a) an X-Ray Powder Diffraction pattern comprising at least 3 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 3.209(7), 13.402(3), 16.056(5), preferably comprising at least 4 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 3.209(7), 13.402(3), 16.056(5), 18.174(10); more preferably comprising at least 5 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 3.209(7), 13.402(3), 16.056(5), 18.174(10), 25.192(4); most preferably comprising at least 6 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 3.209(7), 13.402(3), 16.056(5), 18.174(10), 19.270(16), 25.192(4).
  • the X-Ray Powder Diffraction pattern of crystal form I of b-cryptoxanthin shows also peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg):
  • the crystal form I of b-cryptoxanthin shows also l-b) a Differential Scanning Calorimeter scan showing a phase transition at a temperature in the range of 60 to 120°C, preferably at a temperature in the range of from 80 to 100°C, more preferably at a temperature in the range of from 80 to 90 °C, most preferably at a temperature of 85 °C ⁇ 1 °C.
  • the crystal form I of b-cryptoxanthin shows also
  • I-c a Differential Scanning Calorimeter scan showing melting at a temperature in the range of from 140°C to 200°C, preferably at a temperature in the range of from 150°C to 190°C.
  • an XRPD (X-Ray Powder Diffraction) pattern comprising 3 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 13.646(3), 16.599(3), 21.203(5); preferably comprising 5 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 13.646(3), 14.923(2), 16.599(3), 21.203(5), 24.331 (12); more preferably comprising 7 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 13.266(2), 13.646(3), 14.923(2), 16.599(3), 18.892(7), 21.203(5), 24.331 (12); most preferably comprising 9 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 13.266(2), 13.646(3), 14.562(4), 14.923(2), 15.846(3), 16.599(3), 18.892(7), 21.203(5), 24.331 (12).
  • the X-Ray Powder Diffraction pattern of crystal form II of b-cryptoxanthin shows also peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg):
  • the crystal form II of b-cryptoxanthin shows also ll-b) a Differential Scanning Calorimeter scan showing a de-solvation peak at a temperature in the range of 100 to 160°C, preferably at a temperature in the range of from 110° C to 150°C.
  • the crystal form II of b-cryptoxanthin shows also II-c) a Differential Scanning Calorimeter scan showing a melting peak at a temperature in the range of from 150°C to 195°C, preferably at a temperature in the range of from 155°C to 190°C.
  • Figure 1 shows the results, i.e. an X-Ray diffractogram of crystal form I and II of b- cryptoxanthin.
  • the x-axis shows the 2-theta positions, the y-axis shows the counts.
  • the DSC analysis of crystal form I of b-cryptoxanthin shows a reversible endothermic peak in the range between 80° C and 100°C, followed by an intense endothermic peak between 150°C and 190°C corresponding to the melting peak.
  • the DSC analysis of crystal form II of b-cryptoxanthin shows a endothermic peak in the range between 110°C and 150°C corresponding to a de solvation peak, followed by an intense endothermic peak between 155°C and 190°C corresponding to the melting peak.
  • the X-Ray Powder Diffraction pattern of crystal form IV of b-cryptoxanthin shows also peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg):
  • Crystal form IV of b-cryptoxanthin are platelets.
  • Figure 4 shows the X-Ray diffractogram of crystal form IV of b-cryptoxanthin.
  • the x-axis shows the 2-theta positions, the y-axis shows the counts.
  • Crystal form I is the thermodynamically most stable form among them.
  • Crystal forms II and IV of b- cryptoxanthin transform into crystal form I of b-cryptoxanthin in an edible oil such as corn oil, as well as in acetone.
  • Crystal form VIII of b-cryptoxanthin is an ethanol solvate that crystallizes in a polymorphic form which is different from crystal form II of b-cryptoxanthin. This can be concluded by comparing the XRPD patterns of crystal forms II and VIII of b-cryptoxanthin: The comparison reveals that the XRPD patterns are not similar.
  • crystal form VI of b-cryptoxanthin is obtained by dissolving the crude b-cryptoxanthin in methylene chloride, precipitating it with hexane and filtering it.
  • the inventors have found that crystal form VI may also be obtained by digestion in ethyl acetate or diethyl ether.
  • Figure 10 shows the X-Ray diffractogram of crystal form VIII of b-cryptoxanthin.
  • the x-axis shows the 2-theta positions
  • the y-axis shows the counts.
  • Crystal form VIII of b-cryptoxanthin shows an X-Ray Powder Diffraction pattern comprising at least 3 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 14.7695(13), 15.670(2), 16.2040(19), 18.252(4), 20.577(13), 22.513(7), 23.024(7), preferably comprising at least 5 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 14.7695(13), 15.670(2), 16.2040(19), 18.252(4), 20.577(13), 22.513(7), 23.024(7); more preferably comprising 7 peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg): 14.7695(13), 15.670(2), 16.2040(19), 18.252(4), 20.577(13), 22.513(7), 23.024(7).
  • the X-Ray Powder Diffraction pattern of crystal form VIII of b-cryptoxanthin shows also peaks at the following 2-theta positions (deg) ( ⁇ 0.2 deg):
  • the present invention is also directed to a process for the manufacture of crude b- cryptoxanthin (see Figure 7: compound of formula (1)) comprising the following steps:
  • Step II) is preferably performed by filtration.
  • the halogen X in the compound of formula (2) is Br or Cl, preferably it is Cl.
  • X also HSCV may be used.
  • the substituent R is an aryl or a C1-4 alkyl substituted aryl or alkyl, preferably an aryl, more preferably phenyl.
  • the preferred compound of formula (2) is (/?)-((2E,4E)-5- (4-hydroxy-2,6,6-trimethylcyclohex-1 -en-1 -yl)-3-methylpenta-2,4-dien-1 - yl)triphenylphosphonium halide/hydrogensulfate, especially the corresponding chloride.
  • the amount of sodium methoxide is in the range of from 1.00 to 1.50 equivalents, preferably in the range of from 1.00 to 1.20 equivalents, more preferably in the range of from 1.05 to 1.15 equivalents, based on the amount of 4- (5-(halotriaryl-5-phosphanyl)-3-methylpenta-1,3-dien-1 -yl)-3,5,5-trimethylcyclo- hex-3-en-1-ol, preferably based on the amount of (/?)-((2E,4E)-5-(4-hydroxy-2,6,6- trimethylcyclohex-1 -en-1 -yl)-3-methylpenta-2,4-dien-1 -yl)triphenylphosphonium halide/hydrogensulfate, especially the corresponding chloride.
  • reaction I) is performed in ethanol.
  • an especially preferred process for the manufacture of crude b-cryptoxanthin comprises the following steps:
  • Step II) is preferably performed by filtration.
  • such crude b-cryptoxanthin is subsequently treated as follows: b) suspending the crude b-cryptoxanthin in an organic solvent and optionally heating the suspension; c) optionally cooling the suspension to a temperature of at most 30 °C, preferably of at most 25 °C, more preferably of at most 20° C; d) optionally adding water to the cooled suspension; e) separating the crystal form I of b-cryptoxanthin; f) drying of the crystalline b-cryptoxanthin, preferably at a temperature in the range of from 40 to 60° C.
  • organic solvents that are suitable for carrying out step b) are acetone, a mixture of acetone and tetrahydrofuran with a volume ratio of 9:1, dimethyl carbonate, tert-butyl methyl ether and methyl ethyl ketone.
  • the crude b- cryptoxanthin is suspended in it and the suspension heated to a temperature of at least 20° C, preferably to a temperature of at least 30° C, more preferably to a temperature of at least 40° C, even more preferably to a temperature of at least 45 °C, further preferably to a temperature of at least 50° C, most preferably at reflux. Afterwards the suspension is cooled to a temperature of at most 30° C, preferably of at most 25 °C, more preferably of at most 20° C (step c).
  • the b-cryptoxanthin suspension is heated to reflux, whereby the transformation of b-cryptoxanthin platelets to b-cryptoxanthin needles took place during the heating up.
  • these organic solvents heating to a temperature of at least 10 K below the boiling temperature of the organic solvent may be necessary.
  • the suspension is cooled to a temperature of at most 30° C, preferably of at most 25 °C, more preferably of at most 20 °C (step c).
  • the present invention is directed to a process of obtaining crystal form I comprising the following steps: a) providing crude b-cryptoxanthin; b) to f) as described above.
  • a process of obtaining crystal form II comprises the following steps:
  • the crude b-cryptoxanthin as obtained in the process as disclosed above is dried at a temperature in the range of from 90 to 125°C, preferably at a temperature in the range of from 90 to 120°C, more preferably at a temperature in the range of from 90 to 110°C, even more preferably at a temperature in the range of from 95 to 105°C, most preferably at a temperature around 100°C, the crystal form IV of b-cryptoxanthin is obtained.
  • Crystal form IV of b-cryptoxanthin may also be obtained by digestion of crude b- cryptoxanthin in methanol or in a mixture of methanol and toluene with a volume ratio of 4:1 or in a mixture of methanol and tetrahydrofuran with a volume ratio of 4:1 or in a mixture of methanol and 1 -propanol with a volume ratio of 1 : 1 or in a mixture of methanol and methyl ethyl ketone with a volume ratio of 1 : 1 or in a mixture of ethanol and water with a volume ratio of 1:1, followed by separation, preferably by filtration, and drying.
  • a process of obtaining crystal form IV comprises the following steps:
  • Step e) and Step D), respectively, may be performed by filtration.
  • An alternative process of obtaining crystal form IV of b-cryptoxanthin comprises the following steps:
  • the organic solvent is selected from methanol, a mixture of methanol and toluene with a volume ratio of 4:1 , a mixture of methanol and tetrahydrofuran with a volume ratio of 4:1, a mixture of methanol and 1- propanol with a volume ratio of 1 :1, a mixture of methanol and methyl ethyl ketone with a volume ratio of 1 : 1 and a mixture of ethanol and water with a volume ratio of 1 : 1 ;
  • the invention also relates to a process for the transformation of crystal form II of b-cryptoxanthin into crystal form I of b-cryptoxanthin, which takes place in an organic solvent preferably selected from acetone, a mixture of acetone and tetrahydrofuran with a volume ratio of 9:1, dimethyl carbonate, tert- butyl methyl ether and methyl ethyl ketone, preferably by heating the suspension to reflux, and filtering after the transformation took place.
  • organic solvent preferably selected from acetone, a mixture of acetone and tetrahydrofuran with a volume ratio of 9:1, dimethyl carbonate, tert- butyl methyl ether and methyl ethyl ketone, preferably by heating the suspension to reflux, and filtering after the transformation took place.
  • organic solvent preferably selected from acetone, a mixture of acetone and tetrahydrofuran with a volume ratio of 9:1, dimethyl carbonate, tert-
  • a preferred embodiment of the invention is a process for the transformation of crystal form II of b-cryptoxanthin into crystal form I of b-cryptoxanthin, which takes place in acetone, preferably at a temperature in the range of from 20 to 60° C, more preferably at a temperature in the range of from 40 to 55 °C.
  • crystal form II of b-cryptoxanthin is suspended in acetone, optionally heated to a temperature in the range as disclose above, and filtered after the transformation took place.
  • Another embodiment of the invention is a liquid formulation comprising crystal form I of b-cryptoxanthin and optionally the crystal form II of b-cryptoxanthin, whereby preferably at most 20 weight-%, preferably at most 15 weight-%, more preferably at most 10 weight-%, of crystal form II of b-cryptoxanthin may be present, based on the total amount of crystal form I and II of b-cryptoxanthin in the liquid formulation, as well as the use thereof in the life science industry, especially as dietary supplement, more preferably in soft capsules.
  • crystal form IV of b-cryptoxanthin or any other crystal form of b- cryptoxanthin may also be present. If one or more other crystal form(s) of b- cryptoxanthin such as crystal form II of b-cryptoxanthin and/or crystal form IV of b- cryptoxanthin are present, the total amount of the other crystal form(s) of b- cryptoxanthin together is preferably at most 20 weight-%, preferably at most 15 weight-%, more preferably at most 10 weight-%, based on the total amount of all crystal form(s) of b-cryptoxanthin in the liquid formulation.
  • the crystal form I of b-cryptoxanthin and optionally the crystal form II of b-cryptoxanthin, whereby preferably at most 20 weight-%, preferably at most 15 weight-%, more preferably at most 10 weight-%, of crystal form II of b- cryptoxanthin, based on the total amount of crystal form I and II of b- cryptoxanthin, may be present, may be milled in an edible oil to obtain a liquid formulation.
  • crystal form IV of b-cryptoxanthin may also be used.
  • the total amount of crystal form II and crystal form IV of b-cryptoxanthin together is preferably at most 20 weight-%, preferably at most 15 weight-%, more preferably at most 10 weight-%, based on the total amount of crystal form I, II and IV of b-cryptoxanthin in the liquid formulation.
  • the thus obtained liquid formulation may be directly incorporated in soft capsules or after dilution with an edible oil to the desired concentration incorporated in soft capsules. Therefore, the present invention is also directed to soft capsules comprising the liquid formulations of the present invention.
  • the liquid formulation may further be incorporated in powdered products such as powdered infant formula. Therefore, the present invention is also directed to such powdered infant formula.
  • One formulation according to the present invention is a liquid formulation comprising i) crystal form I of b-cryptoxanthin, whereby optionally one or more other crystal form(s) of b-cryptoxanthin such as e.g crystal form II and/or crystal form IV of b-cryptoxanthin may be present; ii) at least an edible oil; and iii) optionally at least an antioxidant.
  • crystal form(s) of b-cryptoxanthin such as e.g. crystal form II and/or crystal form IV of b-cryptoxanthin is/are present
  • its/their total amount together is preferably at most 20 weight-%, more preferably at most 15 weight-%, most preferably at most 10 weight-%, based on the total amount of all crystal forms of b-cryptoxanthin.
  • b-Cryptoxanthin b-Cryptoxanthin (compound of formula I) can be obtained from a natural source, by fermentation or by chemical synthesis.
  • a natural source might be mandarins.
  • Chemical syntheses are e.g. described in D. E. Loeber et al. , J. Chem. Soc. C 1971, 404; F. Khachik et al., Synthesis 2011, 3, 509-516. The preferred chemical synthesis is disclosed above.
  • the lUPAC name of the isomer of b-cryptoxanthin occurring in nature is (1/?)-3,5,5- Trimethyl-4-[(3E,5E,7E,9E,11E,13E,15E)-3,7,12,16-tetramethyl-18-(2,6,6- trimethylcyclohex-1-en-1 -yl)octadeca-1,3,5,7,9,11,13,15,17-nonaen-1 -yl]cyclohex- 3-en-1 -ol.
  • Another name is (3/?) ⁇ -caroten-3-ol.
  • Another isomer occurring in nature is (3R,6’R)-6,£-carotene-3-ol.
  • b-Cryptoxanthin has two stereoisomers: the 3S-form and the 3/?-form depending on the steric configuration of the hydroxyl group at the 3-position of the ring structure present at one end of the molecule.
  • b-Cryptoxanthin also has cis and trans geometrical isomers with respect to the conjugated double bond system of the polyene chain at the center of the molecule. Examples include the 9-cis isomer, the 13-cis isomer, 15-cis isomer and the all-E isomer.
  • the term “b- cryptoxanthin” as used herein not only encompasses the (all-E)-isomer, but also any of its mono-, oligo- or poly-(Z)-isomers.
  • the liquid formulation according to the present invention comprises preferably 0.1 to 30.0 weight-%/0.5 to 30 weight-%, more preferably 0.8 to 20.0 weight-%, even more preferably 1 to 17.0 weight-%, most preferably 1.0 to 5.0 weight-% or 10.0 to 17.0 weight-%, of b-cryptoxanthin, based on the total weight of the liquid formulation.
  • Edible Oil preferably 0.1 to 30.0 weight-%/0.5 to 30 weight-%, more preferably 0.8 to 20.0 weight-%, even more preferably 1 to 17.0 weight-%, most preferably 1.0 to 5.0 weight-% or 10.0 to 17.0 weight-%, of b-cryptoxanthin, based on the total weight of the liquid formulation.
  • ible oil in the context of the present invention refers to any oil suitable for human or animal consumption and encompasses e.g. any triglyceride such as vegetable oils or fats like corn oil, sunflower oil, soybean oil, safflower oil, rapeseed oil, peanut oil, palm oil, palm kernel oil, cotton seed oil, olive oil or coconut oil or MCT (middle chain triglycerides) as well as any mixture thereof.
  • triglyceride such as vegetable oils or fats like corn oil, sunflower oil, soybean oil, safflower oil, rapeseed oil, peanut oil, palm oil, palm kernel oil, cotton seed oil, olive oil or coconut oil or MCT (middle chain triglycerides) as well as any mixture thereof.
  • oils can be from any origin. They can be natural, modified or synthetic. If the oils are natural they can be plant or animal oils.
  • the term “oil” in the context of the present invention thus also encompasses canola oil, sesame oil, hazelnut oil, almond oil, cashew oil, macadamia oil, mongongo nut oil, pracaxi oil, pecan oil, pine nut oil, pistachio oil, sacha Inchi (Plukenetia volubilis) oil or walnut oil.
  • oils may be present.
  • the oil is a plant oil or MCT or any mixture thereof. More preferably the oil is corn oil or safflower oil or any mixture thereof. Amount of edible oil
  • the liquid formulation according to the present invention comprises preferably 70 to 99.9/99.5 weight-%, more preferably 80 to 99.2 weight-%, even more preferably 83 to 99 weight-%, most preferably 95 to 99 weight-% or 83 to 90 weight-%, of edible oil, based on the total weight of the liquid formulation.
  • any food-grade antioxidant may be used. Such antioxidants are known to the person skilled in the art.
  • the antioxidant is a fat-soluble antioxidant.
  • Preferred fat-soluble antioxidants are selected from the group consisting of tocopherols, e.g. DL-a-tocopherol (i.e. synthetic tocopherol), D-a-tocopherol (i.e. natural tocopherol), b-, g- or d-tocopherol, or a mixture of two or more of these.
  • tocopherols e.g. DL-a-tocopherol (i.e. synthetic tocopherol), D-a-tocopherol (i.e. natural tocopherol), b-, g- or d-tocopherol, or a mixture of two or more of these.
  • the fat-soluble antioxidant is DL-a-tocopherol or a mixture of tocopherols (“mixed tocopherols”). Most preferably the fat-soluble antioxidant is a mixture of tocopherols.
  • Tocomix 70 IP comprises d-a- tocopherol, d- -tocopherol, d-y-tocopherol and d-6-tocopherol, whereby the total amount of tocopherols is at least 70.0 weight-% and the amount of non-a-toco- pherols is at least 56.0 weight-%.
  • the antioxidant since the presence of the antioxidant is optional, its amount in the liquid formulation of the present invention is in the range of from 0 to 10 weight-%, based on the total weight of the liquid formulation.
  • the total amount of the antioxidant(s) (especially DL-a-tocopherol or a mixture of tocopherols) in the liquid formulations according to the present invention is preferably in the range of from 0.1 to 10 weight-%, more preferably in the range of from 0.2 to 2 weight-%, most preferably in the range of from 0.5 to
  • any of the ingredients i) to iii) may comprise water in a small amount as residue, a small amount of water may also be present in the liquid formulation according to the present invention.
  • a small amount of water may also be present in the liquid formulation according to the present invention.
  • Preferably such amount of water is, however, ⁇ 5 weight-%, preferably ⁇ 3 weight-%, based on the total weight of the formulation.
  • a preferred embodiment of the present invention is a formulation consisting essentially of the components i) to iii), whereby the amount of component i) is selected in the range from 0.1 to 30 weight-%/0.5 to 30 weight-%, preferably in the range from 0.8 to 20 weight-%, more preferably in the range from 1 to 17.0 weight- %, most preferably in the range from 1 to 5 weight-% or 10.0 to 17.0 weight-%, and/or the amount component ii) is selected in the range from 70 to 99.9/70 to
  • 99.5 weight-% preferably in the range from 80 to 99.2 weight-%, more preferably in the range from 83 to 99 weight-%, most preferably in the range from 95 to 99 weight-% or from 83 to 90 weight-%, and/or the amount component iii) is selected in the range from 0 to 10 weight-%, preferably in the range from 0.2 to 2 weight-%, more preferably in the range from 0.5 to 1.5 weight-%, all amounts based on the total weight of the liquid formulation.
  • the term “consisting essentially of” in the context of the present invention means that the amount of the listed ingredients sum up to 100 weight-%. However, it cannot be excluded that small amounts of impurities may be present such as e.g. in amounts of less than 5 weight-%, preferably less than weight-%, which are e.g. introduced via the respective raw materials or processes used.
  • said liquid formulation is manufactured by comminuting, preferably by milling, a dispersion of crystal form I of b-cryptoxanthin in an oil, whereby optionally another crystal form of b-cryptoxanthin such as e.g. crystal form II of b- cryptoxanthin and/or crystal form IV of b-cryptoxanthin, and optionally at least an antioxidant may be present. If one or more other crystal form(s) such as e.g.
  • the present invention is also directed to a process for the manufacture of the liquid formulation according to the present invention comprising the following step: comminuting, preferably milling, the crystal form I of b-cryptoxanthin according to the present invention and optionally another crystal form of b- cryptoxanthin such as e.g.
  • Preferably milling is performed until the particle size D (v, 0.9) of b-cryptoxanthin crystals is ⁇ 30 pm, preferably ⁇ 20 pm, more preferably ⁇ 15 pm, measured dispersed in Volasil® 344 by laser diffraction, Mastersizer3000 ex Malvern, Fraunhofer light scattering.
  • Volasil® 344 is a clear colorless volatile blend of cyclic silicones.
  • the milling step is preferably carried out with a commercially available ball mill/stirred media mill.
  • the desired mean particle size of the b-cryptoxanthin particles is achieved by adjusting the following parameters with respect to each other: rotor speed (peripheral speed), mean residence time in the mill, material and size of the milling beads and load of the mill.
  • the milling step can either be performed in circulation or passage mode.
  • a rotor speed, especially a peripheral speed in the range of from 1 to 15 m/s, a short mean residence time in the mill (e.g. 1 to 10 min), and an average bead load of 65 to 90% may be applied.
  • a rotor speed especially a peripheral speed, in the range of from 1 to 15 m/s
  • a short mean residence time in the mill e.g. 1 to 10 min
  • an average bead load of 65 to 90% may be applied.
  • bead milling/grinding stirred media mills using e.g. ZrO beads with
  • the temperature during milling is ranging from 20 to 90° C, more preferably from 25 °C to 80° C, even more preferably from 30 to 70° C, most preferably from 40 to 70° C.
  • the preferred milling parameters may differ depending on the ball mill used in the milling step, but can easily be adjusted by the person skilled in the art, as long as the amount of other crystal forms of b-cryptoxanthin than crystal form I such as the b-cryptoxanthin platelets (crystal form II and/or crystal form IV) does preferably not exceed an amount of 20 weight-%, based on the total amount of the b-cryptoxanthin.
  • formulations according to the present invention are especially suitable for the manufacture of dietary supplements, especially in the form of soft capsules, with the preferences as given above.
  • a soft, soft gel or soft gelatin capsule is a solid capsule (outer shell) surrounding a liquid or semi-solid center (inner fill).
  • An active ingredient can be incorporated into the outer shell, the inner fill, or both.
  • They are oral dosage forms like capsules and tablets.
  • Common soft gel shells are a combination of gelatin, water, opacifier and a plasticizer such as e.g. glycerin and/or sorbitol(s). Processes for their manufacture are well-known to the person skilled in the art (see e.g. Cornelia M. Keck and Rainer H. MCiller: “Moderne Pharmazeutician Technologie” 2009, Chapter 1.8 “Weichkapseln”).
  • infant formula products Besides soft capsules, other dietary supplements also covered by the present invention are powdered products such as infant formula products, whereby the oily suspensions of the present invention may be incorporated by a wet mixing-spray drying process into baby milk powder.
  • This process is known to the person skilled in the art and for example described by Y. J. Jian and M. Guo in their article “Processing technology for infant formula”.
  • the infant formula products may be used as liquid such as ready-to-drink infant milks or as powder, i.e. dried e.g. spray-dried afterwards.
  • the liquid formulation of the present invention may also added to other ready-to-drink beverages than ready-to-drink infant milks.
  • Infant formula products usually contain methylfolate, prebiotics, probiotics, vitamin E, calcium, iron, copper, zinc and magnesium.
  • the present invention is also directed to an infant formula product comprising methylfolate, prebiotics, probiotics, vitamin E, calcium, iron, copper, zinc, magnesium and a liquid b-cryptoxanthin formulation according to the present invention.
  • the present is directed to a dietary supplement comprising the liquid formulation according to the present invention, preferably being in form of soft capsules, more preferably being in form of soft gelatin capsules, or in form of powdered products, preferably in form of powdered infant formula.
  • reaction mixture is cooled to room temperature and filtered.
  • the filter cake is rinsed subsequently with ethanol/water 9:1 and water and then dried in vacuum overnight (50°C/10 mbar). Afterwards the crude product is obtained as purple crystals in 93% yield.
  • the crude material is suspended in acetone (1000 ml) and heated to reflux. When the temperature reaches approximately 42 °C, a change of crystal form is observed. After 30 min at reflux, the reaction mixture is cooled to room temperature. Via addition funnel, water (200 ml) is added and stirring is continued for another 30 min. The red slurry is filtered, and the filter cake is rinsed with acetone/water 8:2. The crystals are dried in vacuum (60°C/10 mbar) for 13 hours. The product is obtained as red crystals (139.4 g, 97% yield).
  • the crude material is suspended in ethanol (2000 ml) and heated to reflux for 30 min. Then the oil-bath is removed, and the reaction mixture is cooled to room temperature.
  • the purple slurry is filtered, and the filter cake is rinsed with ethanol.
  • the crystals are dried in vacuum (100°C/10 mbar) for 13 hours.
  • the purified product is obtained as purple crystals (139.4 g, 98% yield).
  • Comparison Example 4 Synthesis of b-cryptoxanthin crystals with purification in the solvent system acetone/ethanol (volume ratio ⁇ 3:1)
  • the content of b-cryptoxanthin in the prepared liquid formulations has been determined by HPLC. Furthermore, the following particles sizes: D(v, 0.1), D(v, 0.5) and D(v, 0.9) have been measured dispersed in Volasil® 344 (clear colourless volatile blend of cyclic silicones) by laser diffraction, Mastersizer3000 ex Malvern, Fraunhofer light scattering. The per-se stability of the liquid formulations has also been investigated.
  • Example 5 Preparation of an oily suspension with b-cryptoxanthin needles (crystal form I) in safflower oil
  • 16 weight-% of b-cryptoxanthin needles (crystal form I) are suspended in 83 weight- % of safflower oil and 1 weight-% of DL-a-tocopherol, all amounts based on the total weight, with a rotor/stator device starting at 3500 rpm at room temperature and increasing to 6000 rpm and 55 °C within 7 min.
  • Low-viscous crude suspension (see Figure 8) is transferred to a laboratory stirred media mill. Milling is done in passage mode with grinding media size of 1 mm (6 passages), a bead filling ratio of 80% and a rotor speed of 11 m/s. The outlet temperature of the suspension during milling is adjusted to max. 55 °C by water cooling. Decrease of b-cryptoxanthin crystal particle size is measured by laser diffraction analysis after each milling passage. No transformation of the needle-shaped b-cryptoxanthin crystals into another crystal shape is observed under optical microscope with polarized light.
  • Example 6 Preparation of an oily suspension with b-cryptoxanthin needles (crystal form I) in corn oil
  • 11 weight-% of b-cryptoxanthin needles (crystal form I) are suspended in 89 weight- % of corn oil, both amounts based on the total weight, and stirred with a rotor/stator device starting at 4000 rpm at room temperature and increasing to 6000 rpm and 46°C within 6 min.
  • the low-viscous crude suspension is transferred to a laboratory stirred media mill. Milling is done in passage mode with grinding media size of 1 mm (6 passages), a bead filling ratio of 80% and a rotor speed of 11 m/s.
  • the outlet temperature of the suspension during milling is adjusted to max. 55°C by water cooling. Decrease of the b-cryptoxanthin crystal particle size is measured by laser diffraction analysis after each milling passage. No transformation of the needle-shaped b-cryptoxanthin crystals into another crystal shape is observed under optical microscope with polarized light.
  • the final suspension is split in two halves. One half is not further processed. To the second half DL-a-tocopherol is added and the suspension is mixed to end up with 1 weight-% DL-a-tocopherol.
  • Example 7 Preparation of an oily suspension with b-cryptoxanthin needles (crystal form I) in corn oil
  • 16 weight-% of b-cryptoxanthin needles (crystal form I) are suspended in 84 weight- % of corn oil, both amounts based on the total weight, with a laboratory dissolver at room temperature for 20 min, starting at 400 rpm and increasing to 1200 rpm. Afterwards a rotor/stator device is used at 4000 rpm starting at room temperature and increasing to 50° C within 4 min.
  • the low-viscous crude suspension is transferred to a laboratory stirred media mill. Milling is done in passage mode with grinding media size of 1 mm (6 passages), a bead filling ratio of 80% and a rotor speed of 11 m/s.
  • the outlet temperature of the suspension during milling is adjusted to max. 65 °C by water cooling. Decrease of the b-cryptoxanthin crystal particle size is measured by laser diffraction analysis after each milling passage. No transformation of the needle-shaped b-cryptoxanthin crystals into another crystal shape is observed under optical microscope with
  • 16 weight-% of b-cryptoxanthin platelets (crystal form IV) are suspended in 83 weight% safflower oil and 1 weight-% DL-a-tocopherol, all amounts based on the total weight, with a rotor/stator device starting at 3500 rpm at room temperature and increasing to 4500 rpm and 36°C within 3 min.
  • a rotor/stator device While suspending the b- cryptoxanthin platelets in oil, surprisingly the oily suspension turns into a very viscous paste. Due to very high viscosity of the crude suspension, milling of the crude suspension with a laboratory stirred media mill is not possible at this concentration. Suspension with that high viscosity cannot be transferred into the milling chamber. Thus, milling of b-cryptoxanthin platelets in oil is not possible.
  • Comparison example 7 is repeated with corn oil instead of safflower oil and crystal form II of b-cryptoxanthin instead of crystal form IV of b-cryptoxanthin.
  • the result is the same: Milling of b-cryptoxanthin platelets in oil is not possible.
  • Example 10 Preparation of an oily suspension with a mixture of b-cryptoxanthin needles (crystal form I) and b-cryptoxanthin platelets (crystal form II) in a weight ratio of 95:5
  • 11 weight-% of b-cryptoxanthin (whereof 95% are crystal form I and 5% are crystal form II) are suspended in 89 weight% of corn oil, both amounts based on the total weight, with a laboratory dissolver at room temperature at 1200 rpm for 20 min. Further suspending is carried out with a rotor/stator device starting at 5000 rpm at 27°C and increasing to 6000 rpm and 48°C within 5 min. The low-viscous crude suspension is transferred to a laboratory stirred media mill (Dispermat SL-12C1, VMA-Getzmann Gmbh).
  • Milling is done in passage mode with grinding media size of 0.65 mm (8 passages), a bead filling ratio of 80% and a rotor speed of 11 m/s. The temperature is adjusted during milling to max. 63 °C by water cooling. Decrease of b-cryptoxanthin crystal particle size is measured by laser diffraction analysis after each milling passage.
  • Example 11 Preparation of an oily suspension with a mixture of b-cryptoxanthin needles and b-cryptoxanthin platelets in a weight ratio of 95:5
  • 16 weight-% of b-cryptoxanthin (whereof 95% are crystal form I and 5% are crystal form II) are suspended in 84 weight-% of corn oil, both amounts based on the total weight, with a laboratory dissolver at room temperature at 500 rpm for 20 min. Further suspending is carried out with a rotor/stator device starting at 3000 rpm at room temperature and increasing to 7000 rpm and 53 °C within 4 min. Low-viscous crude suspension is transferred to a laboratory stirred media mill (Dispermat SL- 12C1 , VMA-Getzmann Gmbh).
  • Milling is done in passage mode with grinding media size of 1 mm (6 passages), a bead filling ratio of 80% and a rotor speed of 11 m/s. The temperature is adjusted during milling to max. 62°C by water cooling. Decrease of b-cryptoxanthin crystal particle size is measured by laser diffraction analysis after each milling passage.
  • Example 12 Preparation of an oily suspension with b-cryptoxanthin needles and mixed tocopherols as antioxidant
  • 16 weight-% of b-cryptoxanthin needles (crystal form I) are suspended in 83 weight- % of corn oil and 1 weight-% of mixed tocopherol, all amounts based on the total weight, with a laboratory dissolver at room temperature at 1000 rpm for 20 min. Further suspending is carried out with a rotor/stator device starting at 3000 rpm at room temperature and increasing to 7000 rpm and 53 °C within 4 min. Low-viscous crude suspension is transferred to a laboratory stirred media mill. Milling is done in passage mode with grinding media size of 1 mm (6 passages), a bead filling ratio of 80% and a rotor speed of 11 m/s.
  • the outlet temperature of the suspension during milling is adjusted to max. 58° C by water cooling.
  • Decrease of b-cryptoxanthin crystal particle size is measured by laser diffraction analysis after each milling passage. No transformation of the needle-shaped b-cryptoxanthin crystals into another crystal shape is observed under optical microscope with polarized light.
  • Table 1 (FS fluid suspension): The amounts of the ingredients of the compositions are given in weight-%, based on the total weight of the composition

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Abstract

L'invention concerne une nouvelle forme cristalline de β-cryptoxanthine, des procédés pour sa fabrication, des formulations liquides comprenant une telle forme cristalline et des procédés pour la fabrication d'une telle forme cristalline et de ses formulations de produit liquide. L'invention concerne également des compléments alimentaires, en particulier des capsules molles et des produits en poudre de type lait en poudre pour nourrissons comprenant lesdites formulations liquides de β-cryptoxanthine.
PCT/EP2021/070438 2020-07-22 2021-07-21 FORMES CRISTALLINES DE β-CRYPTOXANTHINE, FORMULATIONS LIQUIDES DE CELLES-CI ET PROCÉDÉS POUR LEUR FABRICATION WO2022018161A1 (fr)

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037236A1 (fr) 2002-10-25 2004-05-06 KEMIN FOODS, L. C. d/b/a KEMIN HEALTH, L. C. Promoteur d'osteogenese contenant $g(b)-cryptoxanthine en tant qu'ingredient actif
WO2005110122A1 (fr) 2004-05-18 2005-11-24 Dsm Ip Assets B.V. Utilisation de $g(b)-cryptoxanthine
WO2008045405A2 (fr) 2006-10-12 2008-04-17 Kemin Industries, Inc. Biosynthèse de bêta-cryptoxanthine
WO2008079287A1 (fr) 2006-12-20 2008-07-03 Kemin Foods, L.C. Procédé d'amélioration de la santé cardiovasculaire
US20090093015A1 (en) 2007-10-09 2009-04-09 Kemin Foods, L.C. Beta-cryptoxanthin production using a novel lycopene beta-monocyclase gene
US20090311761A1 (en) 2008-06-13 2009-12-17 Frederick Khachik Process for Synthesis of (3S)- and (3R)-3-Hydroxy-Beta-Ionone, and Their Transformation to Zeaxanthin and Beta-Cryptoxanthin
WO2014115037A2 (fr) 2013-01-24 2014-07-31 Omniactive Health Technologies Ltd. Bêta-cryptoxanthine provenant d'une source végétale et un procédé pour sa préparation
WO2014186683A1 (fr) 2013-05-16 2014-11-20 University Of Maryland, College Park Procédé pour une transformation en enceinte unique directe de lutéine en β-cryptoxanthine par son ester acétate
WO2015089385A1 (fr) 2013-12-12 2015-06-18 Kemin Industries, Inc. Produits de soins d'hygiène personnelle contenant des extraits de lanterne chinoise (physalis alkekengi)
WO2016157157A1 (fr) 2015-04-02 2016-10-06 Omniactive Health Technologies Limited Méthodes de prévention et de traitement du syndrome cardiométabolique et compositions utilisées pour ces dernières
WO2016174600A1 (fr) 2015-04-27 2016-11-03 Omniactive Health Technologies Limited Compositions à base de bêta-cryptoxanthine, ses procédés de préparation et ses utilisations

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037236A1 (fr) 2002-10-25 2004-05-06 KEMIN FOODS, L. C. d/b/a KEMIN HEALTH, L. C. Promoteur d'osteogenese contenant $g(b)-cryptoxanthine en tant qu'ingredient actif
WO2005110122A1 (fr) 2004-05-18 2005-11-24 Dsm Ip Assets B.V. Utilisation de $g(b)-cryptoxanthine
WO2008045405A2 (fr) 2006-10-12 2008-04-17 Kemin Industries, Inc. Biosynthèse de bêta-cryptoxanthine
WO2008079287A1 (fr) 2006-12-20 2008-07-03 Kemin Foods, L.C. Procédé d'amélioration de la santé cardiovasculaire
US20090093015A1 (en) 2007-10-09 2009-04-09 Kemin Foods, L.C. Beta-cryptoxanthin production using a novel lycopene beta-monocyclase gene
US20090311761A1 (en) 2008-06-13 2009-12-17 Frederick Khachik Process for Synthesis of (3S)- and (3R)-3-Hydroxy-Beta-Ionone, and Their Transformation to Zeaxanthin and Beta-Cryptoxanthin
WO2014115037A2 (fr) 2013-01-24 2014-07-31 Omniactive Health Technologies Ltd. Bêta-cryptoxanthine provenant d'une source végétale et un procédé pour sa préparation
WO2014186683A1 (fr) 2013-05-16 2014-11-20 University Of Maryland, College Park Procédé pour une transformation en enceinte unique directe de lutéine en β-cryptoxanthine par son ester acétate
WO2015089385A1 (fr) 2013-12-12 2015-06-18 Kemin Industries, Inc. Produits de soins d'hygiène personnelle contenant des extraits de lanterne chinoise (physalis alkekengi)
WO2016157157A1 (fr) 2015-04-02 2016-10-06 Omniactive Health Technologies Limited Méthodes de prévention et de traitement du syndrome cardiométabolique et compositions utilisées pour ces dernières
WO2016174600A1 (fr) 2015-04-27 2016-11-03 Omniactive Health Technologies Limited Compositions à base de bêta-cryptoxanthine, ses procédés de préparation et ses utilisations

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
D. E. LOEBER ET AL., J. CHEM. SOC. C, vol. 404, 1971
F. KHACHIK ET AL., SYNTHESIS, vol. 3, 2011, pages 509 - 516
R. KUHNC. GRUNDMANN, CHEMISCHE BERICHTE, 1933, pages 1746 - 1750
RICHARD KUHN ET AL: "Über Kryptoxanthin, ein Xanthophyll der Formel C40H56O (Über das Vitamin des Wachstums, V. Mitteil.)", CHEMISCHE BERICHTE, 1 January 1933 (1933-01-01), pages 1746 - 1750, XP055759209, DOI: 10.1002/cber.19330661126 *
XIN WEN ET AL., JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 65, 2017, pages 6140 - 6151
Y. J. JIANM. GUO, PROCESSING TECHNOLOGY FOR INFANT FORMULA

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