WO2024017815A1 - Urolithin a - betain co-crystal (ii) - Google Patents
Urolithin a - betain co-crystal (ii) Download PDFInfo
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- WO2024017815A1 WO2024017815A1 PCT/EP2023/069752 EP2023069752W WO2024017815A1 WO 2024017815 A1 WO2024017815 A1 WO 2024017815A1 EP 2023069752 W EP2023069752 W EP 2023069752W WO 2024017815 A1 WO2024017815 A1 WO 2024017815A1
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- 239000013078 crystal Substances 0.000 title claims abstract description 80
- 229930186301 urolithin Natural products 0.000 title description 2
- RIUPLDUFZCXCHM-UHFFFAOYSA-N Urolithin A Chemical compound OC1=CC=C2C3=CC=C(O)C=C3OC(=O)C2=C1 RIUPLDUFZCXCHM-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 23
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- 238000001238 wet grinding Methods 0.000 claims description 11
- 229960003237 betaine Drugs 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- 235000013305 food Nutrition 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 235000015872 dietary supplement Nutrition 0.000 claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- 229940127557 pharmaceutical product Drugs 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- 150000004292 cyclic ethers Chemical class 0.000 claims description 6
- 238000000227 grinding Methods 0.000 claims description 6
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 229960004132 diethyl ether Drugs 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 3
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 3
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 3
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 238000002441 X-ray diffraction Methods 0.000 claims description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 12
- 238000009472 formulation Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 229920002079 Ellagic acid Polymers 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 235000004132 ellagic acid Nutrition 0.000 description 2
- 229920001968 ellagitannin Polymers 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 244000005709 gut microbiome Species 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- AFSDNFLWKVMVRB-UHFFFAOYSA-N Ellagic acid Chemical compound OC1=C(O)C(OC2=O)=C3C4=C2C=C(O)C(O)=C4OC(=O)C3=C1 AFSDNFLWKVMVRB-UHFFFAOYSA-N 0.000 description 1
- ATJXMQHAMYVHRX-CPCISQLKSA-N Ellagic acid Natural products OC1=C(O)[C@H]2OC(=O)c3cc(O)c(O)c4OC(=O)C(=C1)[C@H]2c34 ATJXMQHAMYVHRX-CPCISQLKSA-N 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 241000758791 Juglandaceae Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108020005196 Mitochondrial DNA Proteins 0.000 description 1
- 244000294611 Punica granatum Species 0.000 description 1
- 235000014360 Punica granatum Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000018927 edible plant Nutrition 0.000 description 1
- 229960002852 ellagic acid Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- FAARLWTXUUQFSN-UHFFFAOYSA-N methylellagic acid Natural products O1C(=O)C2=CC(O)=C(O)C3=C2C2=C1C(OC)=C(O)C=C2C(=O)O3 FAARLWTXUUQFSN-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000021125 mitochondrion degradation Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000004220 muscle function Effects 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000021013 raspberries Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000021012 strawberries Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
Definitions
- the present invention relates to a specific multicomponent crystalline system (cocrystal) comprising Urolithin A as one of the components produced by a specific process.
- Urolithin A is the compound of formula (I)
- Urolithin A is a metabolite compound resulting from the transformation of ellagitannins by the gut bacteria in the body.
- Urolithin A belongs to the class of organic compounds known as benzo-coumarins or dibenzo-a-pyrones. Its precursors - ellagic acids and ellagitannins - are ubiquitous in nature, including edible plants, such as pomegranates, strawberries, raspberries, and walnuts.
- Urolithin A was isolated and identified in the 1960s.
- Urolithin A is a natural food metabolite of the gut microbiome that has been shown to stimulate mitophagy and improve muscle function in aged animals and in models of muscular dystrophy, while also being safe, bioavailable, and able to induce mitochondrial gene expression in older adults.
- Urolithin A Due to the fact, that Urolithin A is not to be found in a natural source, the precursors are supplied and then transformed into Urolithin A in the gut system.
- Urolithin A is available commercially from a variety of suppliers. Urolithin A has poor water solubility (pg/mL) and low bioavailability. Therefore, a large loading (500 mg per serving) is usually used in the current formulation to achieve an acceptable result.
- co-crystal according to the present invention is obtained by using the wet grinding process (also known as liquid, or solvent assisted grinding).
- the wet grinding process comprises the steps: a) wet grinding of the compound of formula (I) and the compound of formula (II) in a small amount of at least one solvent, and b) isolating the obtained compound.
- the present invention relates to the co-crystal (CC) obtainable by a) wet grinding of the compound of formula (I) and the compound of formula (II) in a small amount of at least one solvent, and b) isolating the obtained compound.
- the second component of a co-crystal is also referred to as co-former.
- this co-formed is the compound of formula (II), which is known as betaine (or N,N,N-trimethylglycine).
- co-crystal or “co-crystal” refers herein a crystal formed by combining two or more organic molecules in the same crystal lattice through non-covalent bonds (hydrogen bond, TT-TT stacking, van der Waals force, etc.) in a fixed stoichiometric ratio. It is a way of aggregation of multi-component substances in a solid state.
- a first neutral component crystallizes with at least one second neutral component and interact via non-ionic interactions.
- Said at least one second component in the co-crystal is commonly referred to as a “coformer” or “co-crystal former” and is solid at room temperature and atmospheric pressure.
- This definition distinguishes co-crystals from crystalline solvates, in that in a solvate one of the components is a liquid at room temperature and atmospheric pressure.
- the co-crystal unlike salts, where the components in the crystal lattice are in an ionized state, the co-crystal’s components are in a neutral state and are linked by hydrogen bonding and other non-ionic interactions.
- the co-crystal according to the present invention comprises Urolithin A and betaine.
- the molar ratio of Urolithin A : betaine is 1 :1.
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC1 ), which is the co-crystal (CC), wherein molar ratio of Urolithin A : betaine is 1 : 1 .
- the grinding may be performed with a mechanical mill, for instance, in a ball mill.
- a suitable frequency range is 25-800 kHz, preferred 40-200 kHz.
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC2), which is the co-crystal (CC) or (CC1 ), wherein the grinding is performed in a mechanical mill.
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC2’), which is the co-crystal (CC2), wherein the grinding is performed in a ball mill.
- CC2 specific multicomponent crystalline system
- CC2 co-crystal
- the grinding is performed in a ball mill.
- the solvents which are used in the wet grinding process, are polar or non-polar solvents, which can be protic or non-protic. Suitable solvents are i.e. , alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, non-cyclic ethers, cyclic ethers, esters, ketones, sulfoxides and nitriles.
- Suitable solvents are i.e. water, acetonitrile, benzonitrile, dichloromethane, chloroform, dimethylsulfoxide, methanol, ethanol, isopropyl alcohol, iso pentanol, ethyl acetate, isopentyl acetate, isobutyl acetate, n-butyl acetate, acetone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, diethylether, methyl tert-butyl ether, toluene, cyclohexane, xylene and heptane; preferably water, ethyl acetate, acetonitrile, methanol and ethanol.
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC3), which is the co-crystal (CC), (CC1 ), (CC2) or (CC2’), wherein the at least one solvent is polar or non-polar solvents, which can be protic or non-protic.
- CC3 specific multicomponent crystalline system
- CC1 co-crystal
- CC2 CC2
- the at least one solvent is polar or non-polar solvents, which can be protic or non-protic.
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC3’), which is the co-crystal (CC), (CC1 ), (CC2) or (CC2’), wherein the at least one solvent is chosen from the group consisting of alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, non-cyclic ethers, cyclic ethers, esters, ketones, sulfoxides and nitriles.
- CC3 specific multicomponent crystalline system
- the at least one solvent is chosen from the group consisting of alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, non-cyclic ethers, cyclic ethers, esters, ketones, sulfoxides and nitriles.
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC3”), which is the co-crystal (CC), (CC1 ), (CC2) or (CC2’), wherein the at least one solvent is chosen from the group consisting of water, acetonitrile, benzonitrile, dichloromethane, chloroform, dimethylsulfoxide, methanol, ethanol, isopropyl alcohol, iso pentanol, ethyl acetate, isopentyl acetate, isobutyl acetate, n-butyl acetate, acetone, methyl isobutyl ketone, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentyl methyl ether, diethylether, methyl tert-butyl ether, toluene, cyclohexane, xylene and heptane.
- the at least one solvent
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC3’”), which is the co-crystal (CC), (CC1 ), (CC2) or (CC2’), wherein the at least one solvent is chosen from the group consisting of water, ethyl acetate, acetonitrile, methanol and ethanol.
- the solvent is present in an amount of 0-1 Opl per mg of compound of formula (I) and of the compound of formula (II).
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC4), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”) or (CC3’”), wherein the solvent is present in an amount of 0-1 Opd per mg of compound of formula (I) and of the compound of formula (II).
- the wet grinding process is carried out at a temperature of 15 to 30°C, more preferably at room temperature.
- room temperature or its abbreviation “rt” is considered for a temperature between 20 to 25 °C.
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC5), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”) or (CC4), wherein the process is carried out at a temperature of 15 to 30°C.
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC5’), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”) or (CC4), wherein the process is carried out at room temperature.
- the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC6), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”), (CC4), (CC5) or (CC5’), wherein wet grinding process is carried out at ambient pressure.
- the isolation of the co-crystal may include, for example, one or more of the following operations: such as filtration, filtration under vacuum, evaporation, crystallization by cooling, heating-melting, decantation, and centrifugation and other suitable techniques as known to a person skilled in the art.
- the obtained co-crystal of the invention may be further purified, e.g. by recrystallization.
- the co-crystal can contain traces of the solvent used in the production of the cocrystal. This is depending on the drying (kind of drying as well as length of drying).
- co-crystals of this invention are stable, wherein “stable” means that the cocrystals maintain their crystalline form over a long period of time at standard ambient conditions of temperature and pressure.
- the present invention also relates to the co-crystal of compound of formula (I) and of compound of formula (II), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”), (CC4), (CC5), (CC5’) or (CC6), characterised in that the X- ray diffraction pattern of the obtained co-crystal characteristic peaks exist at 20 angle: 7.52° ⁇ 0.2°, 10.46° ⁇ 0.2°, 16.72° ⁇ 0.2°, 17.22° ⁇ 0.2°, 19.32° ⁇ 0.2°, 21.44° ⁇ 0.2°, 22.08° ⁇ 0.2°, 22.80° ⁇ 0.2°, 27.02° ⁇ 0.2°, 27.48° ⁇ 0.2°, 32.16° ⁇ 0.2°.
- the present invention also relates to co-crystal of Urolithin A and betaine, characterized in that, the X-ray powder diffraction pattern of the co-crystal is shown substantially as the XRPD pattern of Fig. 3.
- the co-crystal according to the present invention has good handling properties of the solid form.
- the co-crystal has good flowability properties.
- the co-crystals according to the present invention may be used in compositions in the same way as other forms of Urolithin A previously known.
- the co-crystal according to the present invention can be used in food products, feed products, dietary supplements, pharmaceutical products as well as personal care products.
- the present invention relates to the use of the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”), (CC4), (CC5), (CC5’) or (CC6) in food products, feed products, dietary supplements, pharmaceutical products and/or personal care products.
- the present invention relates to food products, feed products, dietary supplements, pharmaceutical products and/or personal care products comprising cocrystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”), (CC4), (CC5), (CC5’) or (CC6).
- any commonly known and used excipients can be added to the co-crystal.
- the amount of the co-crystal of the present invention (depends on the type of formulation and the desired dosage regimen during administration time periods.
- the amount in each oral formulation may be from 50 to 300 mg, preferably from 75 to 250 mg.
- Oral formulations may be solid formulations such as capsules, tablets, pills and troches, or a liquid suspension formulation.
- the crystalline composition according to the invention may be used directly as powders (micronized particles), granules, suspensions, or they may be combined with other (pharmaceutically acceptable) ingredients in admixing the components and optionally finely divide them, and then filling capsules, composed for example from hard or soft gelatine: or compressing tablets, or troches, or suspend in suspensions. Coatings may also be applied.
- Acceptable ingredients are well known for the various types of formulation and may be for example binders such as natural or synthetic polymers, excipients, disintegrants, lubricants, surfactants, sweetening and other flavouring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, and carriers for the various formulation types.
- Example 1 Synthesis of Urolithin A - Betaine co-crystal by wet grinding process A mortar was charged with Urolithin A (1 g, 4.4 mmol, 1 eq) and betaine (4.4 mmol, 1 eq).
Abstract
The present invention relates to a specific multicomponent crystalline system (co- crystal) comprising Urolithin A as one of the components produced by a specific process.
Description
UROLITHIN A - BETAIN CO-CRYSTAL (II)
The present invention relates to a specific multicomponent crystalline system (cocrystal) comprising Urolithin A as one of the components produced by a specific process.
Urolithin A is a metabolite compound resulting from the transformation of ellagitannins by the gut bacteria in the body.
Urolithin A belongs to the class of organic compounds known as benzo-coumarins or dibenzo-a-pyrones. Its precursors - ellagic acids and ellagitannins - are ubiquitous in nature, including edible plants, such as pomegranates, strawberries, raspberries, and walnuts.
Urolithin A was isolated and identified in the 1960s.
Urolithin A is a natural food metabolite of the gut microbiome that has been shown to stimulate mitophagy and improve muscle function in aged animals and in models of muscular dystrophy, while also being safe, bioavailable, and able to induce mitochondrial gene expression in older adults.
Due to the fact, that Urolithin A is not to be found in a natural source, the precursors are supplied and then transformed into Urolithin A in the gut system.
The problem with the precursor is that only 30% to 40% people’s microbiome could produce Urolithin A via ellagic acid.
Therefore, the alternative is to provide Urolithin A as such.
Urolithin A is available commercially from a variety of suppliers.
Urolithin A has poor water solubility (pg/mL) and low bioavailability. Therefore, a large loading (500 mg per serving) is usually used in the current formulation to achieve an acceptable result.
Surprisingly, it was found that the co-crystal of Urolithin A with betaine, which is the compound of formula (II)
shows higher solubility compared to its single parts when producing it by a specific process.
It was found that when using betaine as co-crystal former a stable and soluble cocrystal was obtained when producing it by a specific process. The co-crystal according to the present invention is obtained by using the wet grinding process (also known as liquid, or solvent assisted grinding).
The wet grinding process (WGP) comprises the steps: a) wet grinding of the compound of formula (I)
and the compound of formula (II)
in a small amount of at least one solvent, and b) isolating the obtained compound.
Therefore, the present invention relates to the co-crystal (CC) obtainable by a) wet grinding of the compound of formula (I)
and the compound of formula (II)
in a small amount of at least one solvent, and b) isolating the obtained compound.
The second component of a co-crystal is also referred to as co-former. In the present invention, this co-formed is the compound of formula (II), which is known as betaine (or N,N,N-trimethylglycine).
The term “co-crystal” or “co-crystal” refers herein a crystal formed by combining two or more organic molecules in the same crystal lattice through non-covalent bonds
(hydrogen bond, TT-TT stacking, van der Waals force, etc.) in a fixed stoichiometric ratio. It is a way of aggregation of multi-component substances in a solid state.
Thus, in a co-crystal a first neutral component crystallizes with at least one second neutral component and interact via non-ionic interactions. Said at least one second component in the co-crystal is commonly referred to as a “coformer” or “co-crystal former” and is solid at room temperature and atmospheric pressure. This definition distinguishes co-crystals from crystalline solvates, in that in a solvate one of the components is a liquid at room temperature and atmospheric pressure.
Besides, it should be noted that, unlike salts, where the components in the crystal lattice are in an ionized state, the co-crystal’s components are in a neutral state and are linked by hydrogen bonding and other non-ionic interactions.
The co-crystal according to the present invention comprises Urolithin A and betaine. In a particular embodiment the molar ratio of Urolithin A : betaine is 1 :1.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC1 ), which is the co-crystal (CC), wherein molar ratio of Urolithin A : betaine is 1 : 1 .
The grinding may be performed with a mechanical mill, for instance, in a ball mill.
It is also possible to use ultrasound to diminish the starting material. A suitable frequency range is 25-800 kHz, preferred 40-200 kHz.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC2), which is the co-crystal (CC) or (CC1 ), wherein the grinding is performed in a mechanical mill.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC2’), which is the co-crystal (CC2), wherein the grinding is performed in a ball mill.
The solvents, which are used in the wet grinding process, are polar or non-polar solvents, which can be protic or non-protic.
Suitable solvents are i.e. , alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, non-cyclic ethers, cyclic ethers, esters, ketones, sulfoxides and nitriles.
Suitable solvents are i.e. water, acetonitrile, benzonitrile, dichloromethane, chloroform, dimethylsulfoxide, methanol, ethanol, isopropyl alcohol, iso pentanol, ethyl acetate, isopentyl acetate, isobutyl acetate, n-butyl acetate, acetone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, diethylether, methyl tert-butyl ether, toluene, cyclohexane, xylene and heptane; preferably water, ethyl acetate, acetonitrile, methanol and ethanol.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC3), which is the co-crystal (CC), (CC1 ), (CC2) or (CC2’), wherein the at least one solvent is polar or non-polar solvents, which can be protic or non-protic.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC3’), which is the co-crystal (CC), (CC1 ), (CC2) or (CC2’), wherein the at least one solvent is chosen from the group consisting of alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, non-cyclic ethers, cyclic ethers, esters, ketones, sulfoxides and nitriles.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC3”), which is the co-crystal (CC), (CC1 ), (CC2) or (CC2’), wherein the at least one solvent is chosen from the group consisting of water, acetonitrile, benzonitrile, dichloromethane, chloroform, dimethylsulfoxide, methanol, ethanol, isopropyl alcohol, iso pentanol, ethyl acetate, isopentyl acetate, isobutyl acetate, n-butyl acetate, acetone, methyl isobutyl ketone, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentyl methyl ether, diethylether, methyl tert-butyl ether, toluene, cyclohexane, xylene and heptane.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC3’”), which is the co-crystal (CC), (CC1 ), (CC2) or (CC2’), wherein the at least one solvent is chosen from the group consisting of water, ethyl acetate, acetonitrile, methanol and ethanol.
In a preferred embodiment of the wet grinding process the solvent is present in an amount of 0-1 Opl per mg of compound of formula (I) and of the compound of formula (II).
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC4), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”) or (CC3’”), wherein the solvent is present in an amount of 0-1 Opd per mg of compound of formula (I) and of the compound of formula (II).
Preferably the wet grinding process is carried out at a temperature of 15 to 30°C, more preferably at room temperature.
As used herein, "room temperature" or its abbreviation "rt" is considered for a temperature between 20 to 25 °C.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC5), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”) or (CC4), wherein the process is carried out at a temperature of 15 to 30°C.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC5’), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”) or (CC4), wherein the process is carried out at room temperature.
Usually and preferably the wet grinding process is carried out at ambient pressure (about 1 atm = about 101325 Pa).
It is clear, that the process could (if desired) also carried out at other pressures as well.
Therefore, the present invention relates to a specific multicomponent crystalline system (co-crystal) (CC6), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3),
(CC3’), (CC3”), (CC3’”), (CC4), (CC5) or (CC5’), wherein wet grinding process is carried out at ambient pressure.
The isolation of the co-crystal may include, for example, one or more of the following operations: such as filtration, filtration under vacuum, evaporation, crystallization by cooling, heating-melting, decantation, and centrifugation and other suitable techniques as known to a person skilled in the art.
The obtained co-crystal of the invention may be further purified, e.g. by recrystallization.
The co-crystal can contain traces of the solvent used in the production of the cocrystal. This is depending on the drying (kind of drying as well as length of drying).
The co-crystals of this invention are stable, wherein "stable" means that the cocrystals maintain their crystalline form over a long period of time at standard ambient conditions of temperature and pressure.
The present invention also relates to the co-crystal of compound of formula (I) and of compound of formula (II), which is the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”), (CC4), (CC5), (CC5’) or (CC6), characterised in that the X- ray diffraction pattern of the obtained co-crystal characteristic peaks exist at 20 angle: 7.52° ± 0.2°, 10.46° ± 0.2°, 16.72° ± 0.2°, 17.22° ± 0.2°, 19.32° ± 0.2°, 21.44° ± 0.2°, 22.08° ± 0.2°, 22.80° ± 0.2°, 27.02° ± 0.2°, 27.48° ± 0.2°, 32.16° ± 0.2°.
The present invention also relates to co-crystal of Urolithin A and betaine, characterized in that, the X-ray powder diffraction pattern of the co-crystal is shown substantially as the XRPD pattern of Fig. 3.
Furthermore, the co-crystal according to the present invention has good handling properties of the solid form. The co-crystal has good flowability properties.
The co-crystals according to the present invention may be used in compositions in the same way as other forms of Urolithin A previously known.
The co-crystal according to the present invention can be used in food products, feed products, dietary supplements, pharmaceutical products as well as personal care products.
Therefore, the present invention relates to the use of the co-crystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”), (CC4), (CC5), (CC5’) or (CC6) in food products, feed products, dietary supplements, pharmaceutical products and/or personal care products.
Therefore, the present invention relates to food products, feed products, dietary supplements, pharmaceutical products and/or personal care products comprising cocrystal (CC), (CC1 ), (CC2), (CC2’), (CC3), (CC3’), (CC3”), (CC3’”), (CC4), (CC5), (CC5’) or (CC6).
When using the co-crystal according to the present invention in food products, feed products, dietary supplements, pharmaceutical products and/or personal care products, any commonly known and used excipients can be added to the co-crystal.
The amount of the co-crystal of the present invention (depends on the type of formulation and the desired dosage regimen during administration time periods. The amount in each oral formulation may be from 50 to 300 mg, preferably from 75 to 250 mg. Oral formulations may be solid formulations such as capsules, tablets, pills and troches, or a liquid suspension formulation.
It can also be used in other formulation when used in food products, feed products, dietary supplements, pharmaceutical products and/or personal care products.
The crystalline composition according to the invention may be used directly as powders (micronized particles), granules, suspensions, or they may be combined with other (pharmaceutically acceptable) ingredients in admixing the components and optionally finely divide them, and then filling capsules, composed for example from hard or soft gelatine: or compressing tablets, or troches, or suspend in suspensions. Coatings may also be applied.
Acceptable ingredients are well known for the various types of formulation and may be for example binders such as natural or synthetic polymers, excipients, disintegrants, lubricants, surfactants, sweetening and other flavouring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, and carriers for the various formulation types.
The following examples illustrate the present invention.
All the parts and percentages in the Examples are related to the weight (when not otherwise stated) and the temperature is given in °C (when not otherwise stated).
Examples
Example 1 : Synthesis of Urolithin A - Betaine co-crystal by wet grinding process A mortar was charged with Urolithin A (1 g, 4.4 mmol, 1 eq) and betaine (4.4 mmol, 1 eq).
Methanol (50 pL) was added to the mixture and manually grinded for about 20 min to give the co-crystal. The co-crystal was confirmed by XRD-powder. (Fig.3) The product was obtained in a yield of 82% The so obtained co-crystal has a solubility in water, which is 2.7 higher than Urolithin A. (Fig.4)
Claims
2. Co-crystal according to claim 1 , wherein molar ratio of Urolithin A : betaine is 1 :1.
3. Co-crystal according to claim 1 or 2, wherein the grinding is performed in a mechanical mill.
4. Co-crystal according to claim 1 or 2, wherein the grinding is performed in a ball mill.
5. Co-crystal according to any of the preceding claims, wherein the at least one solvent is chosen from the group consisting of water, alcohols, aromatic hydrocarbons, aliphatic hydrocarbons, non-cyclic ethers, cyclic ethers, esters, ketones, sulfoxides and nitriles.
6. Co-crystal according to claim 5, wherein the at least one solvent is chosen from the group consisting of water, acetonitrile, benzonitrile, dichloromethane, chloroform, dimethylsulfoxide, methanol, ethanol, isopropyl alcohol, iso pentanol, ethyl acetate, isopentyl acetate, isobutyl acetate, n-butyl acetate, acetone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, diethylether, methyl tert-butyl ether, toluene, cyclohexane, xylene and heptane.
7. Co-crystal according to any of the preceding claims, wherein the at least one solvent is present in an amount of 0-1 Opd per mg of compound of formula (I) and of the compound of formula (II).
8. Co-crystal according to any of the preceding claims, wherein the compound of formula (I) is added in an equimolar amount in view of the compound of formula (II).
9. Co-crystal according to any of the preceding claims, wherein the process is carried out is carried out at room temperature.
10. Co-crystal according to any of the preceding claims, wherein the process is carried out at ambient pressure.
11. Co-crystal according to any of the preceding claims, wherein the co-crystal is characterised in that the X-ray diffraction pattern of the obtained co-crystal characteristic peaks exist at 20 angle:
7.52° ± 0.2°, 10.46° ± 0.2°, 16.72° ± 0.2°, 17.22° ± 0.2°, 19.32° ± 0.2°, 21.44° ± 0.2°, 22.08° ± 0.2°, 22.80° ± 0.2°, 27.02° ± 0.2°, 27.48° ± 0.2°, 32.16° ± 0.2°.
12. Co-crystal according to any of the preceding claims, wherein the co-crystal is characterized in that, the X-ray powder diffraction pattern of the co-crystal is shown substantially as the XRPD pattern of Fig. 3.
13. Use of the co-crystal according to any of claims 1 - 12 in food products, feed products, dietary supplements, pharmaceutical products and/or personal care products.
14. Food products, feed products, dietary supplements, pharmaceutical products and/or personal care products comprising the co-crystal according to any of claims 1 - 12.
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Non-Patent Citations (2)
Title |
---|
SHAHBAZ MUHAMMAD ET AL: "A new bioactive cocrystal of coumarin-3-carboxylic acid and thiourea: detailed structural features and biological activity studies", ACTA CRYSTALLOGRAPHICA SECTION C. CRYSTAL STRUCTURE COMMUNICATIONS, vol. 78, no. 3, 1 March 2022 (2022-03-01), DK, pages 192 - 200, XP093074842, ISSN: 0108-2701, DOI: 10.1107/S205322962200081X * |
ZHANG ZHIJIE ET AL: "Cocrystals of Natural Products: Improving the Dissolution Performance of Flavonoids Using Betaine", CRYSTAL GROWTH & DESIGN, vol. 19, no. 7, 3 July 2019 (2019-07-03), US, pages 3851 - 3859, XP093074682, ISSN: 1528-7483, DOI: 10.1021/acs.cgd.9b00294 * |
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