CN117327069B - Crystal form of pyrroloquinoline quinone disodium salt, and preparation method and application thereof - Google Patents
Crystal form of pyrroloquinoline quinone disodium salt, and preparation method and application thereof Download PDFInfo
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- CN117327069B CN117327069B CN202311264114.2A CN202311264114A CN117327069B CN 117327069 B CN117327069 B CN 117327069B CN 202311264114 A CN202311264114 A CN 202311264114A CN 117327069 B CN117327069 B CN 117327069B
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- Prior art keywords
- pyrroloquinoline quinone
- disodium salt
- quinone disodium
- crystalline
- pyrroloquinoline
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- UFVBOGYDCJNLPM-UHFFFAOYSA-L disodium;9-carboxy-4,5-dioxo-1h-pyrrolo[2,3-f]quinoline-2,7-dicarboxylate Chemical compound [Na+].[Na+].C12=C(C([O-])=O)C=C(C([O-])=O)N=C2C(=O)C(=O)C2=C1NC(C(=O)O)=C2 UFVBOGYDCJNLPM-UHFFFAOYSA-L 0.000 title claims abstract description 103
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000013078 crystal Substances 0.000 title abstract description 89
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000001914 filtration Methods 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 239000000047 product Substances 0.000 claims description 38
- 239000011343 solid material Substances 0.000 claims description 37
- 239000000706 filtrate Substances 0.000 claims description 35
- 238000003756 stirring Methods 0.000 claims description 29
- 238000001816 cooling Methods 0.000 claims description 28
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000001953 recrystallisation Methods 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 15
- 239000008213 purified water Substances 0.000 claims description 14
- -1 pyrroloquinoline quinone disodium salt compound Chemical class 0.000 claims description 14
- 238000004458 analytical method Methods 0.000 claims description 13
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 11
- 235000013305 food Nutrition 0.000 claims description 11
- 239000003963 antioxidant agent Substances 0.000 claims description 10
- 230000003078 antioxidant effect Effects 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- ZIUYHTQZEPDUCZ-UHFFFAOYSA-N 7h-pyrrolo[2,3-h]quinoline Chemical compound C1=CN=C2C(C=CN3)=C3C=CC2=C1 ZIUYHTQZEPDUCZ-UHFFFAOYSA-N 0.000 claims description 9
- 230000001737 promoting effect Effects 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 claims description 8
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 8
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 claims description 8
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 235000011089 carbon dioxide Nutrition 0.000 claims description 7
- 230000012010 growth Effects 0.000 claims description 7
- 235000013361 beverage Nutrition 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 206010067125 Liver injury Diseases 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000002537 cosmetic Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 244000005700 microbiome Species 0.000 claims description 4
- 210000005036 nerve Anatomy 0.000 claims description 4
- 210000000653 nervous system Anatomy 0.000 claims description 4
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- 230000004792 oxidative damage Effects 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000000490 cosmetic additive Substances 0.000 claims description 3
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- 235000013373 food additive Nutrition 0.000 claims description 3
- 239000002778 food additive Substances 0.000 claims description 3
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- 231100000753 hepatic injury Toxicity 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 230000003859 lipid peroxidation Effects 0.000 claims description 3
- 229910021645 metal ion Inorganic materials 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 230000008635 plant growth Effects 0.000 claims description 3
- 231100000572 poisoning Toxicity 0.000 claims description 3
- 230000000607 poisoning effect Effects 0.000 claims description 3
- 230000002000 scavenging effect Effects 0.000 claims description 3
- 239000003674 animal food additive Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000001569 carbon dioxide Substances 0.000 claims description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 230000004580 weight loss Effects 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 5
- 238000007906 compression Methods 0.000 abstract description 3
- 230000006835 compression Effects 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000012545 processing Methods 0.000 abstract description 3
- MMXZSJMASHPLLR-UHFFFAOYSA-N pyrroloquinoline quinone Chemical compound C12=C(C(O)=O)C=C(C(O)=O)N=C2C(=O)C(=O)C2=C1NC(C(=O)O)=C2 MMXZSJMASHPLLR-UHFFFAOYSA-N 0.000 description 61
- 238000006243 chemical reaction Methods 0.000 description 25
- 239000000463 material Substances 0.000 description 23
- 238000005056 compaction Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 14
- 238000000967 suction filtration Methods 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 229910001415 sodium ion Inorganic materials 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 8
- 229910021641 deionized water Inorganic materials 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000002411 thermogravimetry Methods 0.000 description 6
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- JZCYGONDZRBSSA-UHFFFAOYSA-N 4,5-dioxo-1h-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid;sodium Chemical compound [Na].[Na].[Na].C12=C(C(O)=O)C=C(C(O)=O)N=C2C(=O)C(=O)C2=C1NC(C(=O)O)=C2 JZCYGONDZRBSSA-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 238000006479 redox reaction Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-benzoquinone Chemical group O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 102000004031 Carboxy-Lyases Human genes 0.000 description 1
- 108090000489 Carboxy-Lyases Proteins 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 108020005199 Dehydrogenases Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001323 aldoses Chemical class 0.000 description 1
- 238000012863 analytical testing Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000816 effect on animals Effects 0.000 description 1
- 230000002289 effect on microbe Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 235000015897 energy drink Nutrition 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- DIEUGINJYISDCB-UHFFFAOYSA-N ethyl 6-amino-5-methoxy-1h-indole-2-carboxylate Chemical compound COC1=C(N)C=C2NC(C(=O)OCC)=CC2=C1 DIEUGINJYISDCB-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 235000011496 sports drink Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/116—Heterocyclic compounds
- A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Polymers & Plastics (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Food Science & Technology (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Animal Husbandry (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Mycology (AREA)
- Birds (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The application provides a pyrroloquinoline quinone disodium salt crystal form and a preparation method thereof. The pyrroloquinoline quinone disodium salt crystal compound has diffraction characteristic peaks at least at the following 2θ angles, measured by Cu-kα rays: 8.279, 16.599, 22.558, 23.219, 25.621, 27.26, 47.499, wherein the error in 2 theta angle is + -0.2 deg.. The crystal compound has the advantages of high crystallinity, high purity, high compression density, high stability, almost no hygroscopicity, easy processing, suitability for large-scale production, no solvent residue, environment friendliness and no pollution.
Description
Technical Field
The application relates to the field of organic compound preparation, in particular to a pyrroloquinoline quinone disodium salt crystal form, a preparation method and application thereof.
Background
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
Pyrrolo-quinoline quinone (pyrroloquinoline quineone, PQQ), which is known by the chemical name 4, 5-dihydro-4, 5-dioxo-1-H-pyrrolo (2, 3-f) quinoline-2, 7, 9-tricarboxylic acid, also known as pyrroloquinoline quinone, was originally found to be produced by gram-negative bacteria, has a broad-range nutritional effect on microorganisms, animals and plants, and possesses antioxidant nutritional elements.
Pyrroloquinoline quinone is a cofactor involved in redox reactions in organisms, as a coenzyme for many enzymes such as dehydrogenases, oxidases, hydratases and decarboxylases. Pyrroloquinoline quinone contains an o-quinone structure which can directly participate in redox reaction, and the above enzyme protein can catalyze non-phosphorylated substrates to perform oxidation reaction, such as alcohols, aldehydes and aldoses. According to the prior researches, pyrroloquinoline quinone can protect the heart from oxidative damage, prevent and treat liver damage, promote nerve growth and protect the nervous system, prevent acetaldehyde from being moderate, and the like.
Pyrroloquinoline quinone can be produced by chemical synthesis and fermentation, and pyrroloquinoline quinone disodium salt is administered in the united states as a "generally regarded as safe substance (GRAS)" and can be used as a raw material for foods such as energy drinks, sports drinks, electrolyte drinks, etc.; the European Union and Canada are used as dietary supplements or natural health foods. The currently chemically synthesized pyrroloquinoline quinone is obtained as a new food material in the batch country, can be applied to the field of beverages, is suitable for people except infants, pregnant women and lactating women, and is approved by the safety evaluation materials of pyrroloquinoline quinone disodium salt, and the new food material reported by the safety evaluation materials is already disclosed to be accepted. Commercial products are now available for sale. The pyrroloquinoline quinone disodium salt obtained by the prior art method generally contains two crystal waters, the existing crystal forms are unstable and have high hygroscopicity, the humidity change range is large in a temperature range of normal-temperature storage, and the solid state is not ideal, so that the pyrroloquinoline quinone disodium salt is not suitable for processing, and is unfavorable for application and storage of the pyrroloquinoline quinone disodium salt.
Disclosure of Invention
Therefore, the application aims to provide a pyrroloquinoline quinone disodium salt crystal form and a preparation method thereof. The pyrroloquinoline quinone disodium salt crystal form compound provided by the application has the advantages of high crystallinity, high purity, high stability, high compaction density and almost no hygroscopicity, is easy to process, is suitable for large-scale production, has no solvent residue, and is environment-friendly and pollution-free in preparation method.
Specifically, the invention provides the following technical scheme.
In a first aspect of the invention, there is provided a crystalline compound of pyrroloquinoline quinone disodium salt having diffraction characteristic peaks, measured in Cu-ka radiation, at least at the following 2θ angles: 8.279, 16.599, 22.558, 23.219, 25.621, 27.26, 47.499, wherein the error in 2 theta angle is + -0.2 deg..
Further, the pyrroloquinoline quinone disodium salt crystal compound of the present invention has a diffraction characteristic peak ：8.279、16.599、18.722、19.136、22.558、23.219、25.621、26.061、27.2629.721、30.28、33.579、37.581、38.819、42.143、47.499, at least at the following 2θ angles, as measured by cu—kα rays, wherein the error of the 2θ angle is ±0.2°.
Further, the X-ray powder diffraction pattern of the pyrroloquinoline quinone disodium salt crystal compound is shown in figure 1.
According to the TGA curve, the pyrroloquinoline quinone disodium salt crystal compound has twice weightlessness in sequence within 80-400 ℃, and the decomposition peak temperature is 308.8 ℃.
Further, the TGA curve of the pyrroloquinoline quinone disodium salt crystal compound is shown in fig. 2.
The crystalline compound of pyrroloquinoline quinone disodium salt according to the present invention can be confirmed by the above data such as an X-ray powder diffraction pattern and the like. Those skilled in the art will appreciate that experimental errors therein depend on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is known to those skilled in the art that, for example, X-ray powder diffraction patterns generally vary with the conditions of the instrument. In addition, experimental errors in peak angles are typically 5% or less, and errors in these angles should also be taken into account, typically allowing for errors of + -0.2 deg.. In addition, due to the influence of experimental factors such as the sample height, an overall shift in peak angle is caused, and generally a certain shift is allowed. Thus, it will be appreciated by those skilled in the art that any crystalline form having a pattern identical or similar to the characteristic peaks in the pattern of the present invention is within the scope of the present invention.
In a second aspect of the present invention, there is provided a process for preparing a crystalline compound of pyrroloquinoline quinone disodium salt as described in the first aspect above, comprising: mixing pyrroloquinoline quinic acid and water, adding alkali at 25-30 ℃, heating to 70-80 ℃, and filtering after complete dissolution; cooling the filtrate to below 30deg.C, stirring, adjusting pH to 3.4-4.5, stopping reacting, standing, vacuum filtering to obtain wet solid material, adding purified water for recrystallization, cooling to below 30deg.C, vacuum filtering, and oven drying.
Or in some embodiments of the invention, the method comprises: mixing pyrroloquinoline quinone disodium salt and water, adding alkali at 25-30 ℃, heating to 70-80 ℃, and filtering after complete dissolution; cooling the filtrate to below 20deg.C, stirring, adjusting pH to 3.4-4.5, stopping reacting, standing, vacuum filtering to obtain wet solid material, adding purified water for recrystallization, cooling to below 30deg.C, vacuum filtering, and oven drying.
In some embodiments of the invention, the base is selected from one or more of sodium hydroxide, sodium bicarbonate, and sodium carbonate.
In some embodiments of the invention, the pH is adjusted to 3.4-4.5 by adding dry ice or introducing carbon dioxide under stirring; in these embodiments, the pH may be adjusted to 4.0-4.2, 3.4-4.0, 3.5-4.0, 3.8-4.0, or 3.5-4.5, etc.
In some embodiments of the invention, the drying temperature is 50-70 ℃ and the vacuum degree is 0.06-0.08Mpa; for example, in some embodiments, the drying temperature may be 50-60 ℃, 55-65 ℃, or 60-70 ℃.
In a third aspect of the present invention there is provided a composition comprising a crystalline compound of pyrroloquinoline quinone disodium salt as described in the first aspect above.
In a fourth aspect of the present invention there is provided a product comprising a crystalline compound of pyrroloquinoline quinone disodium salt as described in the first aspect above or a composition comprising said crystalline compound of pyrroloquinoline quinone disodium salt.
In some embodiments of the invention, the product comprises a pharmaceutical product, a food product, a nutraceutical product, a cosmetic product.
In some embodiments of the present invention, the pyrroloquinoline quinone disodium salt crystal compound can be used as a food additive, a cosmetic additive, etc. in foods, health products, and cosmetics.
The food product according to the invention is in particular a functional food product, such as a beverage, which may be a solid beverage or a liquid beverage, etc.
In a fifth aspect of the present invention there is provided the use of a crystalline compound of pyrroloquinoline quinone disodium salt as described in the first aspect above, or a composition comprising said crystalline compound of pyrroloquinoline quinone disodium salt, in the preparation of a product having at least one of the following functions:
1) Promoting the growth of microorganisms;
2) Promoting plant growth;
3) Antioxidant, including but not limited to scavenging free radicals, activating antioxidant enzymes, enhancing the synthesis of antioxidant substances, inhibiting lipid peroxidation, and the like;
4) Protecting the heart from oxidative damage;
5) Preventing and treating liver injury;
6) Promoting nerve growth and protecting nervous system;
7) Preventing acetaldehyde poisoning; and
8) Chelating metal ions such as iron ions.
In some embodiments of the invention, the products include, but are not limited to, food additives and foods containing the same, cosmetic additives and cosmetics containing the same, health products, pharmaceutical carriers (e.g., as carriers for some drugs, for delivering and releasing drugs by complexation with pyrroloquinoline quinone disodium salt crystals), chemical analysis reagents (capable of performing chemical analysis such as metal ion detection), feed additives and feeds containing the same, and the like.
In a sixth aspect of the invention, there is provided a method comprising administering to a subject a crystalline pyrroloquinoline quinone disodium salt compound described in the first aspect above or a composition or product comprising said crystalline pyrroloquinoline quinone disodium salt compound to achieve at least one of the following therapeutic or ameliorating effects:
1) Promoting the growth of microorganisms;
2) Promoting plant growth;
3) Antioxidant, including but not limited to scavenging free radicals, activating antioxidant enzymes, enhancing the synthesis of antioxidant substances, inhibiting lipid peroxidation, and the like;
4) Protecting the heart from oxidative damage;
5) Preventing and treating liver injury;
6) Promoting nerve growth and protecting nervous system; and
7) Preventing acetaldehyde poisoning.
The subject of the invention is a plant, a microorganism or an animal, such as a mammal, in particular a human; such as grain crops, ornamental plants and the like.
In the present invention, the effective amount required to achieve the above-described functions can be determined conventionally by those skilled in the art in view of their own knowledge, state of the art, such as by in vivo, in vitro or ex vivo experiments to determine or demonstrate the amount, and then apply the amount to better practice the methods described herein. For example, in some embodiments of the present invention, the crystalline pyrroloquinoline quinone disodium salt compound of the present invention is recommended to be used in an amount of 20 mg/day or less when used as a food; for another example, the additive amount is not more than 40mg/kg when used as a beverage.
Advantages of the present invention compared to the prior art include:
The invention provides a novel crystal form of pyrroloquinoline quinone disodium salt, which has the advantages of high crystallinity and high purity, and particularly has the advantages of high stability and high compaction density compared with the existing pyrroloquinoline quinone disodium salt, almost has no hygroscopicity, is easy to process, is suitable for large-scale production, has no solvent residue, and has the advantages of environmental protection and no pollution.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application. Embodiments of the present application are described in detail below with reference to the attached drawing figures, wherein:
fig. 1: x-ray powder diffraction pattern of crystalline pyrroloquinoline quinone disodium salt compound in example 1.
Fig. 2: thermogravimetric analysis (TGA) profile of the crystalline form of pyrroloquinoline quinone disodium salt compound of example 1.
Fig. 3: microscopic images (A, B, C), A, B, C of the crystalline form of pyrroloquinoline quinone disodium salt compound of example 1 all show that it is a platelet crystal.
Fig. 4: x-ray powder diffraction pattern of pyrroloquinoline quinone disodium salt crystal form compound in comparative example 1.
Fig. 5: x-ray powder diffraction pattern of pyrroloquinoline quinone disodium salt crystal form compound in comparative example 2.
Fig. 6: x-ray powder diffraction pattern of pyrroloquinoline quinone disodium salt crystal form compound in comparative example 3.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or materials used in the present application may be purchased in conventional manners, and unless otherwise indicated, they may be used in conventional manners in the art or according to the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.
Analytical instrument and test conditions:
1. XRD: japanese physics Rigaku Ultma IV, copper target; a specific scanning angle range (°) is 5-90; the scanning speed is 5 DEG/min.
2. Thermogravimetric analysis: the test gas atmosphere of the TGA German relaxation-resistant STA 449F5 is nitrogen, the specific test temperature range (DEG C) is 30-500, and the heating rate is 10 ℃/min.
3. The liquid chromatography conditions were as follows:
liquid phase detection uses an instrument: shimadzu LC-20A
Chromatographic column: TCI Kaseisorb LC ODS2000 (4.6mm.times.150mm, 5 μm) or a column with comparable performance.
Column temperature: 30 DEG C
Flow rate: 1.0mL/min.
Wavelength: 250nm.
Sample injection amount: 20. Mu.L.
Mobile phase: mobile phase a:10mmol/L dipotassium hydrogen phosphate-15 mmol/L tetrabutylammonium bromide mixed solution (pH 7.4); mobile phase B: acetonitrile.
The starting materials used in the following examples and comparative examples are commercially available or may be obtained according to methods conventional in the art, for example, pyrroloquinolinoquinone acid or pyrroloquinolinoquinone disodium salt may be prepared by organic chemical synthesis. The pyrroloquinoline quinone acid or pyrroloquinoline quinone disodium salt is crystalline, and the raw material may contain impurities. For example, the pyrroloquinoline quinone acid and pyrroloquinoline quinone disodium salt can be prepared by taking 6-amino-5-methoxy-1H-indole-2-carboxylic acid ethyl ester and 2-oxopentene dimethyl dioate as raw materials and through coupling cyclization reaction, quinoline ring formation, oxidation reaction, ester hydrolysis reaction, refining and other processes.
Example 1
Adding 16.5g of pyrroloquinoline quinic acid and 330g of water into a reaction bottle, slowly adding 7g of sodium hydroxide into the reaction bottle at 25-30 ℃, heating to 70-80 ℃ after the completion of the reaction, stirring for 2 hours, basically completely dissolving the materials, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 30 ℃, introducing CO 2 to pH4.0-4.2 into the filtrate under stirring, stopping the reaction, standing for 2h, and filtering to obtain 36.2g of solid wet product. The wet product was added to 362g of purified water for recrystallization. After that, cooling to below 30 ℃, carrying out suction filtration to obtain 35.1g of wet pyrroloquinoline quinone disodium salt solid material, and drying the wet material in a drying oven to obtain 15.9g of pyrroloquinoline quinone disodium salt crystal I. The vacuum drying temperature is 60-70 ℃ (vacuum degree is 0.08 MPa). The obtained crystal I was examined and the purity thereof was 99.9% by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 1.98, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction pattern, thermogravimetric analysis (TGA) pattern and microscopic pattern of the crystalline form are shown in FIGS. 1 to 3, and the X-ray powder diffraction data are shown in Table 1, and the decomposition peak temperature of the crystalline form compound is 308.8 ℃ as seen in FIG. 2. As can be seen from fig. 3, the crystalline compound is a plate-like crystal.
TABLE 1X-ray powder diffraction data for pyrroloquinoline quinone disodium salt crystals I
Example 2
Adding 16.5g of pyrroloquinoline quinic acid and 330g of water into a reaction bottle, slowly adding 7g of sodium hydroxide into the reaction bottle at 25-30 ℃, heating to 70-80 ℃ after the completion of the reaction, stirring for 2 hours, basically completely dissolving the materials, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 30 ℃, adding dry ice into the filtrate under stirring until the pH is 3.4-4.0, stopping the reaction, standing for 2 hours, and carrying out suction filtration to obtain 37.6g of solid wet product. Adding 376g of purified water into the wet product for recrystallization, cooling to below 30 ℃ after the recrystallization, filtering to obtain 36.5g of wet product of pyrroloquinoline quinone disodium salt solid material, and drying the wet product in an oven to obtain 17.3g of pyrroloquinoline quinone disodium salt crystal form II. The vacuum drying temperature is 60-70 ℃ (vacuum degree is 0.08 MPa). Detecting the obtained crystal II, wherein the purity of the crystal II is 99.6% by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 1.97, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction pattern of this crystalline form is consistent with example 1.
Example 3
Adding 16.5g of pyrroloquinoline quinic acid and 330g of water into a reaction bottle, slowly adding 8.7g of sodium carbonate into the reaction bottle at 25-30 ℃, heating to 70-80 ℃ and stirring for 3 hours, wherein the materials are basically completely dissolved, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 30 ℃, adding 3.2g of dry ice into the filtrate under stirring, standing for 2 hours after the pH of the solution is 3.8-4.0, and filtering to obtain 34.6g of solid wet product. Washing with deionized water, suction filtering to obtain wet pyrroloquinoline quinone disodium salt solid material, adding 346g of purified water into the wet pyrroloquinoline quinone disodium salt solid material to recrystallize, cooling to below 30 ℃ after the wet pyrroloquinoline quinone disodium salt solid material is completely recrystallized, suction filtering to obtain 32.8g of pyrroloquinoline quinone disodium salt solid material, and drying the wet pyrroloquinoline quinone disodium salt solid material in an oven to obtain 14.3g of pyrroloquinoline quinone disodium salt crystal form III. The vacuum drying temperature is 50 ℃ -60 ℃ (vacuum degree is 0.08 MPa). Detecting the obtained crystal III, wherein the purity of the crystal III is 99.9% by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 1.96, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction of this crystalline form is consistent with example 1.
Example 4
Adding 16.5g of pyrroloquinoline quinic acid and 330g of water into a reaction bottle, slowly adding 8.7g of sodium carbonate into the reaction bottle at 25-30 ℃, heating to 70-80 ℃ and stirring for 3 hours, wherein the materials are basically completely dissolved, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 30 ℃, introducing CO 2 into the filtrate under stirring until the pH of the solution is between 3.5 and 4.0, standing for 2 hours, and carrying out suction filtration to obtain 32.4g of solid wet product. Washing with deionized water, suction filtering to obtain wet pyrroloquinoline quinone disodium salt solid material, adding 324g of purified water into the wet pyrroloquinoline quinone disodium salt solid material for recrystallization, cooling to below 30 ℃ after the recrystallization, suction filtering to obtain 31.9g of pyrroloquinoline quinone disodium salt solid material, and drying the wet pyrroloquinoline quinone disodium salt solid material in an oven to obtain 13.6g of pyrroloquinoline quinone disodium salt crystal form IV. The vacuum drying temperature is 50 ℃ -60 ℃ (vacuum degree is 0.08 MPa). Detecting the obtained crystal IV, wherein the purity of the crystal IV is 99.8% by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 1.93, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction pattern of this crystalline form is consistent with example 1.
Example 5
Adding 16.5g of pyrroloquinoline quinic acid and 330g of water into a reaction bottle, slowly adding 13.8g of sodium bicarbonate into the reaction bottle at 25-30 ℃, heating to 70-80 ℃ and stirring for 3 hours, wherein the materials are basically completely dissolved, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 30 ℃, introducing CO 2 into the filtrate under stirring until the pH of the solution is between 3.5 and 4.0, standing for 2 hours, and carrying out suction filtration to obtain 33.5g of solid wet product. Washing with deionized water, suction filtering to obtain wet pyrroloquinoline quinone disodium salt solid material, adding 335g of purified water into the wet pyrroloquinoline quinone disodium salt solid material for recrystallization, cooling to below 30 ℃ after the recrystallization, suction filtering to obtain 31.4g of pyrroloquinoline quinone disodium salt solid material, and drying the wet pyrroloquinoline quinone disodium salt solid material in an oven to obtain 12.9g of pyrroloquinoline quinone disodium salt crystal form V. The vacuum drying temperature is 50 ℃ -60 ℃ (vacuum degree is 0.08 MPa). Detecting the obtained crystal V, wherein the purity of the crystal V is 99.9% by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 1.92, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction of this crystalline form is consistent with example 1.
Example 6
Adding 16.5g of pyrroloquinoline quinic acid and 330g of water into a reaction bottle, slowly adding 13.8g of sodium bicarbonate into the reaction bottle at 25-30 ℃, heating to 70-80 ℃ and stirring for 3 hours, wherein the materials are basically completely dissolved, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 30 ℃, adding 3.5g of dry ice into the filtrate under stirring, standing for 2 hours, and filtering to obtain 35.7g of solid wet product. Washing with deionized water, suction filtering to obtain wet pyrroloquinoline quinone disodium salt solid material, adding 357g of purified water into the wet pyrroloquinoline quinone disodium salt solid material for recrystallization, cooling to below 30 ℃ after the recrystallization, suction filtering to obtain 33.6g of pyrroloquinoline quinone disodium salt solid material, and drying the wet pyrroloquinoline quinone disodium salt solid material in an oven to obtain 15.2g of pyrroloquinoline quinone disodium salt crystal form VI. The vacuum drying temperature is 50 ℃ -60 ℃ (vacuum degree is 0.08 MPa). The obtained crystal VI is detected, and the purity of the crystal VI is 99.9 percent by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 1.94, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction of this crystalline form is consistent with example 1.
Example 7
Adding 18.7g of pyrroloquinoline quinone disodium salt and 380g of water into a reaction bottle, slowly adding 8.4g of sodium bicarbonate into the reaction bottle at 25-30 ℃, heating to 70-80 ℃ and stirring for 3 hours, wherein the materials are basically completely dissolved, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 20deg.C, introducing CO 2 into the filtrate under stirring until pH is 3.5-4.5, standing for 2 hr, and vacuum filtering to obtain 38.4g wet solid material. Washing with deionized water, suction filtering to obtain wet product of pyrroloquinoline quinone disodium salt solid material, adding 384g of purified water into the wet product for recrystallization, cooling to below 30 ℃ after the recrystallization, suction filtering to obtain 36.9g of wet product of pyrroloquinoline quinone disodium salt solid material, and drying the wet product in an oven to obtain 17.3g of pyrroloquinoline quinone disodium salt crystal form VII. The vacuum drying temperature is 55 ℃ -65 ℃ (vacuum degree 0.06 MPa). The obtained crystal VII was examined and found to have a purity of 99.94% by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 2.01, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction pattern of this crystalline form is consistent with example 1.
Example 8
Adding 18.7g of pyrroloquinoline quinone disodium salt and 380g of water into a reaction bottle, slowly adding 10.6g of sodium carbonate into the reaction bottle at 25-30 ℃, heating to 70-80 ℃ and stirring for 3 hours, wherein the materials are basically completely dissolved, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 20deg.C, adding dry ice 4.5g into the filtrate under stirring, standing for 2 hr to obtain solid wet product 37.7g. Washing with deionized water, suction filtering to obtain wet pyrroloquinoline quinone disodium salt solid material, adding 377g of purified water into the wet material for recrystallization, cooling to below 30 ℃ after the recrystallization, suction filtering to obtain 36.3g of pyrroloquinoline quinone disodium salt solid material, and drying the wet material in an oven to obtain 16.7g of pyrroloquinoline quinone disodium salt crystal form VIII. The vacuum drying temperature is 55 ℃ -65 ℃ (vacuum degree 0.06 MPa). Detecting the obtained crystal VIII, wherein the purity of the crystal VIII is 99.96% by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 1.99, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction pattern of this crystalline form is consistent with example 1.
Example 9
Adding 18.7g of pyrroloquinoline quinone disodium salt and 380g of water into a reaction bottle, slowly adding 4.0g of sodium hydroxide into the reaction bottle at 25-30 ℃, heating to 65-75 ℃ and stirring for 3 hours, basically completely dissolving the materials, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 20deg.C, introducing CO 2 into the filtrate under stirring until pH is 3.5-4.5, standing for 2 hr, and vacuum filtering to obtain solid wet product 37.3g. Washing with deionized water, suction filtering to obtain wet pyrroloquinoline quinone disodium salt solid material, adding 373g of purified water into the wet pyrroloquinoline quinone disodium salt solid material to recrystallize, cooling to below 30 ℃ after the completion of recrystallization, suction filtering to obtain 35.7g of pyrroloquinoline quinone disodium salt solid material, and drying the wet pyrroloquinoline quinone disodium salt solid material in an oven to obtain 16.8g of pyrroloquinoline quinone disodium salt crystal form IX. The vacuum drying temperature is 55 ℃ -65 ℃ (vacuum degree 0.06 MPa). Detecting the obtained crystal IX, wherein the purity of the crystal IX is 99.93% by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 1.98, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction pattern of this crystalline form is consistent with example 1.
Example 10
Adding 18.7g of pyrroloquinoline quinone disodium salt and 380g of water into a reaction bottle, slowly adding 4.0g of sodium hydroxide into the reaction bottle at 25-30 ℃, heating to 65-75 ℃ and stirring for 3 hours, basically completely dissolving the materials, and carrying out hot suction filtration to obtain filtrate. Cooling the filtrate to below 20 ℃, adding 3.8g of dry ice into the filtrate under stirring, standing for 2 hours at the pH value of 3.5-4.5, and filtering to obtain 36.5g of solid wet product. Washing with deionized water, suction filtering to obtain wet pyrroloquinoline quinone disodium salt solid material, adding 365g of purified water into the wet pyrroloquinoline quinone disodium salt solid material to recrystallize, cooling to below 30 ℃ after the wet pyrroloquinoline quinone disodium salt solid material is finished, suction filtering to obtain 34.9g of wet pyrroloquinoline quinone disodium salt solid material, and drying the wet pyrroloquinoline quinone disodium salt solid material in an oven to obtain 15.8g of pyrroloquinoline quinone disodium salt crystal form X. The vacuum drying temperature is 55 ℃ -65 ℃ (vacuum degree 0.06 MPa). The obtained crystal X was examined and its purity was 99.91% by HPLC; according to Na ion analysis, the mass ratio of pyrroloquinoline quinone to Na contained in the crystal is pyrroloquinoline quinone: na=1: 1.97, indicating that the crystal is pyrroloquinoline quinone disodium salt. The X-ray powder diffraction pattern of this crystalline form is consistent with example 1.
Comparative example 1
Stirring and balancing the pyrroloquinoline quinone disodium salt with solvent acetonitrile at 25 ℃ and 50 ℃ for 48 hours, filtering, and drying in air for 10 minutes to obtain pyrroloquinoline quinone disodium salt crystals. The X-ray powder diffraction pattern of the obtained crystals is shown in FIG. 4, and the characteristic peaks of the obtained crystals are shown in Table 2. Consistent results were obtained when methanol was used as the solvent.
TABLE 2
Comparative example 2
60G of pyrroloquinoline quinone trisodium salt is added into a mixed solution of 500mL of water and 500mL of ethanol, hydrochloric acid is added under stirring at room temperature, and the pH is adjusted to 3.5; the time for dropwise adding hydrochloric acid is 2 hours; filtering after the pH is stable, and drying the crystals at room temperature under reduced pressure for 16 hours to obtain pyrroloquinoline quinone disodium salt crystals. The X-ray powder diffraction pattern of the obtained crystals was examined and shown in FIG. 5, and the characteristic peaks of the obtained crystals are shown in Table 3.
TABLE 3 Table 3
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Comparative example 3
Adding 1.5g of pyrroloquinoline quinone trisodium salt into 100mL of water, and carrying out heat preservation and stirring dissolution at 30 ℃ to obtain an aqueous solution; filtering to obtain filtrate, slowly adding acetic acid into the aqueous solution under stirring, adjusting the pH value to 3.0 for crystallization to obtain solid suspension, filtering, washing the solid with water to be neutral, and drying under reduced pressure at 50 ℃ for 24 hours to obtain pyrroloquinoline quinone disodium salt crystals. The X-ray powder diffraction pattern of the obtained crystals was examined and shown in FIG. 6, and the characteristic peaks of the obtained crystals were shown in Table 4.
TABLE 4 Table 4
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Experimental example
1. Hygroscopicity test:
The experimental method comprises the following steps: about 5g of the sample (obtained from the products prepared in examples 1 to 10 and comparative examples 1 to 3, respectively) was placed in a dish. The conditions of the constant temperature and humidity box are set to be the temperature of 30 ℃ and the humidity of 75% RH, and the weighed sample (W) is quickly placed into the constant temperature and humidity box with the temperature of 30 ℃ and the humidity of 75% for 48 hours and 96 hours to fully absorb moisture. After the moisture absorption is carried out for 48 hours, the materials in the surface dish are taken out and weighed into W1; and taking out the material in the surface dish after moisture absorption for 96 hours, and weighing the material to be W2. The formula for calculating the moisture absorption rate is: moisture absorption (%) = (final mass-initial mass)/initial mass×100%. The results are shown in Table 5.
TABLE 5
As can be seen from Table 5, the disodium salt crystals of comparative examples 1,2 and 3 have a certain hygroscopicity, whereas the disodium salt crystals provided by the present invention have almost no hygroscopicity under high humidity environments, thus making them more widely used.
2. Powder compaction density experiment
The compacted density of the solid powder was measured by a powder compaction densitometer and the mass per unit volume measured after compaction of the powder in the container under the specified conditions was measured in g/cm 3. The compaction density of a crystalline form compound is an important physical parameter describing the solid state density of the crystalline form compound, and is influenced by the crystal structure and chemical composition, and related to the structural characteristics, void fraction, molecular arrangement and the like, and can reflect the close-packed state inside the crystal.
The specific detection method comprises the following steps:
(1) And opening the powder compaction densimeter, and resetting the die by starting up test. The fixed parameters are set as follows: constant pressure time is 10s, mass is 1g, pumping time is 10s, and pressure is 1 ton.
(2) After completion of the zero clearing, the exact mass was weighed and placed in a mold for analytical testing of the samples (obtained from the products prepared in examples 1-10 and comparative examples 1-3). When the sample is added into the mould, the weighing paper is firstly stacked, the sample is poured into the bottom as much as possible without adhering to the wall of the mould, and the mould is placed in the experimental bin after the mould is pumped for about 10 seconds (preventing air holes from being blocked during compaction).
(3) And starting a compaction density test to obtain compaction density data. After the automatic test of the instrument is finished, the demolding mold is replaced for demolding, the mold is cleaned, and then the next sample is tested.
(4) The data of the samples tested are shown in table 6 below.
TABLE 6
| Sample of | Compaction Density (g/cm 3) |
| Example 1 | 2.13 |
| Example 2 | 2.04 |
| Example 3 | 2.01 |
| Example 4 | 2.07 |
| Example 5 | 2.10 |
| Example 6 | 1.95 |
| Example 7 | 2.04 |
| Example 8 | 2.07 |
| Example 9 | 2.01 |
| Example 10 | 1.95 |
| Comparative example 1 | 1.59 |
| Comparative example 2 | 1.48 |
| Comparative example 3 | 1.64 |
Table 6 shows the compaction densities of the pyrroloquinoline quinone disodium salt crystals prepared in each of examples and comparative examples, and according to the results, the compaction densities of the pyrroloquinoline quinone disodium salt crystals prepared in examples 1 to 10 of the present invention are all significantly higher than those of the existing disodium salt crystal forms, which indicates that the pyrroloquinoline quinone disodium salt crystals of the present invention have the following advantages: 1) The stability is good, the compaction density is high, the crystal structure is more compact and relatively more stable, the polycrystal transformation is not easy to occur, and the drug effect is ensured; 2) The fluidity is good, the compaction density is high, the fluidity of the powder can be improved, and the conveying and mixing of an industrial production line are facilitated; 3) The compressibility is good, the high-density crystal can obtain better compressibility, the preparation is facilitated, and the hardness can be higher after compression; 4) The shape retention is good, the crystal structure with large density is compact, and the preparation, especially the tablet, is not easy to break and disintegrate after being formed; the preparation uniformity is good, so that the uniform dispersion of different components is facilitated, and the separation of medicines is avoided; 5) The tabletting yield is high, and the compression density is high under the same pressure condition, so that the tabletting quantity in unit time can be improved, and the production efficiency is improved; 5) The granulation performance is good, and the high density is beneficial to improving the efficiency of wet granulation; 6) The volume required in the preparation process is smaller, the mechanical processing performance is better in the preparation process, and the size of the prepared capsule can be reduced by the higher compaction density, so that the capsule has the advantage of easy administration.
The foregoing description is only a preferred embodiment of the present application, and the present application is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present application has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (16)
1. A crystalline compound of pyrroloquinoline quinone disodium salt having a diffraction characteristic peak ：8.279、16.599、18.722、19.136、22.558、23.219、25.621、26.061、27.26、29.721、30.28、33.579、37.581、38.819、42.143、47.499, at least at the following 2Θ angles, measured by Cu-ka radiation, wherein the error of the 2Θ angle is ± 0.2 °.
2. The crystalline pyrroloquinoline quinone disodium salt compound according to claim 1, wherein the X-ray powder diffraction pattern thereof is shown in fig. 1.
3. The crystalline pyrroloquinoline quinone disodium salt compound according to claim 1, wherein the crystalline compound has two weight loss times in succession within 80-400 ℃.
4. The crystalline pyrroloquinoline quinone disodium salt compound according to claim 1, wherein the decomposition peak temperature is 308.8 ℃.
5. The crystalline pyrroloquinoline quinone disodium salt compound according to claim 1, wherein the TG/DTG curve is shown in fig. 2.
6. A process for preparing the crystalline compound of pyrroloquinoline quinone disodium salt of any one of claims 1 to 5, comprising: mixing pyrroloquinoline quinic acid and water, adding alkali at 25-30 ℃, heating to 70-80 ℃, and filtering after complete dissolution; cooling the filtrate to below 30deg.C, stirring, adjusting pH to 3.4-4.5, stopping reacting, standing, vacuum filtering to obtain wet solid material, adding purified water for recrystallization, cooling to below 30deg.C, vacuum filtering, and oven drying.
7. A process for preparing a crystalline compound of pyrroloquinoline quinone disodium salt according to any one of claims 1 to 5, characterized in that the process comprises: mixing pyrroloquinoline quinone disodium salt and water, adding alkali at 25-30 ℃, heating to 70-80 ℃, and filtering after complete dissolution; cooling the filtrate to below 20deg.C, stirring, adjusting pH to 3.4-4.5, stopping reacting, standing, vacuum filtering to obtain wet solid material, adding purified water for recrystallization, cooling to below 30deg.C, vacuum filtering, and oven drying.
8. The method according to claim 6 or 7, wherein the base is selected from sodium hydroxide, sodium bicarbonate and sodium carbonate.
9. A method according to claim 6 or 7, characterized in that the adjustment of the pH is achieved by adding dry ice or by introducing carbon dioxide.
10. The method according to claim 6 or 7, wherein the drying temperature is 50-70 ℃ and the vacuum degree is 0.06-0.08Mpa.
11. A product comprising the crystalline compound of pyrroloquinoline quinone disodium salt of any one of claims 1 to 5.
12. The product according to claim 11, wherein the product is a pharmaceutical or food product.
13. The product of claim 12, wherein the food product is a beverage.
14. Use of a crystalline pyrroloquinoline quinone disodium salt compound according to any one of claims 1 to 5 or a composition comprising a crystalline pyrroloquinoline quinone disodium salt compound according to any one of claims 1 to 5 for the preparation of a product having at least one of the following functions:
(1) Promoting the growth of microorganisms;
(2) Promoting plant growth;
(3) Oxidation resistance;
(4) Protecting the heart from oxidative damage;
(5) Preventing and treating liver injury;
(6) Promoting nerve growth and protecting nervous system;
(7) Preventing acetaldehyde poisoning; and
(8) Chelating metal ions.
15. The use according to claim 14, wherein the antioxidant means having at least one selected from the group consisting of scavenging free radicals, activating antioxidant enzymes, enhancing the synthesis of antioxidant substances and inhibiting lipid peroxidation.
16. The use according to claim 14, wherein the product comprises: food additives, foods containing the same, cosmetic additives, cosmetics containing the same, health products, feed additives, feeds containing the same, pharmaceutical carriers and chemical analysis agents.
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