CN104496955A - Five different crystal substances of dihydromyricetin - Google Patents
Five different crystal substances of dihydromyricetin Download PDFInfo
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- CN104496955A CN104496955A CN201410715828.5A CN201410715828A CN104496955A CN 104496955 A CN104496955 A CN 104496955A CN 201410715828 A CN201410715828 A CN 201410715828A CN 104496955 A CN104496955 A CN 104496955A
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- Prior art keywords
- dibydro myricetrin
- dextrorotation
- crystallization
- myricetrin
- dibydro
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- 239000013078 crystal Substances 0.000 title abstract description 50
- KJXSIXMJHKAJOD-LSDHHAIUSA-N (+)-dihydromyricetin Chemical compound C1([C@@H]2[C@H](C(C3=C(O)C=C(O)C=C3O2)=O)O)=CC(O)=C(O)C(O)=C1 KJXSIXMJHKAJOD-LSDHHAIUSA-N 0.000 title abstract description 27
- KQILIWXGGKGKNX-UHFFFAOYSA-N dihydromyricetin Natural products OC1C(=C(Oc2cc(O)cc(O)c12)c3cc(O)c(O)c(O)c3)O KQILIWXGGKGKNX-UHFFFAOYSA-N 0.000 title abstract description 14
- 239000000126 substance Substances 0.000 title abstract description 9
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 23
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 18
- 238000004458 analytical method Methods 0.000 claims abstract description 13
- 238000003109 Karl Fischer titration Methods 0.000 claims abstract 2
- DCYOADKBABEMIQ-FLCVNNLFSA-N myricitrin Natural products O([C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O1)C1=C(c2cc(O)c(O)c(O)c2)Oc2c(c(O)cc(O)c2)C1=O DCYOADKBABEMIQ-FLCVNNLFSA-N 0.000 claims description 200
- -1 myricetrin dihydrate Chemical class 0.000 claims description 118
- DCYOADKBABEMIQ-OWMUPTOHSA-N myricitrin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC1=C(C=2C=C(O)C(O)=C(O)C=2)OC2=CC(O)=CC(O)=C2C1=O DCYOADKBABEMIQ-OWMUPTOHSA-N 0.000 claims description 85
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 57
- 238000002425 crystallisation Methods 0.000 claims description 54
- 230000006340 racemization Effects 0.000 claims description 49
- 230000008025 crystallization Effects 0.000 claims description 48
- 230000003287 optical effect Effects 0.000 claims description 16
- 238000000034 method Methods 0.000 abstract description 62
- 238000002411 thermogravimetry Methods 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 11
- 238000005516 engineering process Methods 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 9
- 238000004566 IR spectroscopy Methods 0.000 abstract description 8
- 239000007787 solid Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000007791 liquid phase Substances 0.000 abstract description 5
- 238000003908 quality control method Methods 0.000 abstract description 4
- 238000012216 screening Methods 0.000 abstract description 4
- 238000005102 attenuated total reflection Methods 0.000 abstract description 2
- 239000000375 suspending agent Substances 0.000 abstract description 2
- UWVFAWALJHTHSA-UHFFFAOYSA-N 3,3,5,7-tetrahydroxy-2-(3,4,5-trihydroxyphenyl)-2H-chromen-4-one Chemical group O1C2=CC(O)=CC(O)=C2C(=O)C(O)(O)C1C1=CC(O)=C(O)C(O)=C1 UWVFAWALJHTHSA-UHFFFAOYSA-N 0.000 abstract 1
- 238000007707 calorimetry Methods 0.000 abstract 1
- 239000002552 dosage form Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000005755 formation reaction Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 150000008064 anhydrides Chemical class 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 150000004683 dihydrates Chemical class 0.000 description 10
- 150000004682 monohydrates Chemical class 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000004452 microanalysis Methods 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 235000009388 Parthenocissus quinquefolia Nutrition 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241001018563 Nekemias grossedentata Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000013068 control sample Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 241000563984 Ampelopsis Species 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000219099 Parthenocissus quinquefolia Species 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 238000002983 circular dichroism Methods 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229930003935 flavonoid Natural products 0.000 description 2
- 235000017173 flavonoids Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000010309 melting process Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 241000208231 Bursera Species 0.000 description 1
- 241000546193 Clusiaceae Species 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 241000272175 Cuculidae Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000221017 Euphorbiaceae Species 0.000 description 1
- 235000008584 Hovenia dulcis Nutrition 0.000 description 1
- 244000010000 Hovenia dulcis Species 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 241000220217 Sapotaceae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- URYYYIJUCLTKBY-UHFFFAOYSA-N cyclohexylmethyl 4-(n'-octylcarbamimidoyl)benzoate;hydrochloride Chemical compound Cl.C1=CC(C(N)=NCCCCCCCC)=CC=C1C(=O)OCC1CCCCC1 URYYYIJUCLTKBY-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930003939 flavanonol Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- 238000000207 volumetry Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 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
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- 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
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/40—Separation, e.g. from natural material; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses five crystal forms of dihydromyricetin (chemical name is 3,5,7,3',4',5' -hexahydroxy-2, 3-dihydroflavonol; English name is dihydromyricetin or Ampelopsin). The invention adopts a chiral resolution method of a chiral resolution method and a chiral resolution method of a high performance liquid phase to characterize the three-dimensional configuration of dihydromyricetin. The method has the advantages that the solid state analysis technology including powder X-ray diffraction technology (XRD), differential calorimetry (DSC), thermogravimetric analysis (TGA), Karl Fischer titration and Fourier transform attenuated total reflection infrared spectroscopy (FT-ATR) is utilized to characterize the crystal form of the dihydromyricetin, and the method has important significance in carrying out polycrystalline screening on the dihydromyricetin to the development of the process of raw material medicines, the development of solid preparations, semi-solids, suspending agents and other dosage forms and the quality control.
Description
Technical field
The present invention relates to medical art, refer to a kind of dibydro myricetrin five kinds of different crystal forms materials particularly
Background technology
Dibydro myricetrin (Dihydromyricelin), also known as ampelopsin (Ampelopsin), first to be separated from the leaf of ampelopsis A. Meliaefolia (Ampelopsis meliaefolia) in 1940 by Kotake with Kubota and to obtain, be a kind of flavanonol flavonoids, chemical structure is 3,5,7,3', 4', 5'-hexahydroxy--2,3-flavanonol.Dibydro myricetrin is extensively present in Stem or leaf of Amur Ampelopsis section ampelopsis, is also present in the section plants such as Myruca ceas, Cuculidae, guttiferae, Euphorbiaceae, Bursera family, pulse family, Sapotaceae and Liu Ke.
Dibydro myricetrin is white or faint yellow needle crystal, and water-soluble poor (0.2mg/ml, 25 DEG C), are soluble in hot water, in ethanol, methyl alcohol, acetone and DMSO.Under aqueous solution heated condition, chemical stability is poor, has good chemical stability under its solid state.
There are two chiral centres in dibydro myricetrin molecule steric-configuration, two kinds of dibydro myricetrin configurations have been included in Pubchem compound database, be respectively (2R, 3R) configuration and (2R, 3S) configuration, its absolute configuration can distinguish corresponding dextrorotation, left-handed and racemization dibydro myricetrin.It is given tacit consent to for (2R, 3R) configuration in existing most literature report, as follows,
The dibydro myricetrin structure of (2R, 3R) configuration
Compound steric configuration particularly chiral centre may affect the validity of compound, toxicity and clinical efficacy, and the stability of compound also may be relevant with it.
Under prior art level, when there is chiral centre in compound, the absolute configuration at compound chirality center often adopts single crystal X-ray diffraction and circular dichroism method to determine, chiral separation or specific rotation method can distinguish (+) and (±) dibydro myricetrin.
Existing document (1. Yoo S M at present, Mun S, Kim J H.Recovery and pre-purification of (+)-dihydromyricetin from Hovenia dulcis [J] .Process biochemistry, 2006, 41 (3): 567-570. 2. Du Q, Cai W, Xia M, et al.Purification of (+)-dihydromyricetin from leaves extract of Ampelopsis grossedentata using high-speed countercurrent chromatograph with scale-up triple columns [J] .Journal of Chromatography A, 2002, 973 (1): 217-220. 3. Gao J, Liu B, Ning Z, et al.Characterization and antioxidant activity of flavonoid-rich extracts from leaves of Ampelopsis grossedentata [J] .Journal of food biochemistry, 2009, 33 (6): 808-820.) etc. report crystallisation by cooling in the dibydro myricetrin aqueous solution or aqueous ethanolic solution to separate out as racemic product.Many in meso configuration through measuring commercial samples, consistent with above bibliographical information result.
According to polymorphous definition in Chinese Pharmacopoeia " Quality Control Technology of polymorphic medicine and guide for method principle " exposure draft, hydrate or solvate all belong to polymorph in pharmaceuticals category.Polymorph in pharmaceuticals may cause solubleness, the difference of the aspect such as stability and mechanical properties, affects clinical drug curative effect and preparation technology, therefore needs to keep a close eye under study for action, but present stage has no the report about the screening of dibydro myricetrin crystal formation.In multiple commercial samples, dibydro myricetrin is the crystalline substance with racemization structure dihydrate after measured.
Crystal water is completely different from the planar water of plane of crystal, surface adsorption water easily loses, and formation planar water is the compound of about 400 for molecular weight, weight changes≤0.5%, substantially compound property is not affected, planar water has a certain impact to the reunion of powder and mobility tool, and too high planar water content may cause compound deliquescence.And crystal water directly can change compound crystal structure, >=2% is changed to the weight of compound, may cause compound solubility or stability that larger change occurs, generally speaking, the solubleness of hydrate is less than anhydride, crystal of hydrate in aqueous stability generally higher than anhydride.
At document (Xu, Z., Liu, B., Ning, Z., & Zhang, Y..Racemic dihydromyricetin dihydrate.Acta Crystallographica Section E:Structure Reports Online, 63.11 (2007): 4384.) obtain dibydro myricetrin monocrystalline by crystallisation by cooling legal system in, and its structure is the dihydrate of racemization to adopt Single Crystal X-ray result to show.
In research dibydro myricetrin polymorphous document (Lin Shuying. the extraction purification of dibydro myricetrin and anti-oxidant activity research [D] in Ampelopsis grossedentata. South China Science & Engineering University, 2004), author has investigated the crystal formation of 60% ethanol and the acquisition of aqueous solution crystallisation by cooling, in the XRD result of showing, X-coordinate is that d value is obviously different from the XRD in the present invention, author thinks and obtains two kinds of different crystal formations in addition, but employing microscope is taken pictures, result only can be judged as that crystal habit is different, cannot draw the conclusion of " dibydro myricetrin exists polymorphic " in this article.
At document (Ruan L P, Yu B Y, Fu G M, et al.Improving the solubility of ampelopsin by solid dispersions and inclusion complexes [J] .Journal of Pharmaceutical and Biomedical Analysis, 2005,38 (3): 457-464.) the dibydro myricetrin raw material mentioning use in is dihydrate, but is not described with regard to crystalline structure and compound steric configuration.
Document (Li Yingqi. Yao nationality's vine tea quality standard and main active ingredient pharmacokinetic study [D]. Shenyang Pharmaceutical University, 2003.) in, dihydromyricetin is the dibydro myricetrin mentioned in this patent, author is have employed multinomial means to during dibydro myricetrin structural identification, comprise circular dichroism, be confirmed that it is (2R, 3R) configuration, but do not provide with regard to its crystalline structure and illustrate, only illustrate that it is white, needle-shaped crystals and provides infrared spectrogram.But owing to there is more hydrogen bond in dibydro myricetrin molecule, can be formed in molecule and intermolecular hydrogen bonding, also may contain crystal water, only from compound at 3300cm
-1there is broad peak in place, cannot show its crystalline structure.
Summary of the invention
Technical problem to be solved by this invention just there is provided dibydro myricetrin five kinds of different crystal forms materials.
Adopt specific rotation method and chiral reagent to split in the present invention to differentiate the compound structure type of dibydro myricetrin, (+) and (±) dibydro myricetrin raw material is utilized to carry out screening polymorph respectively, adopt solid-state analytical technology as powder x-ray diffraction, differential calorimetric scan, Karl_Fischer method, thermogravimetric analysis and Fourier Transform Attenuated Total Reflect ion Infrared Spectroscopy are analyzed gained crystal formation.Through confirmation, at least there are 5 kinds of crystal formations in dibydro myricetrin, 5 kinds of crystal formations there are differences in stability and solubleness.
For solving the problems of the technologies described above, the dibydro myricetrin dihydrate crystallization of a kind of dextrorotation provided by the invention, uses polarimeter to record its specific optical rotation [α]
d=+32 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak:
6.63°,8.07°,9.51°,11.50°,13.26°,16.08°,18.72°,27.20°,28.58°,28.88°。
Further, described dextrorotation dibydro myricetrin dihydrate is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3375,3334,3200cm
-1.
Again further, described dextrorotation dibydro myricetrin dihydrate adopts Karl_Fischer method to measure wherein moisture content is 10.1 ± 0.3% (n=3, n are experiment number, lower same).
Present invention also offers the crystallization of a kind of dextrorotation dibydro myricetrin anhydride, use polarimeter to record its specific optical rotation [α]
d=+36 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak:
7.27°,9.69°,11.07°,15.76°,22.74°,26.97°。
Further, the dibydro myricetrin anhydride crystallization of described dextrorotation is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3581,3399,3220cm
-1.
Again further, described dextrorotation dibydro myricetrin anhydride moisture content adopts Karl_Fischer method mensuration to be less than 0.3% (n=3).
Present invention also offers a kind of dibydro myricetrin hydrate crystallization of dextrorotation, use polarimeter to record its specific optical rotation [α]
d=+34 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak:
9.98°,11.36°,13.20°,14.52°,22.74°,22.82°,28.32°。
Further, described dibydro myricetrin hydrate crystallization is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3568,3293,3083cm
-1.
Again further, described dextrorotation dibydro myricetrin monohydrate adopts Karl_Fischer method to measure wherein moisture content 5.30 ± 0.2%.
Present invention also offers a kind of dibydro myricetrin anhydride crystallization of racemization, use polarimeter to record its specific optical rotation [α]
d=0 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak:
10.02°,13.82°,14.50°,16.08°,21.22°,23.54°,25.32°,25.85°,26.72°,26.79°。
Further, the dibydro myricetrin anhydride crystallization of described racemization is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3581,3399,3220cm
-1.
Again further, the dibydro myricetrin anhydride crystallization of described racemization adopts Karl_Fischer method to measure wherein moisture content and be less than 0.4%.
Present invention also offers a kind of dibydro myricetrin hydrate crystallization of racemization, use polarimeter to record its specific optical rotation [α]
d=0 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak:
7.97°,10.01°,11.17°,14.49°,16.70°,25.82°,26.73°。
Further, the dibydro myricetrin hydrate crystallization of described racemization is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3568,3293,3083cm
-1.
Again further, moisture content 5.31 ± 0.5% in the dibydro myricetrin hydrate crystallization of described racemization.
In the present invention, the preparation method of dibydro myricetrin five kinds of different crystal forms materials all belongs to prior art,
The method that the present invention prepares dibydro myricetrin dihydrate comprises crystallisation by cooling method, antisolvent crystallization method, volatilization crystallization process, crystal seed revulsion, solvent rotating crystal method and solid-state rotating crystal method.
Described crystallisation by cooling method be utilize dibydro myricetrin in a solvent solubility with temperature change greatly and design, utilize high-temperature digestion, during cooling, crystallization obtains dibydro myricetrin crystallization.By changing solvent in this process, adding crystal seed or changing rate of temperature fall and control technique, solvent can be water, ethanol, one or more the mixed solvent such as methyl alcohol, acetonitrile.
Described antisolvent crystallization method refers to dibydro myricetrin to be dissolved in have (dibydro myricetrin solubleness > 1mg/ml) in the A solvent of higher solubility, add again and have in a large number compared with low solubility and the B solvent miscible with A solvent (dibydro myricetrin solubleness < 0.2mg/ml), dibydro myricetrin crystallization can be obtained.This technological process, by changing solvent orange 2 A and B kind or volume, changes the speed adding B solvent and controls technique.Wherein A solvent can be in the mixed solvent of DMSO, methyl alcohol, acetonitrile, formic acid, ethanol, DMF and above-mentioned two or more arbitrary proportions of solvent thereof, and B solvent can be cold water etc.
Described volatilization crystallization process refers to dibydro myricetrin to be dissolved in have in volatile solvent, and dibydro myricetrin solubleness > 1mg/ml in a solvent, the slowly obtained dibydro myricetrin crystallization of volatilization.This technological process is by changing solvent species and volume, and rate of volatilization controls, and wherein solvent can be single solvent or arbitrary ratio mixed solvents such as ethanol, methyl alcohol, acetonitrile.
Described solvent rotating crystal method refers to gets dibydro myricetrin raw material, can be anhydride, monohydrate or amorphous state, add in solvent, maintenance solution is suspension, constantly stirs, separate out after the transformation of crystal mediated by generation solvent or dissolution with solvents, and then obtaining dibydro myricetrin crystallization, this technique is by changing solvent volume, water-activity, temperature and stirring velocity are with Controlling Technology, and solvent can the single or mixed solvent such as water and DMSO, methyl alcohol, acetonitrile, formic acid, ethanol, DMF.
Described solid-state rotating crystal method refers to dibydro myricetrin crystallization, can be anhydride and monohydrate, under being positioned over certain temperature and humidity environment, solid-state dibydro myricetrin is by the moisture in the absorption external world, and water molecules is combined with crystalline state dibydro myricetrin and generates dibydro myricetrin dihydrate.This technological process is by changing the crystalline structure of initial feed, and envrionment temperature and humidity, storage period is controlled.
The method that the present invention prepares dibydro myricetrin anhydride comprises heating method and polishing.
Described heating method refers to dibydro myricetrin raw material, can be dihydrate and monohydrate, compound is warming up to comparatively high temps, heating is continued after losing crystal water, dibydro myricetrin anhydride crystalline state changes, can occur to turn brilliant because dibydro myricetrin heating loses crystal water continuation heating, high temperature should at about 180 DEG C to obtain the stable anhydride crystallization of dibydro myricetrin.This technique can change temperature and heat-up time controls.
The method that the present invention prepares dibydro myricetrin monohydrate comprises crystallisation by cooling method and volatilization crystallization process
Described volatilization crystallization process refers to dibydro myricetrin, can be dihydrate and monohydrate, be dissolved in and a kind of there is (dibydro myricetrin solubleness > 1mg/ml) in the solvent of higher solubility, slowly evaporate into crystallization, obtain crystallization.This technique is by feed change crystal formation, and solvent species and volume, rate of volatilization is controlled.Wherein solvent can be the mixed solvent of water and ethanol.
According to Chinese Pharmacopoeia " Quality Control Technology of polymorphic medicine and guide for method principle " exposure draft, original new drug is when developing the preparation containing solid, if drug crystal forms can affect drug quality, the quantitative and qualitative analysis that must carry out crystal formation controls.Consider dihydromyricetin cellulose solution oral after absorption in vivo rapid, solid-state dibydro myricetrin probably causes bioavailability on the low side because solubleness is less than normal, crystal formation often directly affects stability and the solubleness of solid-state drug, and it is that the formulation developments such as bulk drug process exploitation, solid preparation, semisolid, suspension agent and quality control are significant that the present invention has carried out screening polymorph to dibydro myricetrin.
Accompanying drawing explanation
Fig. 1 is the dibydro myricetrin dihydrate of dextrorotation and the liquid chromatogram of commercial samples;
Fig. 2 is the XRD diffractogram of dextrorotation dibydro myricetrin dihydrate;
Fig. 3 is the differential calorimetric scan figure of dextrorotation dibydro myricetrin dihydrate;
Fig. 4 is the thermogravimetric analysis figure of dextrorotation dibydro myricetrin dihydrate;
Fig. 5 is the infrared spectrogram of dextrorotation dibydro myricetrin dihydrate;
Fig. 6 is the liquid chromatogram of dextrorotation dibydro myricetrin anhydride;
Fig. 7 is the XRD diffractogram of dextrorotation dibydro myricetrin anhydride;
Fig. 8 is the differential calorimetric scan figure of dextrorotation dibydro myricetrin anhydride;
Fig. 9 is the thermogravimetric analysis figure of dextrorotation dibydro myricetrin anhydride;
Figure 10 is the infrared spectrogram of dextrorotation dibydro myricetrin anhydride;
Figure 11 is the liquid chromatogram of dextrorotation dibydro myricetrin monohydrate;
Figure 12 is the XRD diffractogram of dextrorotation dibydro myricetrin monohydrate;
Figure 13 is the differential calorimetric scan figure of dextrorotation dibydro myricetrin monohydrate;
Figure 14 is the thermogravimetric analysis figure of dextrorotation dibydro myricetrin monohydrate;
Figure 15 is the infrared spectrogram of dextrorotation dibydro myricetrin monohydrate;
Figure 16 is the liquid chromatogram of the dibydro myricetrin anhydride of racemization;
Figure 17 is the XRD diffractogram of the dibydro myricetrin anhydride of racemization;
Figure 18 is the differential calorimetric scan figure of the dibydro myricetrin anhydride of racemization;
Figure 19 is the thermogravimetric analysis figure of the dibydro myricetrin anhydride of racemization;
Figure 20 is the infrared spectrogram of the dibydro myricetrin anhydride of racemization;
Figure 21 is the liquid chromatogram of the dibydro myricetrin monohydrate of racemization;
Figure 22 is the XRD diffractogram of the dibydro myricetrin monohydrate of racemization;
Figure 23 is the differential calorimetric scan figure of the dibydro myricetrin monohydrate of racemization;
Figure 24 is the thermogravimetric analysis figure of the dibydro myricetrin monohydrate of racemization;
Figure 25 is the infrared spectrogram of the dibydro myricetrin monohydrate of racemization;
Embodiment
In order to explain the present invention better, illustrate main contents of the present invention further below in conjunction with specific embodiment, but content of the present invention is not only confined to following examples.
The preparation of embodiment 1 dextrorotation dibydro myricetrin dihydrate
Get the dextrorotation dibydro myricetrin raw material of about 200mg, can be anhydride or monohydrate, be dissolved in the aqueous solution of 2ml90-100 DEG C, insulation is filtered, after removing filter residue, solution is naturally cooled to crystallization after room temperature, obtained dextrorotation dibydro myricetrin dihydrate.
The preparation of embodiment 2 dextrorotation dibydro myricetrin anhydride
Get the dextrorotation dibydro myricetrin raw material of about 200mg, can be dihydrate and monohydrate, at temperature is 160 DEG C, places 1h, dibydro myricetrin anhydride can be obtained.
The preparation of embodiment 3 dextrorotation dibydro myricetrin monohydrate
Get the dextrorotation dibydro myricetrin raw material of about 200mg, can be dihydrate and anhydride, be dissolved in the ethanolic soln of high density, slowly evaporate into crystallization, dextrorotation dibydro myricetrin monohydrate can be obtained.
The preparation of the dibydro myricetrin anhydride of embodiment 4 racemization
Get the racemization dibydro myricetrin raw material of about 200mg, can be dihydrate and monohydrate, at temperature is 160 DEG C, places 1h, dibydro myricetrin anhydride can be obtained.
The preparation of the dibydro myricetrin monohydrate of embodiment 5 racemization
Get the racemization dibydro myricetrin raw material of about 200mg, can be dihydrate and anhydride, be dissolved in the ethanolic soln of high density, slowly evaporate into crystallization, dextrorotation dibydro myricetrin monohydrate can be obtained.
Dibydro myricetrin five kinds of different crystal forms materials of above-mentioned preparation are carried out Performance Detection
1, analytical procedure:
1.1 specific rotation methods
WZZ-1 indicates polarimeter automatically, Shanghai Physics Optics Instrument Factory.
In the mensuration stage, get dibydro myricetrin crystal-form substances 5.00g and be dissolved in 25ml DMSO, measure solution specific rotation, can specific optical rotation be calculated.
1.2 Chiral Resolution in High Performance Liquid Chromatography methods
Adopt Waters e2695 high performance liquid chromatograph, C18 silica gel chromatographic column, with methyl alcohol: beta-cyclodextrin solution (wherein beta-cyclodextrin 18g, phosphatase 11 0ml, adds water to 1000ml), flow velocity is 1ml/min, column temperature 30 DEG C.Determined wavelength 290nm.
1.3 elemental microanalysis method
CHNSO elemental analyser (Vario EL111)
1.4 karl Fischer aquametries
Instrument: superfinishing science and technology SKF1 (A) karl Fischer moisture content tester
In the mensuration stage, get 100-200mg dibydro myricetrin crystal-form substances powder, to terminal, the amount of moisture of record display, calculates the moisture content in powder to instrument automatic Titration at every turn.
1.5 powder X-ray diffractometry
Instrument: Dutch PANalytical company PANalytical B.V.
Target: Cu-K α radiation
Wavelength: 1.5406A
Pipe pressure: 40KV
Guan Liu: 40mA
Step-length: 0.02 °
Sweep limit: 5-45 °
Sweep velocity: 8 °/min
In the mensuration stage, after rectifying an instrument, get dibydro myricetrin crystal-form substances powder (D
50< 100 μm) put into sample determination pond, after using glass slide pressed powder extremely in plane, put into instrument and measure.
1.6 difFerential scanning calorimetry
Instrument: platinum-Ai Ermo instrument (Shanghai) Co., Ltd. (PerkinElmer Instruments) Diamond DSC
Scope 30-270 DEG C
Heat-up rate 10 DEG C/min
N
2flow velocity: 50ml/min
1.7 thermogravimetry
Instrument: platinum-Ai Ermo instrument (Shanghai) Co., Ltd. (PerkinElmer Instruments) model Pyris1TGA
Scope 30-500 DEG C
Heat-up rate 10 DEG C/min
N
2flow velocity: 50ml/min
1.8 infrared spectroscopy
Instrument: German Bruker company VERTEX 70
Sweep limit: 450cm
-1-4000cm
-1
Resolving power: 4cm
-1
2, the dibydro myricetrin dihydrate of dextrorotation
2.1 specific rotation methods
Get dibydro myricetrin 5.00g, be dissolved in the DMSO solution of 25ml, recording self-control sample specific rotation is 6.491 ± 0.013 ° (n=5), specific optical rotation [α]
d=+32 °.
2.2 Chiral Resolution in High Performance Liquid Chromatography methods
Commercial samples is bimodal as shown in Figure 1, and namely show that it is racemic product, the dibydro myricetrin dihydrate of dextrorotation is unimodal, and shows that it is dextrorotation dibydro myricetrin purity >=98% in dextrorotation dibydro myricetrin dihydrate.
2.3 elemental microanalysis method
C:H:O=50.52%:4.50%:44.98% in dextrorotation dibydro myricetrin dihydrate, namely molecular formula should be C
15h
16o
10, i.e. C
15h
12h
82H
2o.
2.4 karl Fischer volumetrys
Recording moisture content in the dibydro myricetrin dihydrate of dextrorotation through titration is 10.1 ± 0.3% (n=3), i.e. the moisture of corresponding 2 molecules.
2.5 powder X-ray diffractometry
The XRD diffractogram (as shown in Figure 2) of dextrorotation dibydro myricetrin dihydrate and corresponding peak value thereof see the following form 1
2.6 difFerential scanning calorimetry
Dextrorotation dibydro myricetrin dihydrate 109 DEG C (peak values, lower with), 152 DEG C and 252 DEG C there is endotherm(ic)peak, there is exothermic peak at 192 DEG C.Wherein 252 DEG C is crystalline state melting process, and 109 DEG C and 152 DEG C of corresponding stages are and lose crystal water process (Fig. 3).
2.7 thermogravimetry
Namely dihydrate starts to lose crystal water at 60 DEG C, loses completely at 150 DEG C of crystal water.Reach 252 DEG C dissolve after, dibydro myricetrin molecule there occurs decomposition (Fig. 4) along with temperature raises further.
2.8. infrared spectroscopy
Be 3000-3500cm because intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number
-1between, 3375,3334,3200cm dextrorotation dibydro myricetrin dihydrate has following characteristics peak in this interval:
-1(Fig. 5).
3, dextrorotation dibydro myricetrin anhydride
3.1 specific rotation methods
Get dextrorotation dibydro myricetrin anhydride 5.00g, be dissolved in the DMSO solution of 25ml, recording self-control sample specific rotation is 7.221 ± 0.015 ° (n=5), specific optical rotation [α]
d=+36 °.
3.2 Chiral Resolution in High Performance Liquid Chromatography methods
High performance liquid phase chiral separation is adopted to show that it is dibydro myricetrin purity >=98% (Fig. 6) of dextrorotation in dextrorotation dibydro myricetrin anhydride.
3.3 elemental microanalysis method
Dextrorotation dibydro myricetrin anhydride C:H:O=56.26%:3.74%:40.00%, namely molecular formula should be C
15h
12o
8.
4. karl Fischer aquametry
Record dextrorotation dibydro myricetrin anhydride moisture content and be less than 0.3% (n=3).
5. powder X-ray diffractometry
The XRD diffractogram (Fig. 7) of dextrorotation dibydro myricetrin anhydride and corresponding peak value thereof see the following form 2
3.6 difFerential scanning calorimetry
Dextrorotation dibydro myricetrin anhydride fusing point is 253.9 DEG C (with peak meters), there is not any heat absorption and release peak (Fig. 8) in the process of the heating lower than its fusing point.
3.7 thermogravimetry
Dextrorotation dibydro myricetrin anhydride is within the scope of 60-240 DEG C, and heating can not any weight of less loss, reaches 252 DEG C of crystal and dissolve, and continues heating dibydro myricetrin molecule and there occurs decomposition (Fig. 9).
3.8 infrared spectroscopy
Be 3000-3500cm because intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number
-1between, 3581,3399,3220cm anhydride has following characteristics peak:
-1(Figure 10).
4, dextrorotation dibydro myricetrin monohydrate
4.1 specific rotation methods
Get dextrorotation dibydro myricetrin monohydrate 5.00g, be dissolved in the DMSO solution of 25ml, recording dextrorotation dibydro myricetrin monohydrate specific rotation is 6.835 ± 0.020 ° (n=5), specific optical rotation [α]
d=+34 °.
4.2 Chiral Resolution in High Performance Liquid Chromatography methods
High performance liquid phase chiral separation is adopted to show that it is dibydro myricetrin purity >=98% (Figure 11) of dextrorotation in dextrorotation dibydro myricetrin monohydrate.
4.3 elemental microanalysis method
Record dextrorotation dibydro myricetrin monohydrate C:H:O=53.25%:4.14%:42.61%, namely molecular formula should be C
15h
14o
9.
4.4 karl Fischer aquametries
Record moisture content 5.30 ± 0.2% in dextrorotation dibydro myricetrin monohydrate.
4.5 powder X-ray diffractometry
The XRD diffractogram (Figure 12) of dextrorotation dibydro myricetrin monohydrate and corresponding peak value thereof see the following form 3
4.6 difFerential scanning calorimetry
Dextrorotation dibydro myricetrin monohydrate has 3 endotherm(ic)peaks in measuring, peak value corresponding 116.80 DEG C, 146.78 DEG C and 252.72 DEG C respectively, wherein 116.80 DEG C of correspondences lose a part crystal water, the change of 146.78 DEG C of corresponding crystalline state, the fusing point (Figure 13) of 252.72 DEG C of corresponding dibydro myricetrin anhydrides.
4.7 thermogravimetry
Dextrorotation dibydro myricetrin monohydrate is within the scope of 60-240 DEG C, and less loss weight is about 5%, i.e. corresponding a part crystal water, reach 252 DEG C dissolve after, dibydro myricetrin molecule there occurs decomposition (Figure 14).
4.8 infrared spectroscopy
Be 3000-3500cm because intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number
-1between, 3568,3293,3083cm dextrorotation dibydro myricetrin monohydrate has following characteristics peak:
-1(Figure 15).
5, the dibydro myricetrin anhydride of racemization
5.1 specific rotation methods
Cancel and revolve dibydro myricetrin anhydride 5.00g, be dissolved in the DMSO solution of 25ml, the dibydro myricetrin anhydride specific rotation recording racemization is 0 °, specific optical rotation [α]
d=0 °.
5.2 Chiral Resolution in High Performance Liquid Chromatography methods
High performance liquid phase chiral separation is adopted to show that racemization dibydro myricetrin anhydride exists two peaks, and two peak areas are substantially equal, knownly record the reason that specific rotation is 0, be the dextrorotation dibydro myricetrin containing equivalent and left-handed dibydro myricetrin (Figure 16).
5.3 elemental microanalysis method
The dibydro myricetrin anhydride C:H:O=56.27%:3.75%:39.98% of racemization, namely molecular formula should be C
15h
12o
8.
5.4 karl Fischer aquametries
Record moisture content in the dibydro myricetrin anhydride of racemization and be less than 0.4%.
5.5. the XRD diffractogram (Figure 17) of the dibydro myricetrin monohydrate of powder X-ray diffractometry racemization and corresponding peak value thereof see the following form 4
5.6 difFerential scanning calorimetry
The dibydro myricetrin anhydride of racemization only has an endotherm(ic)peak, corresponding crystal melting process, and fusing point is 253.9 DEG C of (with peak meter) (Figure 18).
5.7 thermogravimetry
The dibydro myricetrin anhydride of racemization within the scope of 60-240 DEG C, weight without less loss, reach 252 DEG C dissolve after, dibydro myricetrin molecule there occurs decomposition (Figure 19).
5.8 infrared spectroscopy
Be 3000-3500cm because intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number
-1between, 3581,3399,3220cm anhydride has following characteristics peak:
-1(Figure 20).
6., the dibydro myricetrin monohydrate of racemization
6.1 specific rotation methods
Cancel and revolve dibydro myricetrin monohydrate 5.00g, be dissolved in the DMSO solution of 25ml, recording self-control sample specific rotation is 0 °, specific optical rotation [α]
d=0 °.
6.2 Chiral Resolution in High Performance Liquid Chromatography methods
High performance liquid phase chiral separation is adopted to show that racemization dibydro myricetrin monohydrate exists two peaks, and two peak areas are substantially equal, its specific rotation known is the reason of 0, is dextrorotation dibydro myricetrin and the left-handed dibydro myricetrin (Figure 21) that possible contain equivalent.
6.3 elemental microanalysis method
The dibydro myricetrin monohydrate C:H:O=53.23%:4.15%:42.62% of racemization, namely molecular formula should be C
15h
14o
9, i.e. C
15h
12o
8h
2o.
6.4. karl Fischer aquametry
Record the dibydro myricetrin monohydrate moisture content 5.31 ± 0.1% of racemization.
6.5 powder X-ray diffractometry
The XRD diffractogram (Figure 22) of dextrorotation dibydro myricetrin monohydrate and corresponding peak value thereof see the following form 5
6.6 difFerential scanning calorimetry
After the dibydro myricetrin monohydrate thing of racemization loses crystal water, fusing point is 253.9 DEG C of (with peak meter) (Figure 23).
6.7 thermogravimetry
The dibydro myricetrin monohydrate of racemization is within the scope of 60-240 DEG C, and less loss weight is about 5%, i.e. corresponding a part crystal water, reach 252 DEG C dissolve after, dibydro myricetrin molecule there occurs decomposition (Figure 24).
6.8 infrared spectroscopy
Be 3000-3500cm because intramolecular hydrogen bond and intermolecular hydrogen bonding can be reflected in wave number
-1between, 3568,3293,3083cm monohydrate has following characteristics peak:
-1, basically identical with the dibydro myricetrin of dextrorotation (Figure 25).
7, the water absorbability of dibydro myricetrin five kinds of crystal formations compares
Adopt saturated salt solution in sealed vessel 25 DEG C of obtained different humidity, be respectively: 11% (lithium chloride), 23% (potassium oxalate), 33% (magnesium chloride), 43% (salt of wormwood), 52% (magnesium nitrate), 67% (cupric chloride), 75% (sodium-chlor), 86% (Repone K), 93% (magnesium nitrate).Get obtained dibydro myricetrin dihydrate, anhydride and monohydrate respectively, often kind of crystal formation gets 3 parts, and every increment product are 200-300mg, are positioned in the flat measuring bottle of known weight.Flat measuring bottle is put into sealed vessel, place and weigh after 3 days, the humidity that different crystal forms starts to absorb water can be obtained after analytical data, five kinds of crystal formations are respectively: dextrorotation dibydro myricetrin dihydrate > 93%, dextrorotation dibydro myricetrin anhydride and racemization dibydro myricetrin anhydride are 23%, and the dibydro myricetrin monohydrate of dextrorotation dibydro myricetrin monohydrate and racemization is 33%.
Other unspecified part is prior art.Although above-described embodiment is to invention has been detailed description; but it is only the present invention's part embodiment; instead of whole embodiment, people can also obtain other embodiments according to the present embodiment under without creative prerequisite, and these embodiments all belong to scope.
Claims (15)
1. a dextrorotation dibydro myricetrin dihydrate crystallization, is characterized in that: its specific optical rotation [α]
d=+32 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak: 6.63 °, 8.07 °, 9.51 °, 11.50 °, 13.26 °, 16.08 °, 18.72 °, 27.20 °, 28.58 °, 28.88 °.
2. dextrorotation dibydro myricetrin dihydrate according to claim 1 crystallization, is characterized in that: described dextrorotation dibydro myricetrin dihydrate is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3375,3334,3200cm
-1.
3. dextrorotation dibydro myricetrin dihydrate according to claim 1 and 2 crystallization, is characterized in that: adopt karl Fischer titration measuring moisture content to be 10.1 ± 0.3% in the dibydro myricetrin dihydrate of described dextrorotation.
4. a dextrorotation dibydro myricetrin anhydride crystallization, is characterized in that: its specific optical rotation [α]
d=+36 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak: 7.27 °, 9.69 °, 11.07 °, 15.76 °, 22.74 °, 26.97 °.
5. the dibydro myricetrin anhydride crystallization of dextrorotation according to claim 4, is characterized in that: the dibydro myricetrin anhydride crystallization of described dextrorotation is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3581,3399,3220cm
-1.
6. the dibydro myricetrin anhydride crystallization of described dextrorotation according to claim 4 or 5, is characterized in that: described dextrorotation dibydro myricetrin anhydride moisture content is less than 0.3%.
7. a dibydro myricetrin hydrate crystallization for dextrorotation, is characterized in that: its specific optical rotation [α]
d=+34 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak: 9.98 °, 11.36 °, 13.20 °, 14.52 °, 22.74 °, 22.82 °, 28.32 °.
8. the dibydro myricetrin hydrate crystallization of dextrorotation according to claim 7, is characterized in that: described dibydro myricetrin hydrate crystallization is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3568,3293,3083cm
-1.
9. the dibydro myricetrin hydrate crystallization of dextrorotation according to claim 7 or 8, is characterized in that: moisture content 5.30 ± 0.2% in described dextrorotation dibydro myricetrin monohydrate.
10. a dibydro myricetrin anhydride crystallization for racemization, is characterized in that: its specific optical rotation [α]
d=0 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak: 10.02 °, 13.82 °, 14.50 °, 16.08 °, 21.22 °, 23.54 °, 25.32 °, 25.85 °, 26.72 °, 26.79 °.
The dibydro myricetrin anhydride crystallization of 11. racemizations according to claim 10, is characterized in that: the dibydro myricetrin anhydride crystallization of described racemization is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3581,3399,3220cm
-1.
The dibydro myricetrin anhydride crystallization of 12. racemizations according to claim 10 or 11, is characterized in that: in the dibydro myricetrin anhydride crystallization of described racemization, moisture content is less than 0.4%.
The dibydro myricetrin hydrate crystallization of 13. 1 kinds of racemizations, is characterised in that: its specific optical rotation [α]
d=0 ° [c 0.20, DMSO, 20 DEG C], uses powder x-ray diffraction (XRD) analysis, adopts CuK
αradiation, diffraction peak position 2-Theta (5-45 °), has following characteristic peak: 7.97 °, 10.01 °, 11.17 °, 14.49 °, 16.70 °, 25.82 °, 26.73 °.
14., according to the dibydro myricetrin hydrate crystallization of racemization described in claim 13, is characterized in that: the dibydro myricetrin hydrate crystallization of described racemization is 3000-3500cm in wave number
-1interval in there is following characteristics peak: 3568,3293,3083cm
-1.
The dibydro myricetrin hydrate crystallization of 15. racemizations according to claim 13 or 14, is characterized in that: moisture content 5.31 ± 0.1% in the dibydro myricetrin hydrate crystallization of described racemization.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610277620.9A CN106008438A (en) | 2014-12-01 | 2014-12-01 | Racemic dihydromyricetin anhydride crystal |
| CN201610390126.3A CN106083792A (en) | 2014-12-01 | 2014-12-01 | dextrorotatory dihydromyricetin monohydrate crystal |
| CN201410715828.5A CN104496955A (en) | 2014-12-01 | 2014-12-01 | Five different crystal substances of dihydromyricetin |
| CN201610277767.8A CN106008439A (en) | 2014-12-01 | 2014-12-01 | Racemic dihydromyricetin monohydrate crystal |
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| CN201610277767.8A Pending CN106008439A (en) | 2014-12-01 | 2014-12-01 | Racemic dihydromyricetin monohydrate crystal |
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| CN104628695A (en) * | 2015-02-05 | 2015-05-20 | 华中科技大学同济医学院附属同济医院 | Method for controlling racemization rate of dihydromyricetin |
| CN105241982A (en) * | 2015-09-30 | 2016-01-13 | 广东研捷医药科技有限公司 | Chiral chromatographic separation and analysis method of dihydromyricetin enantiomer |
| CN110054606A (en) * | 2019-06-05 | 2019-07-26 | 闽江学院 | A kind of dihydromyricetin-Halomine pharmaceutical co-crystals and preparation method |
| CN113121486A (en) * | 2021-03-15 | 2021-07-16 | 宁波大学 | Single-configuration extraction method of dihydromyricetin |
| CN113155882A (en) * | 2021-03-15 | 2021-07-23 | 宁波大学 | Chiral identification method for enantiomer of dihydromyricetin |
| CN114404369A (en) * | 2022-03-08 | 2022-04-29 | 陕西科技大学 | Dihydromyricetin nanocrystal and preparation method and application thereof |
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| CN104628695A (en) * | 2015-02-05 | 2015-05-20 | 华中科技大学同济医学院附属同济医院 | Method for controlling racemization rate of dihydromyricetin |
| CN105241982A (en) * | 2015-09-30 | 2016-01-13 | 广东研捷医药科技有限公司 | Chiral chromatographic separation and analysis method of dihydromyricetin enantiomer |
| CN105241982B (en) * | 2015-09-30 | 2017-05-10 | 广东研捷医药科技有限公司 | Chiral chromatographic separation and analysis method of dihydromyricetin enantiomer |
| CN110054606A (en) * | 2019-06-05 | 2019-07-26 | 闽江学院 | A kind of dihydromyricetin-Halomine pharmaceutical co-crystals and preparation method |
| CN110054606B (en) * | 2019-06-05 | 2021-04-27 | 闽江学院 | Dihydromyricetin-berberine hydrochloride pharmaceutical co-crystal and preparation method thereof |
| CN113121486A (en) * | 2021-03-15 | 2021-07-16 | 宁波大学 | Single-configuration extraction method of dihydromyricetin |
| CN113155882A (en) * | 2021-03-15 | 2021-07-23 | 宁波大学 | Chiral identification method for enantiomer of dihydromyricetin |
| CN113121486B (en) * | 2021-03-15 | 2022-07-15 | 宁波大学 | Single-configuration extraction method of dihydromyricetin |
| CN114404369A (en) * | 2022-03-08 | 2022-04-29 | 陕西科技大学 | Dihydromyricetin nanocrystal and preparation method and application thereof |
| CN114404369B (en) * | 2022-03-08 | 2023-01-03 | 陕西科技大学 | Dihydromyricetin nanocrystal and preparation method and application thereof |
| US11834428B2 (en) | 2022-03-08 | 2023-12-05 | Shaanxi University Of Science And Technology | Dihydromyricetin nanocrystals and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106008438A (en) | 2016-10-12 |
| CN106083792A (en) | 2016-11-09 |
| CN106008439A (en) | 2016-10-12 |
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